Cochrane Database of Systematic Reviews (Reviews) || Glatiramer acetate for multiple sclerosis

Glatiramer acetate for multiple sclerosis (Review)

La Mantia L Munari LM Lovati R

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2010 Issue 5

httpwwwthecochranelibrarycom

Glatiramer acetate for multiple sclerosis (Review)

Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON

6BACKGROUND

6OBJECTIVES

6METHODS

8RESULTS

Figure 1 11

Figure 2 12

Figure 3 13

Figure 4 14

Figure 5 15

Figure 6 16

Figure 7 17

Figure 8 18

Figure 9 19

Figure 10 19

19DISCUSSION

21AUTHORSrsquo CONCLUSIONS

21ACKNOWLEDGEMENTS

21REFERENCES

29CHARACTERISTICS OF STUDIES

46DATA AND ANALYSES

47ADDITIONAL TABLES

49FEEDBACK

49WHATrsquoS NEW

50HISTORY

50CONTRIBUTIONS OF AUTHORS

50DECLARATIONS OF INTEREST

51INDEX TERMS

iGlatiramer acetate for multiple sclerosis (Review)


[Intervention Review]

Glatiramer acetate for multiple sclerosis

Loredana La Mantia1 Luca M Munari2 Roberta Lovati3

1Department of Neuroscience Fondazione IRCCS - Istituto Neurologico C Besta Milano Italy 2Sapio Life Monza Italy 3UO

Oncologia Ospedale San Paolo Milano Italy

Contact address Loredana La Mantia Department of Neuroscience Fondazione IRCCS - Istituto Neurologico C Besta Via

Celoria 11 Milano 20133 Italy lamantiaistituto-bestait

Editorial group Cochrane Multiple Sclerosis Group

Publication status and date New search for studies and content updated (no change to conclusions) published in Issue 5 2010

Review content assessed as up-to-date 14 September 2009

Citation La Mantia L Munari LM Lovati R Glatiramer acetate for multiple sclerosis Cochrane Database of Systematic Reviews 2010

Issue 5 Art No CD004678 DOI 10100214651858CD004678pub2


A B S T R A C T

Background

This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2004 Issue 1 Art

No CD004678 DOI 10100214651858CD004678)

Previous studies have shown that glatiramer acetate (Copaxone reg) a synthetic amino acid polymer is effective in experimental allergic

encephalomyelitis (EAE) and improve the outcome of patients with multiple sclerosis (MS)

Objectives

To verify the clinical efficacy of glatiramer acetate in the treatment of MS patients with relapsing remitting (RR) and progressive (P)

course

Search methods

We searched the Cochrane MS Group Trials Register (26 March 2009) the Cochrane Central Register of Controlled Trials (The

Cochrane Library Issue 1 2009) MEDLINE (PubMed) (January 1966 to 26 March 2009) EMBASE (January 1988 to 26 March

2009) and hand searching of symposia reports (1990-2009)

Selection criteria

All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS whatever the admin-

istration schedule and disease course were eligible for this review

Data collection and analysis

Both patients with RR and P MS were analysed Study protocols were comparable across trials No major flaws were found in

methodological quality However efficacy of blinding should be balanced against side effects including injection-site reactions

Main results

Among 409 retrieved references we identified 16 RCTs six of them published between 1987 and 2007 met the selection criteria and

were included in this review Five hundred and forty RR patients and 1049 PMS contributed to the analysis In RR MS a decrease in

the mean EDSS score (-033 and -045) was found respectively at 2 years and 35 months without any significant effect on sustained

disease progression The reduction of mean number of relapse was evident at 1 year (-035 ) 2 years (-051 ) and 35 months (-064)

1Glatiramer acetate for multiple sclerosis (Review)


but significant studies rsquo heterogeneity was found The number of hospitalisations and steroid courses were significantly reduced No

benefit was shown in P MS patients No major toxicity was found The most common systemic adverse event was a transient and self-

limiting patterned reaction of flushing chest tightness sweating palpitations anxiety Local injection-site reactions were observed in

up to a half of patients treated with glatiramer acetate thus making a blind assessment of outcomes questionable

Authorsrsquo conclusions

Glatiramer acetate did show a partial efficacy in RR MS in term of relapse -related clinical outcomes without any significant effect on

clinical progression of disease measured as sustained disability The drug is not effective in progressive MS patients

P L A I N L A N G U A G E S U M M A R Y

The use of glatiramer acetate (Copaxone reg) in people with multiple sclerosis


No CD004678 DOI 10100214651858CD004678)

Treatment with glatiramer acetate (Copaxone reg) of patients with Relapsing-Remitting (RRMS) and with Progressive Multiple Sclerosis

(PMS) seems to have few beneficial effects in RRMS while the drug is not effective in PMS patients

Previous studies indicate that glatiramer acetate a synthetic drug is effective in animal models of MS and shows some benefits in MS

patients The objective of this review was to assess the efficacy of glatiramer acetate in RRMS and PMS patients

Among the pertinent medical literature six studies met the criteria of the methodological quality necessary for their inclusion in this

review 540 RRMS patients and 1049 PMS patients contributed to this analysis

The data showed no beneficial effects on disease progression in both MS forms a slight beneficial effect in the reduction of risk of

relapses in RRMS patients and no benefits in PMS patients Adverse events such as flushing chest tightness sweating palpitations

anxiety and local injection-site reactions occurred quite frequently but no major adverse effects were observed



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Glatiramer acetate versus placebo in relapsing remitting patient for multiple sclerosis

Patient or population patients with multiple sclerosis

Settings

Intervention Glatiramer acetate versus placebo in relapsing remitting patient

Outcomes Illustrative comparative risks (95 CI) Relative effect

(95 CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

Control Glatiramer acetate ver-

sus placebo in relapsing

remitting patient

Patients who progressed

- at 2 years

Study population RR 075

(051 to 112)

299

(2)282 per 1000 212 per 1000

(144 to 316)

Medium risk population

362 per 1000 272 per 1000

(185 to 405)


- at 35 months


(05 to 129)

203

(1)

See comment

288 per 1000 233 per 1000

(144 to 372)


289 per 1000 234 per 1000

(144 to 373)

3G

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Change in disability

score at the end of fol-

low-up - at 2 years of

follow-up

The mean Change in dis-

ability score at the end of

follow-up - at 2 years of

follow-up in the interven-

tion groups was

033 lower

(058 to 008 lower)

301

(2)



low-up - at 35 months of

follow-up



follow-up - at 35 months

of follow-up in the inter-

vention groups was

045 lower

(077 to 013 lower)

203

(1)

See comment

Mean number of re-

lapses - within 1 year of

follow-up

The mean Mean number

of relapses - within 1 year


vention groups was

035 lower

(053 to 016 lower)

287

(2)

Mean number of re-

lapses - at 2 years of fol-

low-up


of relapses - at 2 years of


tion groups was

051 lower

(081 to 022 lower)

298

(2)

The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes The corresponding risk (and its 95 confidence interval) is based on the

assumed risk in the comparison group and the relative effect of the intervention (and its 95 CI)

CI Confidence interval RR Risk ratio

4G

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by

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GRADE Working Group grades of evidence

High quality Further research is very unlikely to change our confidence in the estimate of effect

Moderate quality Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate

Low quality Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate

Very low quality We are very uncertain about the estimatexxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

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B A C K G R O U N D

Multiple sclerosis (MS) is a chronic inflammatory disease of the

central nervous system (CNS) with either relapsingremitting or

progressive course The pathology is characterized by random foci

of demyelination and axonal loss throughout the CNS Despite a

better knowledge of these pathologic findings in the last decade

little is known about their underlying etiology

Based on experimental data an autoimmune damage of the myelin

sheath has been postulated as a mechanism of CNS inflamma-

tion Susceptible animals inoculated with myelin components are

known to develop experimental allergic encephalomyelitis (EAE)

which is considered a laboratory model of MS (Wisniewski 1977)

Glatiramer acetate (Copaxone reg) is a synthetic amino acid poly-

mer empirically found to suppress EAE In animal models the

development of EAE can be prevented by glatiramer acetate ad-

ministration (Teitelbaum 1997) possibly due to a displacement

of immune cells targeted at native myelin components Clinical

results consistent with this rationale have also been shown in hu-

mans leading to regulatory authorization of MS treatment from

1997 in the US and 2000 in Europe Furthermore glatiramer ac-

etate has been recently (June 2009) approved in Italy also for the

treatment of clinically isolated syndrome with MRI parameters

compatible with MS Given the expectations raised by this agent

and its worldwide use we believe that updating of this systematic

review of all randomised controlled trials (RCTs) evaluating glati-

ramer acetate (Munari 2004) needs to be undertaken in order to

provide both clinicians and consumers with the most comprehen-

sive information

O B J E C T I V E S

This review is aimed at determining clinical efficacy and safety of

glatiramer acetate in patients with MS

The main outcomes of interest were

(1) Clinical progression of disease in terms of sustained disability

(2) Mean changes in EDSS disability score

(3) Frequency of clinical relapses

(4) Number of patients relapse free

(5) Incidence of any adverse events

(6) Patientrsquos quality of life

Secondary questions to be answered concern

7) Number of patients treated with steroids and number of steroid

courses administered during acute relapses or active disease pro-

gression

(8) Impact of treatment on hospital admissions and length of stay

in order to detect potential savings both in terms of healthcare

resources and patientrsquos time

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised or quasi-randomised controlled trials (RCTs) com-

paring glatiramer acetate and placebo in patients with definite MS

were eligible for the review Uncontrolled trials and studies where

glatiramer acetate has been compared with interventions other

than placebo were not included Both double-blind and single-

blind studies were eligible

Types of participants

Patients of any age and either gender with definite MS according

to Poser criteria (Poser 1983) whatever disease severity were eligi-

ble for the review Any patterns of MS course (relapsingremitting

(RR) relapsingprogressive secondary progressive or primary pro-

gressive (P) have been considered MS patients receiving cytostat-

ics immuno modulators or immunosuppressants in the 6 months

prior to study enrolment were excluded from the analysis There-

fore information on patient treatment regimens before entering

the trial has been sought

Types of interventions

All therapeutic schedules involving glatiramer acetate administra-

tion whatever the administration route dosage treatment dura-

tion and the interval between symptom onset and randomisation

were considered as test treatment Courses of steroids were per-

mitted provided they were administered without any restriction

in both arms

Types of outcome measures

We sought the following measures in both treatment groups

at 12 and 24 months and at the end of the scheduled follow-

up period

Patients who progressed Whenever unspecified progression has

been defined as a persistent worsening of at least one point in

EDSS (Kurtzke 1983) recorded out of relapse and confirmed by

a follow-up assessment at six months (Rio 2002) However other

definitions of progression given in the original paper could be

accepted including a persistent half-point increase starting from

EDSS score ge 55 (Rio 2006)

Mean changes in EDSS disability score

We considered different relapse-related clinical outcomes and in

particular Frequency of clinical relapses number of patients re-

lapse free and number of patients relapse free over time




Number of patients treated with steroids and number of steroid


gression and impact of treatment on hospital admissions and

length of stay in order to detect potential savings both in terms of

healthcare resources and patientrsquos time

Safety outcomes were assessed among primary endpoints by

unique measures cumulating all events occurred throughout

the trial

Number of both local and systemic side effects

Number of patients with severe side effects If not otherwise speci-

fied side effects have been defined as severe when leading to one of

the following death hospitalisation treatment discontinuation

Search methods for identification of studies

A systematic search without language restrictions was conducted

using the optimally sensitive strategy developed for the Cochrane

Collaboration to identify all relevant published and unpublished

randomised controlled trials (Lefebvre 2008)

For additional information about the Grouprsquos search strategy please

see Cochrane Multiple Sclerosis Group

Electronic searches

We searched the following databases

1 The Cochrane Multiple Sclerosis Group Trials Register (26

March 2009)

2 The Cochrane Central Register of Controlled Trials

(CENTRAL) ldquoThe Cochrane Libraryrdquo (issue 1 2009)

(Appendix 1)

3 MEDLINE (PubMed) (January 1966 to 26 March 2009)

(Appendix 2)

4 EMBASE (EMBASEcom) (1974 to 26 March 2009)

(Appendix 3)

Searching other resources

1 Handsearched references quoted in the identified trials

2 Handsearched symposia reports (1990-2009) from the

most important neurological associations and MS Societies in

Europe and America

3 Contacted researchers who were participating in trials on

GA

Contacts with the owner pharmaceutical company (Teva Pharma-

ceutical Ltd) were attempted without reply So we established

reliable contacts with researchers involved in GA development


DATA EXTRACTION

Selection of eligible studies and data extraction have been carried

out independently by three reviewers (LM LLM RL) Results

were then compared in order to rule out any misunderstandings

mistakes or biases possibly arising from data evaluation Details on

treatment administration schedule patient enrolment criteria di-

agnostic criteria randomisation methods blinding outcome anal-

ysis follow-up length dropouts side effects were also recorded for

each study in order to evaluate quality profiles (see Methodolog-

ical quality) All data were entered in a collection form Disagree-

ments were resolved by discussion amongst reviewers

Trialists were asked to provide further details on study character-

istics if they were unclear in the article

TRIAL QUALITY ASSESSMENT

The methodological quality of each trial was assessed indepen-

dently by reviewers We used the recommended methods outlined

in the Cochrane Reviewers Handbook version 500 (Higgins 2008)

All studies were given a quality score ranging from 0 to 5 (Jadad

1996) based on the following criteria randomisation allocation

concealment blinding decisions about dropouts and withdrawals

Relevant information was collected using a data extraction form

developed by the Multiple Sclerosis Cochrane Review Group

Randomisation has been defined as either telephone calls to a ran-

domisation centre reference to computer-generated random lists

or tables of random numbers Quasi-randomised trials without

properly concealed allocation (eg patient alternation open ran-

dom list date of birth day of the week or hospital admission num-

ber) have been included in the review

Allocation concealment and blinding have been scored in the risk

of bias tables for each included study Disagreements were resolved

by discussion among the authors in order to achieve a unique score

for each considered item In case of significant differences between

treatment and placebo the effect of blinding could be tested in

sensitivity analysis since knowledge of treatment allocation may

affect the assessment of study endpoints

Trial quality scores are listed in the additional Table 1

STATISTICAL ANALYSIS

Data have been analysed according to an intention-to-treat ap-

proach Relative risks risk difference and their 95 confidence

intervals (CI) have been calculated for binary outcomes Contin-

uous outcomes have been evaluated as weighted mean differences

in treatment effects and their standard deviation (SD)

The weighted treatment effect was calculated across trials for each

outcome Combined results were expressed as weighted estimates

of relative risks with their 95 CI when binary variables were

considered Continuous outcomes were combined using weighted

mean differences and their 95 CI

Basically data were analysed in a fixed-effect model (Yusuf 1985)

Homogeneity across trials have been tested in a chi square test

with alpha=010 When significant heterogeneity was found re-

sults were checked in a random-effects model (Brocke 1996)

Characteristics of trials have been listed in the correspond-

ing ldquoCharacteristics of Includedexcluded studiesrdquo All results

have been organised and processed by the Review Manager 50

(RevMan 2008) developed by the Cochrane Collaboration



The effects of potential sources of heterogeneity have been ex-

plored by subgroup analysis where appropriate (see results)

Sensitivity analysis on trial quality and missing data was not

needed

R E S U L T S

Description of studies

See Characteristics of included studies Characteristics of excluded

studies Characteristics of ongoing studies

Out of 409 references identified by the search strategy up to 26

March 2009 133 abstracts were provisionally selected to be read

as full published papers Ninety three papers were then excluded

for the following reasons 53 were uncontrolled open-label stud-

ies (Abramsky 1977 Baumhefner 1988 Boiko 2006 Bornstein

1982Brochet 2008Caon 2006 Capobianco 2008 Carra 2008

Daugherty 2005 De Seze 2000 De Stefano 2008 De Stefano

2009 Debouverie 2007 Duda 2000 Flechter 2002bFord

2006 Fusco 2001 Gajofatto 2009 Garcia-Barragan 2009 Ghezzi

2005 Ghezzi b 2005 Haas 2005 Johnson 2000 Johnson 2003

Johnson 2005 Khan 2001 Kott 1997 Lage 2006 Le Page

2008 Mancardi 1998 Meiner 1997 Milanese 2005 Miller

1998 Miller 2006Miller 2008 Ollendorf 2008 Orlova 2005

Ramtahal 2006 Rio 2005 Rovaris 2007 Schwid 2007 Sindic

2005 Tilbery 2006 Torkildsen 2007Twork 2007 Valenzuela

2007 Vallittu 2005 Weder 2005 Wolinsky 2001Ytterberg 2007

Zavalishin 2005 Ziemssen 2008 Zwibel 2006)

Five studies were controlled not randomised studies evaluating

the efficacy of GA and other immunomodulating agents with-

out placebo group (Castelli-Haley 2008Deen 2008 Flechter

2002aKhan 2005 Zavalishin 2006) 7 studies restricted the anal-

ysis to MRI parameters (Cohen 1995 Mesaros 2008 Rovaris

2005 Shipova 2009 Sormani 2002 Sormani 2005 Sormani

2007) 7 studies reported on experimental investigations where

only laboratory endpoints have been assessed (lymphocyte activity

cytokine outburst uric acid increase) or clinical immunological

studies ( Blanco 2006 Brenner 2001 Chen 2001 Constantinescu

2000 Farina 2001 Karandikar 2002 Qin 2000) 21 studies

aimed to evaluate adverse events during treatment with GA (

Achiron 2005 Ball 2008 Bosca 2006 Charach 2008 Cicek

2008 Feigin 2005 Fiore 2005 Harde 2007 khan 2008 La

Mantia 2006 Madray 2008 Neumann 2007 Nolden 2005

Patten 2008Poumlllmann 2006 Rauschka 2005 Sidoti 2007Soares

2006 Then Bergh F 2006 Thouvenot 2007 Tremlett 2007) (See

table of excluded studies)

The remaining papers were related to 16 RCTs nine RCTs were

excluded because comparative trials evaluating the efficacy of two

dosages of GA (Cohen 2007 Wynn 2008) of GA versus IFN beta

(Cadavid 2009Mikol 2008 ) of natalizumab versus placebo in

Ga -treated MS patients (Goodman 2009 ) of GA after induction

with mitoxantrone vs GA alone (Vollmer 2008Arnold 2008) or

cognitive function in GA versus placebo ( Weinstein 1999) or

treatment of local reaction (Jolly 2008 ) One study was excluded

because evaluating the efficacy of GA in isolated central nervous

system syndrome ( Comi 2008)

Six RCTs contributing to this review (29 related references) pub-

lished between 1987 and 2007 (Bornstein 1987 Bornstein 1991

Johnson 1995 Comi 2001Filippi 2006 Wolinsky 2007) These

studies account for a total of 3233 patients 2043 of whom al-

located to glatiramer acetate and 1190 to placebo Four studies

enrolled patients with relapsing-remitting (RR) disease (Bornstein

1987 Johnson 1995 Comi 2001 Filippi 2006) Two RCTs inves-

tigated the effect of glatiramer acetate in progressive MS (Bornstein

1991 Wolinsky 2007) Therapeutic schedules were homogeneous

except for Filippi 2006 study evaluating oral administration of

GA This trial was separately analyzed for concerns about the com-

parability of parenteral and oral administration Therefore the

following treatments have been compared with placebo

bull glatiramer acetate 20 mg subcutaneously self-administered

daily in RR MS

bull glatiramer acetate 50-5 mg oral-administered daily in

RRMS

bull glatiramer acetate 30 mg-20 mg subcutaneously self-

administered daily in P MS

The treatment has been given for 9 (Comi 2001) 14 (Filippi 2006

) 24 (Bornstein 1987 Bornstein 1991) or 35 months (Johnson

1995) and 36 months (Wolinsky 2007) The characteristics of

the studies are reported in the corresponding tables

All trials on RR MS enrolled patients with definite disease (Poser

1983) Bornstein et al (Bornstein 1987) randomised patients

within an age range of 20 to 35 years with at least two exacerba-

tions in the two years before admission provided they were not

severely disabled (EDSS score below 6) andor emotionally un-

stable Fifty-eight percent of study population were female and

64 of initially screened patients were excluded due to any of

the following age low frequency of exacerbations lack of docu-

mentation impaired psychological profile transition to CP MS

distance from the clinic or pregnancy

The US phase III pivotal trial (Johnson 1995) was a multicen-

tre study involving 11 centres in the US Eligible patients had an

EDSS le 5 and at least two documented relapses in the two years

prior to entry the last one occurring at least one year before ran-

domisation they should also be neurologically stable and free from

corticosteroid therapy for at least 30 days prior to entry Patients

could be enrolled within a larger age range (18 to 45) and the final

proportion of female subjects was 73 Only 12 of candidate

participants were excluded based on the following criteria treat-

ment with glatiramer acetate or previous immunosuppression with

cytotoxic therapy or lymphoid irradiation pregnancy or lactation

diabetes mellitus positive HIVHTLV-1 serology Lyme disease

need of aspirin or chronic non-steroidal anti-inflammatory drugs



throughout the trial unwillingness to undergo adequate contra-

ception Only EDSS modifying attacks confirmed by current neu-

rological examination were accepted as relapses Out of 215 pa-

tients who completed the first 24-month follow-up 203 entered

an additional 11-month treatment schedule (Johnson 1995) re-

producing the same trial design The investigators also carried out

a further open-label follow-up up to six years from randomisation

in 208 patients (Johnson 2000Johnson 2003) to 8 years in 142

patients (Johnson 2005 ) to 10 years in 108 patients (Ford 2006)

from the original cohort of 251 not included in this review

The European-Canadian MRI study (Comi 2001) applied the fol-

lowing inclusion criteria patients aged 18 to 50 with an EDSS

le 5 with MS from at least one year One documented relapse in

the preceding two years was deemed sufficient to enter the study

but at least 1 enhancing lesion was essential in the screening brain

MRI Moreover all randomised patients were clinically relapse-

free and steroids-free in the 30 days before entry A total of 29

centres participated in the study and 51 of screened patients

were excluded due to any of the following previous use of glati-

ramer acetate or oral myelin prior lymphoid irradiation use of im-

munosuppressant or cytotoxic agents in the past two years use of

azathioprine andor other immunosuppressant including steroids

during the previous six months concomitant therapy with an ex-

perimental drug for either MS or another disease serious inter-

current systemic or psychiatric illnesses unwillingness to practice

reliable contraception during study and known hypersensitivity

to gadolinium unavailability to repeat MRI studies We excluded

from the review the 9-month open-label extension phase of this

trial

Flippirsquo study (Filippi 2006) was separately evaluated This study

assessed whether two doses of glatiramer acetate given orally could

improve clinical and MRI measures of inflammation and neu-

rodegeneration in a large cohort of patients with relapsing-remit-

ting multiple sclerosis One thousand nine hundred and twelve

patients with relapsing-remitting multiple sclerosis were screened

and 1651 were randomised to receive 50 mg or 5 mg of glatiramer

acetate or placebo by daily oral administration over 14 months

The intention-to-treat cohort consisted of 1644 patients who took

at least one dose of study medication (50 mg glatiramer acetate

[n=543] 5 mg glatiramer acetate [n=553] placebo [n=548]) Af-

ter baseline investigation clinical assessments were done every 2

months and MRI was obtained for all patients at baseline and at

study exit

The main clinical data of the patients are reported in Table 2

Briefliy RR showed a disease duration ranging from 55 to 81

years low disability and active clinical disease Patients enrolled

in the European-Canadian MRI study may represent a less se-

vere subset since they were eligible after a single relapse in the

two previous years however in this study an active MRI scan was

needed Patients enrolled had to be free of any steroid treatment

for at least 30 days (Bornstein 1987 Johnson 1995 Comi 2001

Filippi 2006) and clinically stable for at least 30 days (Johnson

1995 Comi 2001) Minimum time elapsed from the last relapse

was not specified in one study (Bornstein 1987)

The study of Bornstein 1991 randomised patients between the

age of 20 and 60 with a chronic-progressive course for at least 18

months less than two exacerbations in the previous 24 months

disability 2-65 on EDSS emotional stability and a favourable psy-

chosocial profile These criteria were assessed in a pre-trial obser-

vation period lasting no more than 15 months and led to exclude

47 of candidate participants The inclusion criteria may suggest

that patients were affected by secondary progressive or progressive

relapsing courseThe primary outcome was confirmed progression

(worsening of 1 EDSS or 15 according to basal EDSS ( 5 or less)

maintained at 3 months

The Wolinsky 2007 study included primary progressive multiple

sclerosis randomized to GA or placebo (PBO) in a 3-year double-

blind trial 37 patients out of 943 have been confirmed relapses

during the follow-up suggesting that a small proportion of patients

exhibited the progressive relapsing phenotype The primary end

point was an intention-to-treat analysis of time to 1- (entry EDSS

30-50) or 05-point expanded disability status scale change (entry

EDSS 55-65) sustained for 3 months The trial was stopped

after an interim analysis by an independent data safety monitoring

board indicated no discernible treatment effect on the primary

outcome

The main clinical data of the Progressive patients are reported in

the Table 3 the patients were more disable than RR MS and had

a longer disease duration

CLINICAL OUTCOMES

The studies on RR MS reported as primary outcome measures

Proportion of relapse-free patients at the end of follow-up

(Bornstein 1987) mean number of relapses (Johnson 1995) total

number of enhancing lesions on T1-weighted MRI images (Comi

2001) the total number of confirmed relapses (Filippi 2006)

Studies on RR MS also evaluated the following secondary (and

tertiary) endpoints time to progression (Bornstein 1987) pro-

portion of patients with sustained disease progression (Johnson

1995)change in EDSS scores from baseline (Johnson 1995

Bornstein 1987 Filippi 2006) and area under curve for the EDSS

change (Filippi 2006) time to walk and ambulation index (Filippi

2006) relapse rate (Bornstein 1987 Comi 2001) number of re-

lapses (Comi 2001) proportion of relapse-free patients (Johnson

1995 Comi 2001Filippi 2006 ) time to first relapse after ran-

domisation ( Comi 2001Filippi 2006 ) the proportion of patients

with two or more relapses (Comi 2001 ) steroid courses (Comi

2001 Filippi 2006 ) and relapse-related hospitalizations (Comi

2001Filippi 2006 ) and other MRI measures (Comi 2001 Filippi

2006) MRI data of Johnson 1995rsquos study were reported in 135

out of the 251 patients of the original cohort in the open -label

extension trial (Wolinsky 2001)

Progression was defined in all studies as an increase of at least 1

point EDSS maintained for at least 3 months (Bornstein 1987

Johnson 1995) It is noteworthy that the review protocol was



more conservative requiring at least 6 months of sustained 1-point

EDSS worsening to be classified as progression even if other def-

initions could be accepted

As a separate endpoint from progression 2 trials analysed the pro-

portion of patients worsened by at least 1 point in disability score

at the end of follow-up as compared to baseline (Bornstein 1987

Johnson 1995) It assumed that this endpoint does not take into

account if a sustained increase in EDSS score has occurred and

it is open to misinterpretations as to the final patient outcome

Therefore we have chosen not to analyse clinical worsening as re-

ported by these studies in order to avoid misleading results when

inconsistent with those obtained in disease progression (see Dis-

cussion) Consistently clinical improvement based on a ge1 point

decrease in EDSS score versus baseline was not analysed

Relapse was defined as the appearance or reappearance of one

or more neurologic symptoms with signs persisting for at least

48 hours and immediately preceded by a relatively stable or im-

proving neurologic state of at least 30 days (Johnson 1995 Comi

2001Filippi 2006 ) Another trial protocol required that patient

symptoms were associated with changes in the neurologic exam

involving an increase of at least 1 point in any of the 8 Kurtzke

functional groups Sensory symptoms alone were not considered

(Bornstein 1987)The relapse was confirmed when the symptoms

were accompanied by objectives changes corresponding to an in-

crease of 05 EDSS or 1 grade in the two or more functional sys-

tems (Comi 2001 Filippi 2006)

The studies on Progressive MS reported as primary outcome mea-

sures

time to sustained confirmed at 3 months of 1 point of EDSS

increase (according to baseline EDSS of 50 or more) (Bornstein

1991) of 15 EDSS increase ( Baseline EDSS less than 5)

(Bornstein 1991) or 1 (basal EDSS 3-5) and 05 (basal EDSS 55

or more) ( Wolinsky 2007)

as secondary outcome measures unconfirmed progression and pro-

gression of 05 EDSS units (Bornstein 1991) and proportion of

progression free changes from baseline in mean EDSS score and

mean MSFC scores and MRI measures (Wolinsky 2007)

SIDE EFFECTS AND ADVERSE EVENTS

The number of patients experiencing side effects of treatment have

been counted by event in all studies However information on

how many patients reported at least one adverse event whatever

was unavailable so that the overall incidence of side effects could

not be calculated

The number of patients who dropped out because of adverse effects

could be extracted from studies (Bornstein 1987 Johnson 1995

Comi 2001 Wolinsky 2007)

SECONDARY ENDPOINTS

Two studies have compared the number of hospitalisations ob-

served at the end of follow-up between glatiramer acetate and

placebo arms (Johnson 1995 Comi 2001) Number of relapses re-

quiring hospitalisation was also evaluated in Filippirsquos study (Filippi

2006) but that data were not shown Data on the number of

steroid courses administered were also available from two studies

(Bornstein 1991 Comi 2001)

MRI PARAMETERS

One study (Comi 2001) evaluated the total number of enhancing

lesions on MRI as the primary endpoint clinical outcomes being

analysed as tertiary endpoints Secondary outcomes of this trial

were total volume of enhancing lesions number of new enhancing

lesions number of new lesions on T2-weighted images percent-

age change of lesion volume on T2-weighted images change in

the volume of hypointense lesions on T1-weighted images MRI

parameters were also analysed in secondary reports from the US

phase III pivotal study both for a small subset of the main trial

(Ge 2000) and the open-label extension phase (Wolinsky 2001)

CONCOMITANT MEDICATION

In two studies standard steroid treatment could be administered

during relapses without restrictions (Bornstein 1987 Johnson

1995) Moreover symptomatic medications (Bornstein 1987)

or conventional therapy received at the time of randomisation

(Johnson 1995) could be maintained throughout the study A stan-

dard treatment schedule for relapses was specified in one trial pro-

tocol as 10 g iv methylprednisolone for three consecutive days

(Comi 2001) Limitations to the use of steroids were introduced in

the CP study (Bornstein 1991) where the maximum dose should

not exceed 100 mg prednisone or 80 UI ACTH daily during ex-

acerbations lasting no more than four weeks

Risk of bias in included studies

(summary data are reported in Figure 1 and Figure 2)



Figure 1 Methodological quality summary review authorsrsquo judgements about each methodological quality

item for each included study



Figure 2 Methodological quality graph review authorsrsquo judgements about each methodological quality

item presented as percentages across all included studies

RANDOMISATION

Method of randomization are reported in risk of bias tables (see

tables of characteristics of included studies)Allocation conceal-

ment was adequate in four studies Bornstein 1991 Johnson

1995 Comi 2001 Filippi 2006 ) and not reported in one study

(Wolinsky 2007) In another study (Bornstein 1987) patients were

randomised within matched pairs but the method to obtain treat-

ment allocation was not clearly specified Allocation concealment

was therefore defined as ldquounclearrdquo for this report

BLINDING

All trials were double-blind in design However the occurrence

of peculiar side effects of glatiramer acetate (eg injection site

and skin reactions) casts doubts on the possibility to ensure a reli-

able masking In the attempt to reduce this flaw all study proto-

cols introduced a separate evaluation by two independent physi-

cians an examining neurologist was responsible for the scheduled

monitoring of clinical endpoints while a treating physician was

in charge of managing side effects and concomitant therapy The

latter physician could be either aware (Bornstein 1987 Bornstein

1991Filippi 2006 Wolinsky 2007) or unaware (Johnson 1995)

of patient allocation In another study blinding of physicians was

not formally assessed because clinical endpoints were only consid-

ered as tertiary outcomes (Comi 2001)

Independently of investigatorsrsquo accuracy it can be assumed that

all trials failed to carry out a fully blind assessment In one study

claimed to be double blind (Bornstein 1987) both patients and

physicians correctly identified 70 to 80 of treatment allocations

Surprisingly however investigators stated that ldquothe ability to guess

treatment correctly was influenced by the effect of treatment rather

than by side effectsrdquo

WITHDRAWALS AND LOST TO FOLLOW-UP

Bornstein et al (Bornstein 1987) report that two patients out of

25 allocated to placebo discontinued the study and were excluded

from the analysis because of unreliable data due to an altered psy-

chological profile This was considered as a violation of the inten-

tion-to-treat analysis Therefore we had to count 23 participants

in the placebo arm when data were extracted from either percent-

ages or means in the original paper Data from other five patients

who dropped out were analysed two in the placebo arm and three

allocated to glatiramer acetate One exacerbation and two adverse

events were counted in this group

The US pivotal trial (Johnson 1995) counted 19 withdrawals

in glatiramer acetate-treated patients and 17 among those tak-

ing placebo Causes of discontinuation were not reported in 10

glatiramer acetate-allocated patients and 14 controls representing

96 of the randomised sample altogether Out of 215 patients

who completed the first 24-month follow-up 12 refused to enter

the 11-month extension having opted to receive the newly emerg-

ing beta-interferon therapy The two-year clinical profiles exhib-

ited by these patients and those enrolled in the extension trial were

comparable A further nine subjects dropped out at the end of the

35-month follow-up (three in the treatment arm seven allocated

to placebo) All data related to this group were included in the

analysis although causes of dropout are not reported in detail

The EuropeanCanadian trial (Comi 2001) had 14 dropouts

equally balanced between treatment and placebo All of them

where included in the analysis

The oral study (Filippi 2006) had 141213 of withdrawn in the

three experimental groups



The CP MS study also reported a balanced withdrawal pattern

(Bornstein 1991) with 10 glatiramer acetate treated patients and

10 controls discontinuing medication Early withdrawals were all

included in the analysis 17 were censored at the time of dis-

continuation the other 3 (glatiramer acetate=2 placebo=1) being

counted as confirmed progression

In the Wolinsky 2007 study 188627 GA and 98316 Placebo

treated patients withdrew for various reasons before sponsor deci-

sion for trial termination At the end of follow-up only 114621

(GA) and 46314 (P) were available for the analysis of the main

outcome (See Fig 2 of the paper) Four GA and 7 death Placebo -

treated were also reported

VALIDITY SCORE

The Jadad score was calculated as a measure of internal validity

The Jadad score is reported in the additional table (Table 1) One

study was given three because of unclear allocation concealment

and insufficient details on withdrawn patients and unsuccessful

blinding (Bornstein 1987)One study was given three because of

unclear allocation concealment and insufficient details on blind-

ness (Wolinsky 2007) The others studies obtained a full score

Effects of interventions

See Summary of findings for the main comparison Glatiramer

acetate versus placebo in relapsing remitting patient for multiple

sclerosis

PRIMARY OUTCOMES

The efficacy of GA versus placebo was evaluated separately in

RR and Progressive MS patients

A total of 3233 patients 2184 affected by RR (1365 actively and

819 placebo treated) and 1049 by Progressive MS (678 actively

and 371 placebo treated) were included in these trials although

only 540 RR patients and 1049 PMS contributed to the analysis

of treatment efficacy

Relapsing Remitting MS

PATIENTS WHO PROGRESSED

Information about progression of disability was available from two

trials and 226 patients (Bornstein 1987 Johnson 1995)The risk

of progression was not significantly modified by the therapy at 2

years 075 (95 CI [051 112] p=016) and at 35 months 081

(95 CI [050 to 129] (Figure 3)

Figure 3 Forest plot of comparison 1 Glatiramer acetate versus placebo in relapsing remitting patient

outcome 11 Patients who progressed



CHANGE IN DISABILITY SCORE

Mean changes in EDSS disability score were calculated in two trials

(Bornstein 1987 Johnson 1995) As different follow-up durations

are available from the US phase III trial both 24- and 35-month

data are shown although results are not pooled A slight decrease in

EDSS score favouring glatiramer acetate is observed at two years

(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35

months (WMD= -045 95 [-077 to -013] p = 0006) (Figure

4)


outcome 12 Change in disability score at the end of follow-up

PATIENTS RELAPSE-FREE

This information was available in three studies and 255 subjects

with RR MS evaluated at different follow-up lengths (Bornstein

1987 Johnson 1995 Comi 2001) Results have been split into

three time windows within 1 year (which includes the 9-month

assessment reported in the EuropeanCanadian study) at 2 years

and at 35 months Relative risks of experiencing no exacerbation

were respectively 128 (95 CI[102 162] p= 003) within 1

year of treatment and 139 (95C I[099 194] p=0-06 at 2

years and 133 (95 CI [086 206] at 35 months ( Figure 5)

Since the same study appears in more than one stratum (Johnson

1995) no pooled analysis is provided for this outcome Significant

heterogeneity was found between Bornsteinrsquos pilot trial and the

EuropeanCanadian study (p=003) possibly related to different

trial duration Then we tested pooled relative risk of relapse within

1 year of randomisation in a random-effect model without any

significant difference between glatiramer acetate and placebo rel-

ative risk = 064 (95 CI [031 to 134] p= 02)

MEAN NUMBER OF RELAPSES




outcome 13 Patients relapse free

A significant reduction was found at 1 year (-035) at 2 years (-051)

and at 35 months (-064) However a significant heterogeneity was

found between the studies( Figure 6)




outcome 14 Mean number of relapses

RELAPSE-FREE SURVIVAL

Median time to first relapse was analysed in one study (Johnson

1995) with a median time of 287 days in patients treated with

glatiramer acetate and 198 days in controls (Weibull regression

model p =0097) Our elaboration on individual patient data

extracted from the pilot trial paper (Bornstein 1987) point to

a median of 5 months (95 CI [2 to 8]) in the placebo arm

while the median of glatiramer acetate-treated group could not

be calculated as more than 50 of those subjects were censored

without relapse at 24 months (log-rank chi-square = 668 p =

00098) These results could not be combined

ORAL TREAMENT WITH GA

This treatment was considered only by one study (Filippi 2006 )

the available data did not allowed a meta-analysis according to the

predefined protocol

The cumulative number of confirmed relapses did not differ be-

tween the two active treatment groups and the placebo group

Relative to placebo the rate ratio for the 50 mg glatiramer acetate

treated group was 092 (95 CI 077-108 p=030) and for the 5

mg glatiramer acetate treated group was 098 (083-115 p=076)

No drug effect was seen for any of the secondary and tertiary end-

points

Progressive MS


This information was available in two studies (Bornstein 1991

Wolinsky 2007) including 832 patients

Risk of progression was not reduced by GA at 1 year (088 (95

CI 060127) at 2 years ( 084 ( 060119) and 3 years 075

(038150) (Figure 7)The data must be considered with caution

since they were obtained from the survival curve because not

clearly reported in the paper



Figure 7 Forest plot of comparison 4 glatiramer acetate versus placebo in progressive patients outcome

41 progression of disability


This information was available only from one study (Wolinsky

2007) including 943 cases

Mean EDSS scores increased from baseline by 061+-113 in the

placebo group and by 058+-100 point in the GA group (not

statistically different) (data unshown)

CHANGES IN QUALITY OF LIFE SCORES

No study planned to analyse patient quality of life as an outcome

measure

ADVERSE EFFECTS

All trials evaluated adverse events accounting for 407 to 646 pa-

tients Two studies (Johnson 1995 Comi 2001) mainly focused on

injection-site changes and patterned transient systemic reactions

while the other two (Bornstein 1987 Bornstein 1991) reported a

more analytical list of all observed side effects Patterned reactions

were most commonly reported consisting of a transient self-lim-

iting combination of flushing chest tightness sweating palpi-

tations anxiety These symptoms unpredictably occurred within

minutes of injection and spontaneously resolved before 30 min-

utes Patterned reactions were more often observed in glatiramer

acetate treated patients with a relative risk of 327 (95 CI[207

516]p lt000001]) Other systemic side effects significantly re-

lated to glatiramer acetate administration were palpitations (rel-

ative risk = 358 [116 1106] p =003) dyspnoea 358 [116

1106] p 0 0005 The incidence of headache anxiety faintness

drowsiness cramps joint pain appetite loss constipation abdom-

inal discomfort nausea and vomiting was not significantly differ-

ent between groups Rash was more common in placebo treated

patients

Local injection-site reactions included any of the following itch-

ing (relative risk = 828 [499 1373] p lt000001]) swelling (rel-

ative risk = 401 [267 603] p lt000001]) redness or erythema

(relative risk = 458 [358 588] p lt00001]) and pain (relative

risk = 246 [205 295] p lt000001])

No adverse events leading to patientrsquos death or major toxicity were

reported One study (Comi 2001) mentioned the occurrence of

ldquoserious adverse experiencesrdquo in 10 glatiramer acetate treated and

6 placebo patients respectively but these unspecified events were

classified as unrelated to treatment

Side effects causing treatment discontinuation were observed in

three trials (Bornstein 1987 Johnson 1995 Comi 2001) but their

relation with glatiramer acetate is not definitely established (rela-

tive risk = 144 [094 223] p=010] (Figure 8)



Figure 8 Forest plot of comparison 3 Glatiramer acetate versus placebo adverse effects outcome 31

Localised to the injection site

Side effects were similar in oral GA -treated and placebo

patients mainly involving the gastrointestinal and nervous

system headacheasthenia pain depression accidental in-

juryparaesthesia nauseaabdominal pain arthralgia back pain

diarrhoea constipation anxiety and dyspepsia (Filippi 2006)

SECONDARY OUTCOMES

HOSPITALISATIONS AT THE END OF FOLLOW-UP

Data from hospital admission rates at nine or 35 months were ex-

tracted from two studies and 449 patients [Comi 2001 Johnson

1995] Hospitalisations were significantly decreased in the glati-

ramer acetate group relative risk = 060 (95 CI [040 to 091

p = 002]) ( Figure 9)



Figure 9 Forest plot of comparison 2 Glatiramer acetate versus placebo secondary outcomes outcome

21 Number of hospitalisations at the end of follow-up

STEROID COURSES AT THE END OF FOLLOW-UP

Two studies evaluated the number of administered steroid cycles

on a total of 345 patients In RR MS at nine months (Comi 2001)

a significantly lower number in the glatiramer acetate arm was

found relative risk = 069 (95 CI [055 to 087 p = 0001])(

Figure 10 ) In progressive MS at 2 years (Bornstein 1991) the

steroid treatment was administered in 755 in the placebo group

and 851 in GA treated group (data unknown)


22 Number of steroid courses at the end of follow-up

D I S C U S S I O N

We have undertaken this systematic review to explore the amount

of evidence currently supporting the use of glatiramer acetate in

the management of MS Our pragmatic approach to include all

MS candidates for the administration of this agent whatever the

disease pattern was aimed at collecting and reviewing all available

data on this compound Unfortunately we should remark that 22

years after the first randomised pilot trial (Bornstein 1987) infor-

mation on efficacy of glatiramer acetate did not move so far ahead

from the original phase III database On the other hand the few

completed company-supported RCTs available are rather homo-

geneous in their protocols and treatment schedules It is proba-

ble that other RCTs evaluating glatiramer acetate efficacy versus

placebo will be no more available since serious ethical concerns

regarding the use of placebo when approved therapies are available

(McFarland 2008)

The first outcome of interest considered in this review ie disease

progression seems unaffected by daily glatiramer acetate admin-

istration up to 35 months (RR MS) or 3 years (P MS) It should

be noted that all studies required only three months of sustained

EDSS worsening to classify patient outcome as a progression in-

stead of six months as it was established in the review protocol

Althought we had to accept this definition given in the original

papers we cannot exclude that some patients classified as develop-

ing progression may actually have experienced a prolonged relapse

(transient treatment failure) since the adopted criterion was not



able to capture permanent treatment failure that is irreversible

disability (Rio 2002 ) It should be noticed however that concern

about validity of clinical surrogates of unremitting disability used

in MS trials has been recently raised (Ebers 2008) However no

data are till now available on the shift to secondary progression

phase in RR MS- GA treated patients of the included studies

When average EDSS changes versus baseline are analysed a slight

improvement in EDSS score has been shown at two years and

at about three years in RR These results may suggest that GA

reduces residual relapse-related disability Some remarks however

should be taken into account We should balance these findings

against the reliability of blinding when evaluating glatiramer ac-

etate-treated patients given a two to five fold increase in injection-

site reactions The more sensitive the endpoint the more exposed

to insufficient masking would be the results Again EDSS score

is an ordinal scale and it would be more appropriate to analyse it

as a threshold to detect disease progression rather than calculating

a mean difference Finally combined results on clinical improve-

ment are driven by a single largest trial (Johnson 1995) account-

ing itself for up to 87 of data

Benefit of glatiramer acetate on clinical relapses seems to be more

consistent However an increase of probability (28) to remain

free of relapse was found at 1 year but no more detectable in the

follow-up The mean number of relapses was reduced over time

from 1 to 3 years These results should be considered with caution

due to a significant heterogeneity among included trials When

the average number of relapses is considered results are no bet-

ter after correcting for heterogeneity This heterogeneity might re-

flect differences in patient selection since risk estimates of con-

trols (basal risks) appear uneven across studies Using a random

effects model no significant decrease in the average relapse counts

can be observed at one year and two years while a single study

suggests that the frequency of relapses experienced at three years

could be slightly reduced by less than one on average in glatiramer

acetate-treated patients In this respect it should be noted that

the weighted mean difference may not be an appropriate measure

to analyse relapse counts Actually this variable seems to follow a

positive asymmetric distribution (standard deviations tend to in-

crease with increasing mean values across studies) rather than ap-

proximating the normal function as it is assumed by the weighted

mean difference analysis

A recent meta-analysis from Boneschi et al (Boneschi 2003) of

glatiramer acetate trials in patients with RRMS based on the same

trials we have included in this review (Bornstein 1987 Johnson

1995 Comi 2001) has found a statistically significant difference

between glatiramer acetate and placebo as to the following end-

points

bull adjusted annualised relapse rate

bull adjusted risk ratio for the on-trial total number of relapses

bull time to first relapse

Actually Boneschi and co-workers developed a multiple regression

model where all raw data from enrolled patients have been pooled

irrespectively from differences across trials His model has been

used to select those covariates significantly associated with the

concerned outcome measures Based on such covariates as ldquoclinical

predictors of outcomerdquo adjusted estimates of treatment effect are

provided to test treatment efficacy Unfortunately the Authors

do not mention how much of the total variance is explained by

the model in order to support the introduction of data-driven

covariates

In the paper from Boneschi et al (Boneschi 2003) Kaplan -Meyer

estimates of the survival function over a three-year period are also

shown but their denominators are not given along the curve so

that we miss any information on censored data We know from

study protocols that 239 patients completed the study after 9

months (Comi 2001) 98 patients after 2 years (Bornstein 1987

Johnson 1995) and only 203 out of 540 initially enrolled patients

have been followed up for 3 years So apparently less than 40 of

randomised patients contribute to the overall estimate of time to

first relapse but we really cannot say Indeed it has been empha-

sized that ldquoBoneschi and colleagues had access to the raw data from

all 540 patients in these studies whereas Munari and co-workers

had access to only the results from those subsets of these data that

were published in the original articlerdquo (Caramanos 2005) How-

ever since the total number of RRMS patients included in our re-

view counts 540 it would be surprising if data published in peer-

review journals would miss some relevant information available in

the original phase III data set Further details on the debate around

Boneschirsquos study and this review is also available in the literature

(Caramanos 2005 Comi 2005 Munari 2005)

As regards adverse events no major toxicity was observed Reac-

tions are predominantly localised to the injection site or self-lim-

iting The most common side effect is a combination of flushing

chest tightness sweating palpitations anxiety referred to as ldquopat-

terned reactionrdquo and it cannot be considered a harmful event We

have found a little higher incidence (24 of glatiramer acetate-

treated patients and 7 of those taking placebo) than reported in

the literature (15 and 5) Rare side effects however cannot be

explored in phase III trial settings and deserve a careful post-mar-

keting surveillance (Mancardi 2000) Lipoatrophy for instance

has been observed in some patients after prolonged injections of

glatiramer acetate Following scattered reports in the literature

(Drago 1999 Hwang 2001) this finding has been described in 34

out of a case series of 76 patients treated with glatiramer acetate

involving at least one injection site (Edgar 2004) Skin lesions

however were usually mild and only 5 and 9 patients developed

severe or moderate lipoatrophy respectively



Secondary endpoint analysis supports a decrease in hospital ad-

mission rates and steroid courses related to glatiramer acetate

treatment Despite increasing speculation on process endpoints in

pharmacoeconomics models it should be noted that

bull they are strictly related to the local healthcare financing

system

bull they reflect healthcare policies rather than consumersrsquo needs

bull they ultimately depend on physicianrsquos choices For instance

treating neurologists may tend to manage more aggressively

patients that were not given a presumably beneficial therapy

Therefore both hospitalisation and virtually costless steroids are

actually of little help in estimating the economic profile of glati-

ramer acetate

It has been recently suggested that the evaluation of MRI param-

eters in trials of MS may introduce an objective measure of treat-

ment effect (Sormani 2002) MRI parameters are still surrogates of

therapeutic efficacy and cannot represent a therapeutic goal them-

selves Moreover according to Prenticersquos validity criteria (Prentice

1989) surrogate endpoints should fully capture the net effect of

treatment on clinical outcomes and this cannot be shown in the

absence of a significant clinical benefit (Munari 2004a

A U T H O R S rsquo C O N C L U S I O N SImplications for practice

Glatiramer acetate seems to have no beneficial effect on the first

outcome measure in this disease ie disease progression The ef-

ficacy on relapse-related clinical outcomes seems to be more con-

sistent but the entity of the effect appear to be light Its use on

RRMS should be considered taking into account its partial effi-

cacy The therapy is not suitable for progressive MS

Implications for research

Future studies on glatiramer acetate should taken into considera-

tion with the following issues

bull undertake a really blind assessment of patients treated with

subcutaneous glatiramer acetate

bull develop a sensitive comprehensive and reliable measure of

patient disability over time

bull establish a unique and reliable clinical definition of patient

progression

bull make definitely clear the relationship between MRI

parameters and clinical outcomes fully accomplishing Prentice

criteria (Prentice 1989)

A C K N O W L E D G E M E N T S

Reviewers wish to thank Prof Boiko (Professor in the Department

of Neurology and Neurosurgery of the Russian State Medical Uni-

versity) who gave the idea of the review and wrote a first draft

version of the protocol Prof George Rice (Dept of Clinical Neu-

rological Sciences University of Western Ontario London On-

tario) and Dr Graziella Filippini (Neuroepidemiology Unit and

MS Cochrane Review Group Ist Nazionale Neurologico C Besta

Milan Italy) for their support in collecting data and appreciated

remarks We thank Deirdre Beecher Trials Search Coordinator for

her support on papers retrieval and Liliana Coco Managing Editor

for her precious technical assistance and support in drawing up

the paper

R E F E R E N C E S

References to studies included in this review

Bornstein 1987 published data onlylowast Bornstein MB Miller A Slagle S Weitzman M Crystal

H Drexler E et alA pilot trial of Cop 1 in exacerbating-

remitting multiple sclerosis New England Journal of

Medicine 1987317(7)408ndash14

Bornstein 1991 published data only

Bornstein MB Miller A Slagle S Weitzman M Drexler

E Keilson M et alA placebo-controlled double-blind

randomized two-center pilot trial of Cop 1 in chronic

progressive multiple sclerosis Neurology 199141533ndash9

Comi 2001 published data only

Comi G Filippi M Wolinsky J The extension phase of the

European-Canadian MRI study demonstrates a sustained

effect of glatiramer acetate in relapsing-remitting multiple

sclerosis Journal of Neurosurgery 2001Suppl 1187lowast Comi G Filippi M Wolinsky JS and the European

Canadian Glatiramer Acetate Study Group European

Canadian multicenter double-blind randomized placebo-

controlled study of the effects of Glatiramer acetate on

magnetic resonance imaging-measured disease activity

and burden in patients with relapsing-remitting multiple

sclerosis Annals of Neurology 2001149(3)290ndash7

Comi G Filippi M for The Copaxone MRI study Group

Milan Italy The effect of glatiramer acetate (Copaxone) on

disease activity as measured by cerebral MRI in patients

with relapsing-remitting multiple sclerosis (RRMS) a



multi-center randomized double-blind placebo-controlled

study extended by open-label treatment Neurology 199952

Suppl 2A289

Filippi M Rovaris M Rocca MA Sormani MP Wolinsky

JS Comi G Glatiramer acetate reduces the proportion of

new MS lesions evolving into ldquoblack holesrdquo Neurology

200157(4)731ndash3

Rovaris M Comi G Rocca MA Valsasina P Ladkani D

Pieri E et alLong-term follow-up of patients treated with

glatiramer acetate a multicentre multinational extension of

the EuropeanCanadian double-blind placebo-controlled

MRI-monitored trial Multiple Sclerosis 200713502ndash8

Rovaris M Comi G Wolinsky JS Filippi M The effect

of glatiramer acetate on brain volume changes in patients

with relapsing-remitting multiple sclerosis Journal of

Neurosurgery 200194 Suppl 1187

Filippi 2006 published data only

Filippi M Wolinsky JS Comi G Effects of oral glatiramer

acetate on clinical and MRI-monitored disease activity in

patients with relapsing multiple sclerosis a multicentre

double-blind randomised placebo-controlled study Lancet

Neurology 20065213ndash20

Markowitz C A multinational multicenter randomized

double-blind placebo-controlled study to evaluate the

efficacy tolerability and safety of 2 doses of glatiramer

acetate orally administered in relapsing remitting multiple

sclerosis patients httpwwwuphsupenneduneuro

clintrialMS-Coral-Markowitzhtm

Mesaros S Rocca MA Sormani MP Charil A Comi G

Filippi M Clinical and conventional MRI predictors of

disability and brain atrophy accumulation in RRMS A

large scale short-term follow-up study Journal of neurology

20082551378ndash83

Johnson 1995 published data only

Brochet B Long-term effects of glatiramer acetate in

multiple sclerosis Revue Neurologique 2008164917ndash25

Ge Y Grossman RI Udupa JK Fulton J Constantinescu

CS Gonzales - Scarano F et alGlatiramer acetate

(Copaxone) treatment in relapsing-remitting MS

quantitative MR assessment Neurology 200054(4)813ndash7

Greenstein JI Extended use of glatiramer acetate

(Copaxone) for MS [Letter] Neurology 199952(4)897ndash8

Johnson KP Experimental therapy of relapsing-remitting

multiple sclerosis with copolymer-1 Annals Neurology

199436 SupplS115ndash7

Johnson KP Management of relapsingremitting multiple

sclerosis with copolymer 1 (Copaxone) Multiple Sclerosis

19961(6)325ndash6

Johnson KP The USPhase III Copolymer 1 Study Group

Antibodies to Copolymer 1 do not interfere with the clinical

effect [Abstract] Annals of Neurology 199538973lowast Johnson KP Brooks BR Cohen JA Ford CC Goldstein

J Lisak RP et alCopolymer 1 reduces relapse rate and

improves disability in relapsing-remitting multiple sclerosis

results of a phase III multicenter double-blind placebo-

controlled trial Neurology 199545(7)1268ndash76

Johnson KP Brooks BR Cohen JA Ford CC Goldstein J

Lisak RP et alExtended use of glatiramer acetate (copaxone)

is well tolerated and maintains its clinical effect on multiple

sclerosis relapse rate and degree of disability Copolymer 1

Multiple Sclerosis Study Group Neurology 199850(3)

701ndash8

Johnson KP Brooks BR Ford CC Goodman A Guarnaccia

J Lisak RP et alSustained clinical benefits of glatiramer

acetate in relapsing multiple sclerosis patients observed for

6 years Copolymer 1 Multiple Sclerosis Study Group

Multiple Sclerosis 20006(4)255ndash66

Johnson KP Brooks BR Ford CC Goodman AD Lisak

RP Myers LW et alGlatiramer acetate (Copaxone)

comparison of continuous versus delayed therapy in a six-

year organized multiple sclerosis trial Multiple Sclerosis

20039585ndash91

Johnson KP Copolymer Multiple Sclerosis Treatment

Group Effects of copolymer on neurologic disability in

patients with relapsing-remitting multiple sclerosis results

of a phase III trial [Abstract] Journal of Neurology 1995

242S38

Liu C Blumhardt LD Benefits of glatiramer acetate

on disability in relapsing-remitting multiple sclerosis

An analysis by area under disabilitytime curves The

Copolymer 1 Multiple Sclerosis Study Group Journal of

Neurological Sciences 2000181(1-2)33ndash7

Schiffer RB Johnson KP Brooks BR Cohen J Ford CC

Goldstein J et alCopolymer-1 reduces the relapse rate

and positively influences disability in relapsing-remitting

multiple sclerosis results of a phase III multi-center double-

blind placebo- controlled trial [Abstract] European Journal

of Neurology 19952103

Schwid SR Goodman AD Weinstein A McDermott

MP Johnson KP Cognitive function in relapsing multiple

sclerosis minimal changes in a 10-year clinical trial Journal

of the neurological sciences 200725557ndash63

Wolinsky 2007 published data only

Markowitz C A multinational multicenter double-

blind placebo-controlled study to evaluate the efficacy

tolerability and safety of glatiramer acetate for injection

in primary progressive multiple sclerosis patients http

wwwuphsupenneduneuroclintrialMS-Promise-

Markowitzhtm 2000

Sajja BR Narayana PA Wolinsky JS Ahn CW and

the PROMiSe trial longitudinal magnetic resonance

spectroscopic imaging of primary progressive multiple

sclerosis patients treated with glatiramer acetate

multicenter study Multiple Sclerosis 20081473ndash80

Wolinsky JS The PROMiSe trial baseline data review and

progress report Multiple Sclerosis 200410 Suppl 1S65ndash71lowast Wolinsky JS Narayana PA OrsquoConnor P Coyle PK

Ford C Johnson K et alGlatiramer acetate in primary

progressive multiple sclerosis results of a multinational

multicenter double-blind placebo-controlled trial Annals

of neurology 20076114ndash24

References to studies excluded from this review



Abramsky 1977 published data only

Abramsky O Teitelbaum D Arnon R Effect of a synthetic

polypeptide (COP 1) on patients with multiple sclerosis and

with acute disseminated encephalomyelitis Preliminary

report Journal of Neurological Sciences 197731(3)433ndash8

Achiron 2005 published data only

Achiron A Barak Y Gail M Mandel M Pee D Ayyagari

R et alCancer incidence in multiple sclerosis and effects of

immunomodulatory treatments Breast cancer research and

treatment 200589265ndash70

Arnold 2008 published data only

Arnold DL Campagnolo D Panitch H Bar-Or A Dunn J

Freedman M et alGlatiramer acetate after mitoxantrone

induction improves MRI markers of lesion volume and

permanent tissue injury in Multiple Sclerosis Journal of

neurology 20082551473ndash8

Ball 2008 published data only

Ball NJ Cowan BJ Moore GR Hashimoto SA Lobular

panniculitis at the site of glatiramer acetate injections for

the treatment of relapsing-remitting multiple sclerosis A

report of two cases Journal of cutaneous pathology 200835

407ndash10

Baumhefner 1988 published data onlylowast Baumhefner RW Tourtellotte WW Syndulko K Shapshak

P Osborne M Rubinshtein G Copolymer 1 as therapy for

multiple sclerosis the cons Neurology 198838 Suppl 2(7)

69ndash72

Blanco 2006 published data only

Blanco Y Moral EA Costa M Gomez-Choco M Torres-

Peraza JF Alonso-Magdalena L et alEffect of glatiramer

acetate (Copaxone) on the immunophenotypic and cytokine

profile and BDNF production in multiple sclerosis a

longitudinal study Effect of glatiramer acetate (Copaxone)

on the immunophenotypic and cytokine profile and BDNF

production in multiple sclerosis a longitudinal study 2006

406270ndash5

Boiko 2006 published data only

Boiko AN Davydovskaia MF Demina TL Lashch

NI Ovcharov VV Popova NF et al[The results of

longitudinal use of copaxone and betaferon in Moscow

Multiple Sclerosis Center issues of efficacy and

adherence to therapy] Zhurnal nevrologii i psikhiatrii

imeni SSKorsakova Ministerstvozdravookhraneniiai

meditsinskoipromyshlennostiRossiiskoiFederatsii

Vserossiiskoeobshchestvonevrologov[i]

Vserossiiskoeobshchestvopsikhiatrov 2006Spec No 3

101ndash10


Bornstein MB Miller AI Teitelbaum D Arnon R Sela M

Multiple sclerosis trial of a synthetic polypeptide Annals of

Neurology 198211(3)317ndash9

Bosca 2006 published data only

Bosca I Bosca M Belenguer A Evole M Hernandez M

Casanova B et alNecrotising cutaneous lesions as a side

effect of glatiramer acetate Journal of neurology 2006253

1370ndash1

Brenner 2001 published data only

Brenner T Arnon R Sela M Abramsky O Meiner Z

RivenKreitman R et alHumoral and cellular immune

responses to Copolymer 1 in multiple sclerosis patients

treated with Copaxone Journal of Neuroimmunology 2001

115(1-2)152ndash60

Brochet 2008 published data only



Cadavid 2009 published data only

Cadavid D Wolansky LJ Skurnick J Lincoln J Cheriyan

J Szczepanowski K et alEfficacy of treatment of MS with

IFNbeta-1b or glatiramer acetate by monthly brain MRI

in the BECOME study Neurology 200972(23)1972ndash3

Caon 2006 published data only

Caon C Din M Ching W Tselis A Lisak R Khan O

Clinical course after change of immunomodulating therapy

in relapsing-remitting multiple sclerosis European journal


Capobianco 2008 published data only

Capobianco M Rizzo A Malucchi S Sperli F Di Sapio A

Oggero A et alGlatiramer acetate is a treatment option in

neutralising antibodies to interferon-beta-positive patients

Neurological sciences 200829S227ndash9

Carra 2008 published data only

Carra A Onaha P Luetic G Burgos M Crespo E Deri

N et alTherapeutic outcome 3 years after switching of

immunomodulatory therapies in patients with relapsing-

remitting multiple sclerosis in Argentina European journal


Castelli-Haley 2008 published data only

Castelli-Haley J Oleen-Burkey M Lage MJ Johnson

KP Glatiramer acetate versus interferon beta-1a for

subcutaneous administration comparison of outcomes

among multiple sclerosis patient Advances in therapy 2008

25658ndash73

Charach 2008 published data only

Charach G Grosskopf I Weintraub M Development of

Crohnrsquos disease in a patient with multiple sclerosis treated

with copaxone Digestion 200877198ndash200

Chen 2001 published data only

Chen M Gran B Costello K Johnson K Martin R Dhib-

Jalbut S Glatiramer acetate induces a Th2-biased response

and cross reactivity with myelin basic protein in patients

with MS Multiple Sclerosis 20017(4)209ndash19

Cicek 2008 published data only

Cicek D Kandi B Oguz S Cobanoglu B Bulut S Saral Y

An urticarial vasculitis case induced by glatiramer acetate

The Journal of dermatological treatment 200819305

Cohen 1995 published data only

Cohen JA Grossman RI Udupa JK Smatasekera S Miki Y

Polansky M et alAssessment of the efficacy of Copolymer-

1 in the Treatment of Multiple Sclerosis by Quantitative

MRI Neurology 199545 Suppl 4A470




Cohen JA Rovaris M Goodman AD Ladkani D Wynn D

Filippi MT Randomized double-blind dose-comparison

study of glatiramer acetate in relapsing-remitting Neurology

200768 939ndash44

Constantinescu 2000 published data only

Constantinescu CS Freitag P Kappos L Increase in serum

levels of uric acid an endogenous antioxidant under

treatment with glatiramer acetate for multiple sclerosis


Daugherty 2005 published data only

Daugherty KK Butler JS Mattingly M Ryan M Factors

leading patients to discontinue multiple sclerosis therapies

Journal of the American Pharmacists Association 200545

371ndash5

De Seze 2000 published data only

De Seze J Edan G Labalette M Dessaint JP Vermersch

P Effect of glatiramer acetate (Copaxone) given orally in

human patients interleukin-10 production during a phase

1 trial Annals of Neurology 200047(5)686

De Stefano 2008 published data only

De Stefano N Filippi M Hawkins C Short-term

combination of glatiramer acetate with iv steroid treatment

preceding treatment with GA alone assessed by MRI-

disease activity in patients with relapsing-remitting multiple

sclerosis Journal of the neurological sciences 2008266(1-2)

44ndash50


De Stefano N Fillippi M Confavreux C Vermesch P Simu

M Sindic C et alThe results of two multicenter open

label studies assessing efficacy tolerability and safety of

protiramer a high molecular weight synthetic copolymer

mixture in patients with relapsing remitting multiple

sclerosis multiple sclerosis 200915(2)238ndash243

Debouverie 2007 published data only

Debouverie M Moreau T Lebrun C Heinzlef O Brudon F

Msihid J A longitudinal observational study of a cohort of

patients with relapsing-remitting multiple sclerosis treated

with glatiramer acetate European journal of neurology 2007

141266ndash74

Deen 2008 published data only

Deen S Bacchetti P High A Waubant E Predictors of the

location of multiple sclerosis relapse Journal of neurology

neurosurgery and psychiatry 2008791190ndash3

Duda 2000 published data only

Duda PW Schmied MC Cook SL Krieger JI Hafler

DA Glatiramer acetate (Copaxone) induces degenerate

Th2-polarized immune responses in patients with multiple

sclerosis Journal of Clinical Investigation 2000105(7)

967ndash76

Farina 2001 published data only

Farina C Bergh FT Albrecht H Meinl E Yassouridis A

Neuhaus O Hohlfeld R Elispot assay detects COP-induced

interleukin-4 and interferon-gamma response in blood cells

Brain 2001124(4)705ndash19

Rovaris M Comi G Filippi M Can glatiramer acetate

reduce brain atrophy development in multiple sclerosis

Journal of the neurological sciences 2005233139

Feigin 2005 published data only

Feigin PD On cancer incidence in multiple sclerosis and

effects of immunomodulatory treatments Breast cancer

research and treatment 200592197

Fiore 2005 published data only

Fiore AP Fragoso YD Tolerability adverse events and

compliance to glatiramer acetate in 28 patients with

multiple sclerosis using the drug continuously for at least six

month Arquivos de Neuro-psiquiatria 200563738ndash40

Flechter 2002a published data only

Flechter S Kott E Steiner-Birmanns B Nisipeanu P

Korczyn AD Copolymer 1 (glatiramer acetate) in relapsing

forms of multiple sclerosis open multicenter study of

alternate-day administration Clinical Neuropharmacology

200225(1)11ndash5

Flechter 2002b published data only

Flechter S Vardi J Pollak L Rabey JM Comparison of

glatiramer acetate (Copaxone) and interferon beta-1b

(Betaferon) in multiple sclerosis patients an open-label 2-

year follow-up Journal of Neurological Sciences 2002197(1-

2)51ndash5

Ford 2006 published data only

Ford CC Johnson KP Lisak RP Panitch HS Shifronis

G Wolinsky JS A prospective open-label study of

glatiramer acetate over a decade of continuous use in

multiple sclerosis patient Multiple Sclerosis 200612

309ndash20

Fusco 2001 published data only

Fusco C Andreone V Coppola G Luongo V Guerini F

Pace E et alHLA-DRB11501 and response to copolymer-

1 therapy in relapsing-remitting multiple sclerosis


Gajofatto 2009 published data only

Gajofatto A Bacchetti P Grimes B High A Waubant

E Switching first-line disease-modifying therapy after

failure impact on the course of relapsing-remitting multiple

sclerosis Multiple sclerosis 20091550ndash8

Garcia-Barragan 2009 published data only

Garcia-Barragan N Villar LM Espino M Sadaba MC

Gonzalez-Porque P Alvarez-Cermeno JC Multiple sclerosis

patients with anti-lipid oligoclonal IgM show early

favourable response to immunomodulatory treatment

European journal of neurology 200916380ndash5

Ghezzi b 2005 published data only

Ghezzi A Amato MP Capobianco M Gallo P Marrosu G

Martinelli V et alDisease-modifying drugs in childhood-

juvenile multiple sclerosis results of an Italian co-operative

study Multiple Sclerosis 200511420ndash4

Ghezzi 2005 published data only

Ghezzi A Immunomodulatory Treatment of Early Onset

MS (ITEMS) Group Immunomodulatory treatment of



early onset multiple sclerosis results of an Italian Co-

operative Study Neurological sciences 200526(4)S183ndash6

Goodman 2009 published data only

Goodman AD Rossman H Bar-Or A Miller A Miller

DH Schmierer K et alGLANCE results of a phase

2 randomized double-blind placebo-controlled study


Haas 2005 published data only

Haas J Firzlaff M Twenty-four-month comparison of

immunomodulatory treatments - a retrospective open label

study in 308 RRMS patients treated with beta interferons

or glatiramer acetate (Copaxone) European journal of


Harde 2007 published data only

Harde V Schwarz T Embolia cutis medicamentosa

following subcutaneous injection of glatiramer acetate

Journal der DeutschenDermatologischenGesellschaft 20075

1122






Multiple Sclerosis 20006255ndash66






20039585ndash91


Johnson KP Ford CC Lisak RP Wolinsky JS Neurologic

consequence of delaying glatiramer acetate therapy

for multiple sclerosis 8-year data Acta Neurologica

Scandinavica 200511142ndash7

Jolly 2008 published data only

Jolly H Simpson K Bishop B Hunter H Newell C

Denney D et alImpact of warm compresses on local

injection-site reactions with self-administered glatiramer

acetate The Journal of neuroscience nursing 200840232ndash9

Karandikar 2002 published data only

Karandikar NJ Crawford MP Yan X Ratts RB Brenchley

JM Ambrozak DR et alGlatiramer acetate (Copaxone)

therapy induces CD8+ T cella response in patients with

multiple sclerosis Journal of Clinical Investigation 2002109

(5)641ndash9

Khan 2001 published data only

Khan OA Tselis AC Kamholz JA Garbern JY Lewis

RA Lisak RP A prospective open-label treatment trial

to compare the effect of IFNbeta-1a (Avonex) IFNbeta-

1b (Betaseron) and glatiramer acetate (Copaxone) on the

relapse rate in relapsing--remitting multiple sclerosis results

after 18 months of therapy Multiple Sclerosis 20017(6)

349ndash53


Khan O Shen Y Caon C Bao F Ching W Reznar M et

alAxonal metabolic recovery and potential neuroprotective


sclerosis Multiple sclerosis 200511646

khan 2008 published data only

Khan O Shen Y Bao F Caon C Tselis A Latif Z et

alLong-term study of brain 1H-MRS study in multiple

sclerosis effect of glatiramer acetate therapy on axonal

metabolic function and feasibility of long-Term H-MRS

monitoring in multiple sclerosis Journal of neuroimaging

200818314ndash9

Kott 1997 published data only

Kott E Kessler A Biran S Optic Neuritis in Multiple

Sclerosis Patients Treated with Copaxone Journal of

Neurology 1997 Vol 244S23ndash4

La Mantia 2006 published data only

La Mantia L DrsquoAmico D Rigamonti A Mascoli N

Bussone G Milanese C Interferon treatment may trigger

primary headaches in multiple sclerosis patients Multiple

sclerosis (Houndmills Basingstoke England) 200612(1352-

4585)476ndash80

Lage 2006 published data only

Lage MJ Castelli-Haley J Oleen-Burkey MA Effect

of immunomodulatory therapy and other factors on

employment loss time in multiple sclerosis Work (Reading

Mass) 200627(2)143ndash51

Le Page 2008 published data only

Le Page E Leray E Taurin G Coustans M Chaperon J

Morrissey S et alMitoxantrone as induction treatment in

aggressive relapsing remitting multiple sclerosis treatment

response factors in a 5 year follow-up observational study of

100 consecutive patients Journal of neurology neurosurgery

and psychiatry 20087952ndash6

Madray 2008 published data only

Madray MM Greene JF Jr Butler DF Glatiramer acetate-

associated CD30+ primary cutaneous anaplastic large-cell

lymphoma Archives of neurology 2008651378ndash9

Mancardi 1998 published data only

Mancardi GL Sardanelli F Parodi RC Melani E Capello E

et alEffect of copolymer-1 on serial gadolinium-enhanced

MRI in relapsing remitting multiple sclerosis Neurology

199850(4)1127ndash33

Meiner 1997 published data only

Meiner Z Kott E Schechter D et alCopolymer 1 in

relapsing-remitting multiple sclerosis a multi-centre trial

In Abramsky O Ovadia H editor(s) Frontiers in Multiple

Sclerosis Clinical Research and Therapy London Martin

Dunitz 1997213ndash21

Mesaros 2008 published data only





20082551378ndash83



Mikol 2008 published data only

Mikol DD Barkhof F Chang P Coyle PK Jeffery DR

Schwid SR et alComparison of subcutaneous interferon

beta-1a with glatiramer acetate in patients with relapsing

multiple sclerosis (the REbif vs Glatiramer Acetate in

Relapsing MS Disease [REGARD] study) a multicentre

randomised parallel open-label trial Lancet neurology

20087903ndash14

Milanese 2005 published data only

Milanese C Beghi E Giordano L La Mantia L Mascoli

N Confalonieri P et alA post-marketing study on

immunomodulating treatments for relapsing-remitting

multiple sclerosis in Lombardia preliminary results

Neurological sciences 200526 Suppl 4S171ndash3

Miller 1998 published data only

Miller A Shapiro S Gershtein R Kinarty A Rawashdeh

H Honigman S et alTreatment of multiple sclerosis

with copolymer-1 (Copaxone) implicating mechanisms

of Th1 to Th2Th3 immune-deviation Journal of

Neuroimmunology 199892(1-2)113ndash21


Miller CE Jezewski MA Relapsing MS patientsrsquo experiences

with glatiramer acetate treatment a phenomenological

study The Journal of neuroscience nursing journal of the

American Association of Neuroscience Nurses 20063837ndash41


Miller A Spada V Beerkircher D Kreitman RR Long-term

(up to 22 years) open-label compassionate-use study of

glatiramer acetate in relapsing-remitting multiple sclerosis


Neumann 2007 published data only

Neumann H Csepregi A Sailer M Malfertheiner

PT Glatiramer acetate induced acute exacerbation of

autoimmune hepatitis in a patient with multiple sclerosis

Journal of neurology 2007254816ndash7

Nolden 2005 published data only

Nolden S Casper C Kuhn A Petereit HF Jessner-

Kanof lymphocytic infiltration of the skin associated with

glatiramer acetate Multiple sclerosis 200511245ndash8

Ollendorf 2008 published data only

Ollendorf DA Castelli-Haley J Oleen-Burkey M Impact of

co-prescribed glatiramer acetate and antihistamine therapy

on the likelihood of relapse among patients with multiple

sclerosis The Journal of neuroscience nursing journal of

the American Association of Neuroscience Nurses 200840

281ndash90

Orlova 2005 published data only

Orlova IuIu Alifirova VM Cherdyntseva NV Zagrebina IA

Bychkova IV [3-year results of clinical and immunological

monitoring of patients with multiple sclerosis treated

by copaxone] Zhurnal nevrologii i psikhiatrii imeni

SSKorsakova Ministerstvozdravookhraneniiai



Vserossiiskoeobshchestvopsikhiatrov 2005105(5)23ndash7

Patten 2008 published data only

Patten SB Williams JV Metz LM Anti-depressant use in

association with interferon and glatiramer acetate treatment

in multiple sclerosis Multiple Sclerosis 200814406ndash11

Poumlllmann 2006 published data only

Poumlllmann W Erasmus LP Feneberg W Straube A The

effect of glatiramer acetate treatment on pre-existing

headaches in patients with MS Neurology 200666275ndash7

Qin 2000 published data only

Qin Y Zhang DQ Prat A Pouly S Antel J Characterization

of T cell lines derived from glatiramer-acetate-treated

multiple sclerosis patients Journal of Neuroimmunology

2000108(1-2)201ndash6

Ramtahal 2006 published data only

Ramtahal J Jacob A Das K Boggild M Sequential

maintenance treatment with glatiramer acetate after

mitoxantrone is safe and can limit exposure to

immunosuppression in very active relapsing remitting

multiple sclerosis Journal of Neurology 20062531160ndash4

Rauschka 2005 published data only

Rauschka H Farina C Sator P Gudek S Breier F

Schmidbauer M Severe anaphylactic reaction to glatiramer

acetate with specific IgE Neurology 2005641481ndash2

Rio 2005 published data only

Rio J Porcel J Tellez N Sanchez-Betancourt AT Factors

related with treatment adherence to interferon beta and

glatiramer acetate therapy in multiple sclerosis Multiple

sclerosis (Houndmills Basingstoke England) 200511306ndash9

Rovaris 2005 published data only



Journal of the Neurological Sciences 2005233139ndash43


Rovaris M Comi G Rocca MA Valsasina P Ladkani

D Pieri E Long-term follow-up of patients treated with



MRI-monitored trial Multiple sclerosis 200713502ndash8

Schwid 2007 published data only





Shipova 2009 published data only

Shipova EG Spirin NN Kasatkin DS Shumakov EI

Stepanov I O State of the cervical section of the spinal

cord in patients with remitting multiple sclerosis during

immunomodulatory treatment Neuroscience and behavioral

physiology 20093947ndash51

Sidoti 2007 published data only

Sidoti V Lorusso L Multiple sclerosis and Capgrasrsquo

syndrome Clinical neurology and neurosurgery 2007109

786ndash7



Sindic 2005 published data only

Sindic CJ Seeldrayers P Vande Gaer L De Smet E Nagels

G De Deyn PP et alLong-term follow up of glatiramer

acetate compassionate use in Belgium Acta Neurologica

Belgica 2005105(2)81ndash5

Soares 2006 published data only

Soares Almeida LM Requena L Kutzner H Angulo J

de Sa J Pignatelli J Localized panniculitis secondary

to subcutaneous glatiramer acetate injections for the

treatment of multiple sclerosis a clinicopathologic and

immunohistochemical study Journal of the American

Academy of Dermatology 200655(6)968ndash74

Sormani 2002 published data only

Sormani MP Bruzzi P Comi G Filippi M MRI metrics

as surrogate markers for clinical relapse rate in relapsing-

remitting MS patients Neurology 200258(3)417ndash21


Sormani MP Bruzzi P Comi G Filippi M The distribution

of the magnetic resonance imaging response to glatiramer

acetate in multiple sclerosis Multiple sclerosis 200511

447ndash9


Sormani MP Rovaris M Comi G Filippi MT A composite

score to predict short-term disease activity in patients with

relapsing-remitting MS Neurology 2007691230ndash5

Then Bergh F 2006 published data only

Then Bergh F Niklas A Strauss A von Ahsen N

Niederwieser D Schwarz J et alRapid progression of

Myelodysplastic syndrome to acute myeloid leukemia on

sequential azathioprine IFN-beta and copolymer-1 in a

patient with multiple sclerosis Acta Haematologica 2006

116207ndash10

Thouvenot 2007 published data only

Thouvenot E Hillaire-Buys D Bos-Thompson MA Rigau

V Durand L Guillot B et alErythema nodosum and

glatiramer acetate treatment in relapsing-remitting multiple

sclerosis Multiple Sclerosis 200713941ndash4

Tilbery 2006 published data only

Tilbery CP Mendes MF Oliveira BE Thomaz RB Kelian

G R Immunomodulatory treatment in multiple sclerosis

experience at a Brazilian center with 390 patients Arquivos

de Neuro-psiquiatria 20066451ndash4

Torkildsen 2007 published data only

Torkildsen O Grytten N Myhr KM Immunomodulatory

treatment of multiple sclerosis in Norway Acta Neurologica

Scandinavica Supplementum 200711546ndash50

Tremlett 2007 published data only




Twork 2007 published data only

Twork S Nippert I Scherer P Haas J Pohlau D Kugler

J Immunomodulating drugs in multiple sclerosis

compliance satisfaction and adverse effects evaluation in

a German multiple sclerosis population Current medical

research and opinion 2007231209ndash15

Valenzuela 2007 published data only

Valenzuela RM Costello K Chen M Said A Johnson

KP Dhib-Jalbut S Clinical response to glatiramer acetate

correlates with modulation of IFN-gamma and IL-4

expression in multiple sclerosis Multiple sclerosis 200713

754ndash62

Vallittu 2005 published data only

Vallittu AM Peltoniemi J Elovaara I Kuusisto H Farkkila

M Multanen J et alThe efficacy of glatiramer acetate in

beta-interferon-intolerant MS patients Acta Neurologica

Scandinavica 2005112(4)234ndash7

Vollmer 2008 published data only

Vollmer T Panitch H Bar-Or A Dunn J Freedman MS

Gazda SK et alGlatiramer acetate after induction therapy

with mitoxantrone in relapsing multiple sclerosis Multiple

sclerosis 200814663ndash70

Weder 2005 published data only

Weder C Baltariu GM Wyler KA Gober HJ Lienert C

Schluep M et alClinical and immune responses correlate

in glatiramer acetate therapy of multiple sclerosis European

journal of neurology 200512869ndash78

Weinstein 1999 published data only

Weinstein A Schwid SI Schiffer RB McDermott MP

Giang DW Goodman AD Neuropsychologic status in

multiple sclerosis after treatment with glatiramer Archives

of Neurology 199956(3)319ndash24


Wolinsky JS Narayana PA Johnson KP MRI and clinical

correlates Multiple Sclerosis Study Group and the MRI

Analysis Center Multiple Sclerosis 20017(1)33ndash41

Wynn 2008 published data only

Wynn D Meyer C Allen N OrsquoBrien D Optimal

dosing of immunomodulating drugs A dose-comparison

study of GA in RRMS Progress in Neurotherapeutics and

Neuropsychopharmacology 20083(1)137ndash51

Ytterberg 2007 published data only

Ytterberg C Johansson S Andersson M Olsson D Link

H Holmqvist LW von Koch L Combination therapy with

interferon-beta and glatiramer acetate in multiple sclerosis

Acta Neurologica Scandinavica 200711696ndash9

Zavalishin 2005 published data only

Zavalishin I A Peresedova A V Stoida N I

Adarcheva L S Zakharova M N Niiazbekova A S

Askarova L S Rebrova O I Experience in copaxon

treatment in Russia Zhurnal nevrologii i psikhiatrii




Vserossiiskoeobshchestvopsikhiatrov 200510529ndash31


Zavalishin IA Peresedova AV Stoida NI Rebrova O

Zakharova MN Adarcheva LS et al[A comparative

analysis of rebif 22-mcg and copaxone efficacy in



multiple sclerosis] Zhurnal nevrologii i psikhiatrii




Vserossiiskoeobshchestvopsikhiatrov 2006Spec No 3111ndash5

Ziemssen 2008 published data only

Ziemssen T Hoffman J Apfel R Kern S Effects of

glatiramer acetate on fatigue and days of absence from work

in first-time treated relapsing-remitting multiple sclerosis

Health and quality of life outcomes 200861ndash6

Zwibel 2006 published data only

Zwibel HL Glatiramer acetate in treatment-naive and prior

interferon-beta-1b-treated multiple sclerosis patients Acta

Neurologica Scandinavica 2006113378ndash86

References to ongoing studies


Comi G PreCISe study Group early glatiramer acetate

treatment in delaying conversion to clinically definite

multiple sclerosis (CDMS) in subjects presenting with a

clinically isolated syndrome Neurology 200870 Suppl9lowast Comi G Carragrave A Fazekas F Rieckmann P Bajenaru O

Hillert J et alTreatment with glatiramer acetate delays

conversion to clinically definite multiple sclerosis in patients

with clinically isolated syndrome subgroup analysis

Multiple Sclerosis World Congress on treatment and

Research in Multiple Sclerosis Montreal 2008 2008 Vol

14 issue suppl 1S38

Tintore Mar New options for early treatment of multiple

sclerosis Journal of Neurological Sciences 2009277(S1)

S9ndash11

Additional references

Boneschi 2003

Martinelli Boneschi F Rovaris M Johnson KP Miller A

Wolinsy JS Ladkani D et alEffects of glatiramer acetate on

relapse rate and accumulated disability in multiple sclerosis

meta-analysis of three double-blind randomized placebo-

controlled clinical trials Multiple Sclerosis 20039349ndash55

Brocke 1996

Brocke S Gijbels K Allegretta M Ferber I Piercy

C Blankenstein T et alTreatment of experimental

encephalomyelitis with a peptide analogue of myelin basic

protein Nature 1996379(6563)343ndash6

Caramanos 2005

Caramanos Z Arnold DL Evidence for use of glatiramer

acetate in multiple sclerosis Lancet Neurology 20054(2)

74ndash5

Comi 2005

Comi G Hartung HP Boneschi FM Evidence for use of

glatiramer acetate in multiple sclerosis Lancet Neurology

20054(2)75ndash6

Drago 1999

Drago F Brusati C Mancardi GL Murialdo A Rebora A

Localized lipoatrophy after glatiramer acetate injection in

patients with remitting-relapsing multiple sclerosis (letter)

Archives of Dermatology 1999135(10)1277ndash8

Ebers 2008

Ebers GC Heigenhauser L Daumer M Lederer C

Noseworthy JH Disability as an outcome in MS clinical

trials Neurology 200871624ndash631

Edgar 2004

Edgar CM Brunet DG Fenton P McBride EV Green P

Lipoatrophy in patients with multiple sclerosis on glatiramer

acetate Canadian Journal of Neurological Sciences 200431

(1)58ndash63

Ge 2000


CS Gonzales-Scarono F et alGlatiramer acetate (Copaxone)

treatment in relapsing-remitting MS quantitative MR

assessment Neurology 200054(4)813ndash7

Higgins 2008

Higgins JPT Green S (editors) Cochrane Handbook

for systematic Reviews of Interventions Version 500

(updated February 2008)The Cochrane Collaboration

2008 wwwcochrane-handbook org

Hwang 2001

Hwang L Orengo I Lipoatrophy associated with glatiramer

acetate injections for the treatment of multiple sclerosis

Cutis 200168(4)287ndash8

Jadad 1996

Jadad A Moore A Carroll D Assessing the quality of

randomised trials is blinding necessary Controlled clinical

trials 199617(1)1ndash12

Kurtzke 1983

Kurtzke JF Rating neurological impairment in multiple

sclerosis an expanded disability status scale (EDSS)


Lefebvre 2008

Lefebvre C Manheimer E Glanville J Chapter 6 Searching

for studies In Higgins JPT Green S (editors) Cochrane

Handbook for Systematic Reviews of Interventions

Version 501 (updated September 2008) The Cochrane

Collaboration 2008 Available from wwwcochrane-

handbookorg

Mancardi 2000

Mancardi GL Murialdo A Drago F Brusati C Croce

R Inglese M et alLocalized lipoatrophy after prolonged

treatment with copolymer 1 Journal of Neurology 2000247

(3)220ndash1

McFarland 2008

McFarland H F Aletuzumab versus interferon beta-1a

implications for pathology and trial design neurology 2008

826ndash28

Munari 2004a

Munari LM Filippini G Lack of evidence for use of


20043(11)641



Munari 2005

Munari LM Filippini G Evidence for use of glatiramer

acetate in multiple sclerosis (Authorsrsquo reply) Lancet


Poser 1983

Poser CM Paty DW Scheinberg L McDonald WI Davis

FA Ebers GC et alNew diagnostic criteria for multiple

sclerosis guidelines for research protocols Annals of


Prentice 1989

Prentice RL Surrogate endpoints in clinical trials definition

and operational criteria Statistics in Medicine 19898(4)

431ndash40

RevMan 2008

The Nordic Cochrane Centre The Cochrane Collaboration

Review Manager (RevMan) Copenhagen The Nordic

Cochrane Centre The Cochrane Collaboration 2008

Rio 2002

Rio J Nos C Tintoregrave M Borras C Galagraven I Comabella

M Montalban X assessment of different treatment failure

criteria in a Cohort of relapsing-remitting multiple sclerosis

patients treated with interferon betaimplications for clinical

trials Ann Neurol 200252400ndash406

Rio 2006

Rio J Nos C Tintoreacute egravellez N Galagraven I Pelayo R Comabella

M Montalban X Defining the response to interferon beta

in relapsing-remitting multiple sclerosis patients Ann

Neurol 200659344ndash352

Teitelbaum 1997

Teitelbaum D Arnon R Sela M Coplymer 1 from basic

research to clinical application Cellular and Molecular Life

Sciences CMLS 199753(1)24ndash8

Wisniewski 1977

Wisniewski HM Keith AB Chronic relapsing experimental

allergic encephalomyelitis an experimental model of

multiple sclerosis Annals of Neurology 19771(2)144ndash8

Yusuf 1985

Yusuf S Peto R Lewis J Collins R Sleight P Beta-blockade

during and after myocardial infarction an overview of the

randomised trials Progress in Cardiovascular Diseases 1985

27(5)335ndash71

References to other published versions of this review

Munari 2004

Munari LM Lovati R Boiko A Therapy with glatiramer

acetate for multiple sclerosis Cochrane Database of

Systematic Reviews 2004 Issue 1 [DOI 101002

14651858CD004678]lowast Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Bornstein 1987

Methods Design Randomised controlled trial

Enrollement Patients have been enrolled in matched pairs with random assignment of

either patient

Intention-to-treat analysis

Blindness Double-blind but patientrsquos self-evaluation of either side effects or changes in

neurologic status were reported to an unblinded clinical assistant

Treatment duration 24 months

Follow-up duration 24 months

Withdrawn criteria of inclusion unusable data (2 placebo)

Dropouts = 7 placebo = 4 (2 psychological reason and 2 unstated) 17 GA = 3 (1

exacerbation 2 unstated) 12

Participants 50 patients GA 25 placebo 25

Israel 1 centre

Sex both

Age 20-35

Included (36) definite MS with RR course gt= 2 exacerbations in the 2 years before

admission Kurtzke lt= 6 emotionally stable Patients enrolled when ldquoclinically stablerdquo

and out of steroid treatment Excluded (64) age (23) low frequency of exacerbations

(21) lack of documentation (19) psychologic profile (15) transition to chronic (8)

distance from the clinic (3) pregnancy (1)

Baseline characteristics

58 female

mean age GA 300 yrs placebo 311 yrs

mean EDSS GA 29 placebo 32

disease duration GA 49 yrs placebo 61 yrs

Interventions Rx GA 20 mg

Placebo bacteriostatic saline

Subcutaneous GA or placebo self-administered daily

Co-interventions unspecified steroid treatment during exacerbations symptomatic

medications (eg cholinergic and spasmolytic drugs)

Outcomes Primary outcome proportion of relapse-free patients at the end of follow-up

Secondary outcomes frequency of relapses change in EDSS scores from baseline time

to progression

Relapse defined as patient symptoms accompanied by observed objective changes on

the neurologic exam involving an increase of at least 1 point in the score for 1 of the 8

functional group of Kurtzke scale Sensory symptoms alone not considered

Progression defined as increase of at least 1 point EDSS maintained for at least 3 months

Notes Jadad score = 3

Two different preparations of Copolymer-1 have been used in the study but patients

treated with either preparation cannot be identified throughout the trial



Bornstein 1987 (Continued)

Assumptions 2 withdrawn in placebo group

Risk of bias

Item Authorsrsquo judgement Description

Adequate sequence generation Unclear Quote ldquothe random assignment of the first

patient of a pair determined the assignment

of both rdquo pg 409

Allocation concealment No see above

Blinding

All outcomes

Yes Quote pg 409 ldquoA neurologist unaware of

the patientrsquos treatment group completed a

neurologic examination and status evalu-

ation The patientrsquos self evaluation of ()

side effects were reported to the clinical as-

sistant who was not blinded to the treat-

mentrdquo However the trial failed to carry out

a fully blind assessment

Incomplete outcome data addressed

All outcomes

Yes Withdrawn criteria of inclusion unusable

data (2 placebo)

Dropouts = 7 placebo = 4 (2 psychological

reason and 2 unstated) 17

GA = 3 (1 exacerbation 2 unstated) 12

Quote pg 410 ldquothe partial data obtained

from the other five patients were included

in the analysesrdquo

Free of selective reporting Yes

Free of other bias Yes

Bornstein 1991

Methods Randomized controlled study

Two center

Randomization within centers with two baseline EDSS strata (lt 5 and gt or equal 5)

Double blind


Withdrawals 189 (10 GA-10 P) 6 for not consent 5 for side effects and 3 for clinical

worsening and 6 for various reasons

Participants 51 GA and 55 Placebo

Definte diagnosis of MS according to Poser criteria

Chronic progressive course for at least 18 months

no more than two exacerbation in the previous 2 years




20-60 years of age

2-65 EDSS

Interventions GA 20 mg or placebo (saline alone) self injected subcutaneously twice a day

Limited use of steroids was allowed during exacerbation

Outcomes PrimaryConfirmed progression (worsening of 1 EDSS or 15 according to basal EDSS

( 5 or less) maintained at 3 months

Secondary time to progression EDSS change

Notes The change from baseline in EDSS score over the study period was evaluated but the

corresponding data were not reported in the paper but described in term of percentage

of improved stable or worse patients This study was not included in the analysis for

this outcome (see 44)

Risk of bias


Adequate sequence generation Yes quoteldquo by randomized block design with

two baseline EDSS strata lt 50 and 50 or

greaterrdquo

pg 534

Allocation concealment Yes quote ldquo the investigator notified the statis-

tical center which assigned a randomiza-

tion code number rdquo pg 534

Blinding

All outcomes

Yes Quote pg 534 ldquothe side effects were not

discussed with the neurologist Another

blinded neurologist was available to exam-

ine patients with severe or unusual side ef-

fectsrdquo


All outcomes

Yes The 20 withdrawals had been considered

in the statistical analyses pg 536





Comi 2001

Methods Randomised controlled trial

Double -blind

placebo controlled


Treatment period 9 months

Follow-up period 9 months

Drop-outs

- GA = 7 (3 adverse events 1 moved away from study center 1 severe exacerbation 4

withdrew consent more than one causes are counted for the same patient) 6

- Placebo = 7 (2 adverse events 1 treatment believed ineffective 1 poor compliance 1

lost to follow-up 2 refused to continue MRI monitoring) 6


Europe and Canada 29 centres

Sex both

Age 18-50

Included (49) definite MS with RR course a diagnosis of MS for at least 1 year

age 18-50 inclusive EDSS of 0 to 5 at least 1 documented relapse in the preceding 2

years at least 1 enhancing lesion in their screening brain MRI clinically relapse-free and

steroids-free in the 30 days before entry

Excluded (51) previous use of GA or oral myelin prior lymphoid irradiation use

of immunosuppressant or cytotoxic agents in the past 2 years use of azathioprine cy-

closporine interferons deoxyspergualin chronic corticosteroids during the previous 6

months Concomitant therapy with an experimental drug for MS or for another disease

Serious intercurrent systemic or psychiatric illnesses unwilling to practice reliable con-

traception during study known hypersensitivity to Gadolinium-DTPA or unavailable to

undergo repeat MRI studies Currently on relapse or steroid treatment (13) unspecified

requirement unmet (233)


Unspecified gender distribution

mean age GA 341 placebo 340


disease duration GA 79 years placebo 83 years


Placebo unspecified preparation


Co-interventions relapses could be treated by a standard dose of 10 g iv methylpred-

nisolone for 3 consecutive days

Outcomes Primary outcome total number of enhancing lesions on MRI

Secondary outcomes total volume of enhancing lesions number of new enhancing

lesions number of new lesions on T2-weighted imagespercentage change of lesion

volume on T2-weighted images change in the volume of hypointense lesions on T1-

weighted images

Tertiary outcomes relapse rate number of relapses proportion of relapse-free patients

Relapse defined as appearance or reappearance of one or more neurologic symptoms

accompanied by abnormalities persisting for at least 48 hours and immediately preceded

by a relatively stable or improving neurologic state of at least 30 days A relapse was



Comi 2001 (Continued)

confirmed when patientrsquos symptoms were accompanied by objective changes in neuro-

logic examination consistent with at least 05 EDSS increase 1 grade in the score of two

or more functional systems or 2 grades in one functional system Transient neurologic

deterioration associated with fever or infection in MS patients was not considered as

relapse nor was a change in bowel bladder or cognitive function alone


The Authors state that physician blinding was not formally assessed because primary

and secondary outcome measures were MRI patterns Nevertheless both the treating

neurologist and the patient were informed of the importance of not discussing safety

issues with the examining neurologist

The change from baseline in EDSS score over the study period was evaluated but the

corresponding data (mean +-SD) were not reported in the paper This study was not

included in the analysis for this outcome (see 11)

Risk of bias


Adequate sequence generation Yes The randomization list stratified by cen-

ters was central computer-generated

Allocation concealment Yes see above

Blinding

All outcomes

Yes All personnel were unaware of treatment

allocation patient and physician blinding

was not formally assessed as outcome mea-

sures focused on MRI parametersQuote ldquo

both the treating neurologist and the pa-

tient were informed on the importance of

not discussing safety issue with the exam-

ining neurologist rdquo pg 291


All outcomes

Yes Only 6 drop-out for each group

- GA = 7 (3 adverse events 1 moved away

from study center 1 severe exacerbation

4 withdrew consent more than one causes

are counted for the same patient)

- Placebo = 7 (2 adverse events 1 treat-

ment believed ineffective 1 poor compli-

ance 1 lost to follow-up 2 refused to con-

tinue MRI monitoring)





Filippi 2006

Methods Design of the study Randomised controlled trial

Allocation Central allocation at trial office list 111

158 participating clinical centers worldwide

Blindness double blind



Withdrawals 37-7 (50 mg) 41 -7 (5 mg) 42 -7(placebo)

Participants 1651 patients randomized 7 were excluded and 1644 were treated 543 ( 50 mg) 553

(5 mg) 548 placebo

Inclusion criteria clinically definite MS relapsing-remitting course Disease duration at

least 6 months age 18-50 EDSS 0-50 one year pre study relapse frequency 10 lack

of steroid in the last one month before entry birth control when appropriate

relapse defined as occurrence or reappearance of a new or more symptoms accompanied

by a change od at least 05 EDSS or one or more grade in at least two functional systems

Exclusionprevious use of cladribine oral myelin or total irradiation immunoglobulins

instable significant clinical conditions gadolinium sensitivity

Interventions Enteric -coated tablets containing 50 or 5 mg of glatiramer acetate or placebo (unspeci-

fied)

Outcomes primary outcome the total number of confirmed relapses observed during the study

period

Secondary

clinical number of relapses treated with corticosteroids are under curve of the EDSS

change

MRI (cohort of 486 patients) number and volume of GAD+lesionsnumber of new T2

lesions

Tertiary outcomes EDSS changes proportion of patients relapse free time to second

relapse number of relapse requiring hospitalisation

MRI number and volume of hypointense lesions

Notes Jadad score =5

A descriptive analysis of the study was made because the published data were not con-

sistent with the required parameters of treatment effect (see 15)

Risk of bias


Adequate sequence generation Yes Quoteldquo Randomization list stratified by

centers was central computer generated by

Teva rdquo pg 214


Blinding

All outcomes

Yes Quote ldquo all personnel involved in the study

were unaware of the treatment allocation




Filippi 2006 (Continued)





All outcomes

Yes Only 7 withdrawal for each group

Withdrawals 37 (50 mg) 41 (5 mg) 42

(placebo)

Free of selective reporting Yes Some secondary and tertiary clinical out-

comes data were un showed

Free of other bias No Standard Deviation of results was not re-

ported

Johnson 1995


Central allocation at trial office


Blindness Double-blind

Treatment period 24 months (+ 11 in the extension phase)

Follow-up period 24 months (+ 11 in the extension phase)

Withdrawals GA = 19 (3 pregnancy 1 progression 2 serious adverse event 3 transient

self-limited systemic reactions 10 not specified) 15

placebo = 17 (2 poor protocol compliance 1transient self-limited reaction 14 not spec-

ified) Nine additional patients (GA= 2 placebo= 7) dropped out during the extension

study 135


USA 11 centres

Sex both

Age 18-45

Included (88) criteria clinically definite MS or laboratory-supported definite with RR

course ambulatory with an EDSS of 00 to 50 a history of at least 2 clearly defined

and documented relapses in the 2 years prior to entry onset of the first relapse at least

1 year before randomisation neurologically stable and free from corticosteroid therapy

for at least 30 days prior to entry

Excluded (12) treatment with GA or previous immunosuppression with cytotoxic

therapy or lymphoid irradiation pregnancy or lactation IDDM positive HIVHTLV-1

serology Lyme disease required use of aspirin or chronic NSAID during trial unwilling

to undergo adequate contraception


73 female






Johnson 1995 (Continued)


Placebo not specified


Co-interventions standard steroid protocol during exacerbations conventional medica-

tion received at the time of randomisation

Outcomes Primary outcome mean number of relapses Secondary endpoints proportion of re-

lapse-free patients time to first relapse after randomisation proportion of patients with

sustained disease progression and mean change in EDSS score Relapse defined as ap-

pearance or reappearance of one or more neurologic abnormalities persisting for at least

48 hours and immediately preceded by a relatively stable or improving neurologic state

of at least 30 days A relapse was confirmed when patientrsquos symptoms were accompa-

nied by objective changes in neurologic examination consistent with at least 05 EDSS

increase 2 points on one of the seven functional systems or 1 point on two or more of

the functional systems



Authors carried out both an intention-to treat and an on-treatment analyses claiming

that results are comparable

This study has been extended for an additional 11 months until all 203 remaining

patients (ie excluding 36 already withdrawn and 12 who refused to participate in

the extension trial) have received 24 months of treatment Clinical status of these 12

withdrawn between the early and the extension phase are no different from the remaining

cohort Extension study was carried out double blind After this period a cohort of

patients participate in the open label phase until 10 years (see text)

Risk of bias


Adequate sequence generation Yes Quote ldquo a centralized randomization

scheme was used rdquo pg 1270

Allocation concealment Yes

Blinding

All outcomes

Yes quote ldquonurse coordinator and neurologists

were blinded rdquo

pg 1270


All outcomes

Yes Withdrawals GA = 19 (3 pregnancy 1 pro-

gression 2 serious adverse event 3 tran-

sient self-limited systemic reactions 10 not

specified) 15

placebo = 17 (2 poor protocol compli-

ance 1transient self-limited reaction 14

not specified) Nine additional patients

(GA= 2 placebo= 7) dropped out during




the extension study 135

They were included in the statistical anal-

yses



Wolinsky 2007

Methods Randomised Placebo- controlled study

Allocation 21

Multinational multicenter

Blindness double-blind

Treatment duration 3 years

Follow-up duration and blinded extension until the completion of the last included

patient (4 years and 5 months)


interim treatment analysis 2 planned

Assessment treating and blind examining neurologist

Discontinuation 197 patients 21

Lost at follow-up GA 18 (29) 9 Plac 7 (22)

Drop out GA 170 (27) Plac 91 (29)

Participants 943 randomized 627 GA and 316 Placebo

eligibility criteria

Age 30-65

EDSS 30-65

Progressive course from at least 6 months with objective evidence of functional piramidal

dysfunction ( gt 2) and of disseminated involvement of the CNS by clinical MRI or

evoked potentials and CSF abnormalities

Excluded patients with history of any relapse spondylitic myelopathy and other progres-

sive neurological disorders previous immunosuppressive or immunomodulating therapy

within 3 months pregnancy or lactation lymphopenia and allergy to gadolinium

Interventions Therapy GA 20 mg



Co-interventions with corticosteroid discouraged and limited to iv methylprednisolone

for 5 consecutive days

concomitant treatment with immunosuppressive immunomodulating not allowed

Outcomes Primary outcome proportion of patients with sustained at 3 months disease progression

of at least 1 EDSS (basal score 3 - 5) and 05 (basal score 55-65 )

Secondary outcome

Clinical proportion of progression free patients mean change in EDSS score and

mean MSFC scores

MRI change in cerebral flair lesion volume and number number of Gd -enhancing



Wolinsky 2007 (Continued)

lesions volume of black holes as percentage of FLAIR -defined lesion burden and brain

volume loss

Safety adverse event reporting vital signs ECG and laboratory tests

Notes Data safety monitoring board recommended early study termination ( November 2002

3 years after study onset at July 1999) for futility analysis

Posthoc sensitivity analysis was made

Risk of bias


Adequate sequence generation Unclear Quote ldquorandomizedrdquo pg 15

Allocation concealment Unclear see above

Blinding

All outcomes

Unclear Quote pg 16 ldquoAll patients were attended by

a treating neurologist and examining neu-

rologist who were blinding to treatmentrdquo

No further information were given


All outcomes

No Discontinuation 197 patients 21

Lost at follow-up GA 18 (29) 9 Plac 7

(22)

Drop out GA 170 (27) Plac 91 (29)

Free of selective reporting No results are mentioned but not reported ad-

equated

Free of other bias No Data safety monitoring board recom-

mended early study termination (Novem-

ber 2002 3 years after study onset at July

1999) for futility analysis

GA prepared and supplied by Weinzmann Institute of Science and Bio-Yeda Co (Rehovot Israel) GA prepared and supplied by

TEVA Pharmaceutical Industries Ltd Petah Tiqva Israel)

Characteristics of excluded studies [ordered by study ID]



Study Reason for exclusion

Abramsky 1977 Uncontrolled open-label study

Achiron 2005 Safety (Cancer risk) during GA and IFN therapy

Arnold 2008 Randomized comparative trial in RR MS evaluating GA (20 mgd SC) after the last of 3 monthly mitox-

antrone infusions (36 mgm2 total) or GA alone

Ball 2008 Safety (AE Panniculitis)

Baumhefner 1988 Uncontrolled open-label study

Blanco 2006 Observational clinic-immunological study

Boiko 2006 Longitudinal not randomized study not controlled

Bornstein 1982 Uncontrolled open-label study

Bosca 2006 Safety (Necrotising cutaneous) in a patients treated with GA

Brenner 2001 Experimental series Only laboratory measures of treatment effect are reported

Brochet 2008 Re-analysis of long term open label study until 10 years of Johnsonrsquos RCT 1995

Cadavid 2009 Randomized CTof IFNbeta-1b versus GA on MRI -clinical activity in RR MS

Caon 2006 Clinical not randomized not controlled study (GA after IFN therapy)

Capobianco 2008 Clinical not randomized study

Carra 2008 Prospective longitudinal observational comparative not randomized study

Castelli-Haley 2008 Comparative (GA vs IFN 1a) not randomized study

Charach 2008 Safety (AE Crohnrsquos disease) in a patient with multiple sclerosis treated with copaxone

Chen 2001 Experimental series from subset of the US copaxone phase III core study Only laboratory measures of

treatment effect are reported

Cicek 2008 Safety (AE urticarial vasculitis) in a patient GA treated

Cohen 1995 Report from a subset of the US copaxone phase III core study where only MRI parameters are reported

Cohen 2007 Randomized double-blind dose-comparison study of glatiramer acetate in relapsing-remitting MS

Constantinescu 2000 Open-label controlled trial Only laboratory measures of treatment effect are reported



(Continued)

Daugherty 2005 Clinical not randomized study of patients treated with immunomodulating agents

De Seze 2000 Report from a phase I uncontrolled trial of oral copaxone

De Stefano 2008 Observational not controlled study evaluating the efficacy of GA and Methylprednisolone followed by GA

alone

De Stefano 2009 Open label studies evaluating protiramer a high molecular weight synthetic copolymer mixture in RR MS

Debouverie 2007 Observational not controlled study

Deen 2008 Clinical study of patients treated with immunomodulating agents

Duda 2000 Uncontrolled study

Farina 2001 Non-randomised open-label controlled trial Only laboratory measures of treatment effect are reported

Feigin 2005 Safety (AE cancer ) in MS patients treated with GA

Fiore 2005 Observational v study on GA focused on side effects

Flechter 2002a Open label trial comparing two Copaxone administration schedules and interferon-beta1b

Flechter 2002b Report from an open-label uncontrolled trial

Ford 2006 Prospective open-label study extension at 10 years of Johnson 1995 trial

Fusco 2001 Non-randomised study evaluating copaxone in relapsing-remitting MS

Gajofatto 2009 Observational open label study evaluating switching first-line disease-modifying therapy after failure

Garcia-Barragan 2009 Observational clinic- immunological study evaluating immunomodulating agents

Ghezzi b 2005 Observational study evaluating immunomodulating agents

Ghezzi 2005 Observational study evaluating immunomodulating agents

Goodman 2009 RCT evaluating the efficacy of GA and natalizumab versus GA alone

Haas 2005 Retrospective and open-label clinical study of first line immunomodulating therapies

Harde 2007 Safety (AE Embolia cutis medicamentosa ) in a MS patient treated with GA

Johnson 2000 Extension study open label of Johnson 1995 at 6 years

Johnson 2003 Extension at 6 years open label of Johnson 1995 study



(Continued)

Johnson 2005 Extension of Johnson rsquos study 1995 Patients treated with GA after 36 months of RCT study (open label

extension phase at 8 years)

Jolly 2008 RCT crossover open -label on Impact of warm compresses on local injection-site reactions

Karandikar 2002 Experimental series Only laboratory measures of treatment effect are reported

Khan 2001 Non-randomised open-label study comparing interferon-beta1a interferon-beta1b and copaxone

Khan 2005 Controlled not randomized study evaluating MRI (spectroscopy) outcome

khan 2008 Observational study evaluating MRI outcome

Kott 1997 Open-label uncontrolled study of copaxone in MS patients with or without optic neuritis

La Mantia 2006 Comparative study evaluating headache in MS patients treated with IFN vs Ga or azathioprine

Lage 2006 Observational study (outcome time missed from work)

Le Page 2008 Observational study in patients treated with mitoxantrone(induction) followed by immunomodulating

agents

Madray 2008 Safety (AE Lymphoma ) in 1 patients treated with GA

Mancardi 1998 Report from an open study on copaxone where pretreatment data served as controls of treatment effect

Only MRI parameters are reported

Meiner 1997 Phase III uncontrolled open-label trial

Mesaros 2008 MR study of placebo group of Filippi rsquotrial

Mikol 2008 RCT open label comparing IFN1 a vs GA in RR

Milanese 2005 Observational post-marketing study in Italy

Miller 1998 Report from a non-randomised open study on copaxone where pretreatment data served as controls of

treatment effect

Miller 2006 Observational not controlled study in Buffalo

Miller 2008 Observational not controlled open label study GA (follow-up 22 years)

Neumann 2007 Safety ( AE hepatitis) in a GA treated MS patient

Nolden 2005 Safety ( AE depression) in GA treated MS patients

Ollendorf 2008 Observational not controlled study on co-prescription in GA



(Continued)

Orlova 2005 Observational not controlled clinical-immunological study

Patten 2008 Safety ( AE depression) in GA treated MS patients

Poumlllmann 2006 Safety (AE headache) in GA treated MS patients

Qin 2000 Experimental series comparing the effect of copaxone on MS patients and healthy volunteers on laboratory

immunological measures of treatment effect

Ramtahal 2006 Observational study not controlled after mitoxantrone therapy

Rauschka 2005 safety (AE anaphylaxis) in a patient GA treated

Rio 2005 observational study evaluating reasons for treatment discontinuation

Rovaris 2005 Review of MRI effects of GA

Rovaris 2007 Extension of Comirsquos study 2001 at 58 years Open label phase after RCT

Schwid 2007 Extensions study of Johnson 1995open label follow-up at 10 year of GA treatment (cognitive function)

Shipova 2009 MRI (Spinal cord)observational study during immunomodulatory treatment (GA IFN)

Sidoti 2007 Case report (GA in psychosis)

Sindic 2005 Observational not controlled study in Belgium

Soares 2006 Safety (Adverse events -panniculitis-) in patients GA-treated

Sormani 2002 Re-analysis of the European-Canadian MRI study aimed at validating MRI endpoints as surrogates of clinical

outcomes in MS patients

Sormani 2005 Additional trial analysis (Comi 2001) focused on MRI measures

Sormani 2007 Additional trial analysis (Comi 2001) focused on MRIclinical measures

Then Bergh F 2006 Safety (Adverse events -leukemia -) in a patient GA-treated

Thouvenot 2007 Safety (Adverse event -erithema nodoso -) in a patient GA-treated

Tilbery 2006 Post marketing study at a Barzilian center

Torkildsen 2007 Observational not controlled study in Norway

Tremlett 2007 Safety study

Twork 2007 Post marketing study on tolerability of GA and IFN treatment in MS patients



(Continued)

Valenzuela 2007 observational not controlled clinic- immunological study on GA therapy in MS

Vallittu 2005 Observational not controlled study of GA efficacy in IFN intolerant MS patients

Vollmer 2008 RCT comparative evaluating GA treated MS patients after or without previous induction with mitoxantrone

Weder 2005 observational not randomised clinical immunological study on GA treated vs untreated RR MS

Weinstein 1999 RCT evaluating cognitive function In GA vs placebo Baseline test performance was normal and improved

over time in both treatment groups

Wolinsky 2001 Extension study of the US copaxone phase III core study evaluating clinical- MRI parameters

Wynn 2008 Multicenter randomized double-blind study comparing the safety and efficacy of two GA doses 20mg

day the currently approved dose versus 40 mgday

Ytterberg 2007 observational comparative study in patients treated with copaxone and IFNbeta versus copaxone alone

Zavalishin 2005 Open label observational study in Russia

Zavalishin 2006 Comparative not randomized study evaluating copaxone versus Rebif 22 Russian

Ziemssen 2008 uncontrolled open-label study

Zwibel 2006 open-label not randomized study

Characteristics of ongoing studies [ordered by study ID]

Comi 2008

Trial name or title PreCISe

Methods Randomised prospective double-blind placebo controlled multinational trial

Participants 481 patients presenting with a clinically isolated syndrome (CIS) suggestive of MS

Interventions GA sc 20 mg qd or placebo for three years

Outcomes The primary outcome was time to clinically definite MS based on a second clinical attack

Starting date January 2004

Contact information Prof G Comi Institute of Experimental Neurology Department of Neurology University Vita-Salute

Scientific Institute S Raffaele Milan Italy




Notes



D A T A A N D A N A L Y S E S

Comparison 1 Glatiramer acetate versus placebo in relapsing remitting patient

Outcome or subgroup titleNo of

studies

No of

participants Statistical method Effect size

1 Patients who progressed 2 Risk Ratio (M-H Fixed 95 CI) Subtotals only

11 at 2 years 2 299 Risk Ratio (M-H Fixed 95 CI) 075 [051 112]

12 at 35 months 1 203 Risk Ratio (M-H Fixed 95 CI) 081 [050 129]

2 Change in disability score at the

end of follow-up

2 Mean Difference (IV Fixed 95 CI) Subtotals only

21 at 2 years of follow-up 2 301 Mean Difference (IV Fixed 95 CI) -033 [-058 -008]

22 at 35 months of follow-up 1 203 Mean Difference (IV Fixed 95 CI) -045 [-077 -013]

3 Patients relapse free 3 Risk Ratio (M-H Fixed 95 CI) Subtotals only

31 at 1 year 2 287 Risk Ratio (M-H Fixed 95 CI) 128 [102 162]



4 Mean number of relapses 3 Mean Difference (IV Fixed 95 CI) Subtotals only

41 within 1 year of follow-up 2 287 Mean Difference (IV Fixed 95 CI) -035 [-053 -016]



Comparison 2 Glatiramer acetate versus placebo secondary outcomes


studies

No of


1 Number of hospitalisations at

the end of follow-up

2 489 Risk Ratio (M-H Fixed 95 CI) 060 [040 091]

2 Number of steroid courses at the

end of follow-up


Comparison 3 Glatiramer acetate versus placebo adverse effects


studies

No of


1 Localised to the injection site 4 Risk Ratio (M-H Fixed 95 CI) Subtotals only

11 Itching 3 1244 Risk Ratio (M-H Fixed 95 CI) 828 [499 1373]

12 Swelling 3 1244 Risk Ratio (M-H Fixed 95 CI) 401 [267 603]

13 Redness 3 1244 Risk Ratio (M-H Fixed 95 CI) 458 [358 588]

14 Pain 4 1483 Risk Ratio (M-H Fixed 95 CI) 246 [205 295]

2 Systemic adverse effects 4 Risk Ratio (M-H Fixed 95 CI) Subtotals only

21 Patterned reaction 3 540 Risk Ratio (M-H Fixed 95 CI) 327 [207 516]



22 Dizziness 1 50 Risk Ratio (M-H Fixed 95 CI) 07 [032 154]

23 Palpitations 2 301 Risk Ratio (M-H Fixed 95 CI) 358 [116 1106]

24 Headache 2 991 Risk Ratio (M-H Fixed 95 CI) 088 [068 114]

25 Dyspnea 1 250 Risk Ratio (M-H Fixed 95 CI) 80 [188 3407]

26 Anxiety 1 250 Risk Ratio (M-H Fixed 95 CI) 10 [014 699]

27 Faintness 1 48 Risk Ratio (M-H Fixed 95 CI) 153 [041 571]

28 Drowsiness 1 48 Risk Ratio (M-H Fixed 95 CI) 077 [027 218]

29 Rash 1 48 Risk Ratio (M-H Fixed 95 CI) 033 [012 090]

210 Cramps 1 48 Risk Ratio (M-H Fixed 95 CI) 138 [025 753]

211 Joint pain 1 48 Risk Ratio (M-H Fixed 95 CI) 102 [051 206]

212 Appetite loss 1 48 Risk Ratio (M-H Fixed 95 CI) 077 [027 218]

213 Constipation 1 48 Risk Ratio (M-H Fixed 95 CI) 131 [060 287]

214 Abdominal discomfort 2 991 Risk Ratio (M-H Fixed 95 CI) 131 [078 220]

215 Nausea 1 48 Risk Ratio (M-H Fixed 95 CI) 138 [045 428]

216 Vomiting 1 48 Risk Ratio (M-H Fixed 95 CI) 092 [006 1387]

3 Adverse effects causing treatment

withdrawal


Comparison 4 Glatiramer acetate versus placebo in progressive patients


studies

No of


1 progression of disability 2 Odds Ratio (M-H Fixed 95 CI) Subtotals only

11 at 1 year 1 726 Odds Ratio (M-H Fixed 95 CI) 088 [060 127]

12 at 2 years 2 662 Odds Ratio (M-H Fixed 95 CI) 084 [060 119]


A D D I T I O N A L T A B L E S

Table 1 Jadad score

Study Bornstein 87 Johnson Comi Filippi Bornstein 91 Wolinsky

Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1



Table 1 Jadad score (Continued)

Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3

Table 2 Included studies RR patients Clinical characteristics

Study Bornstein 1987 Johnson 1995 Comi 2001 Filippi 2006

Alloca-

tion (GA

Placebo)

GA Placebo GA placebo GA Placebo GA 50 mg GA 5 mg placebo

Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15

Table 3 Included studies progressive patients Clinical characteristics

Study Wolinsky2007 Bornstein 1991

Allocation(GAPlacebo) GA Placebo GA placebo

Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423

Disease duration 11+73 107+77 not reported not reported



Table 3 Included studies progressive patients Clinical characteristics (Continued)

EDSS 49+12 49+12 57 55

Type of progression PP PP PR PR

F E E D B A C K

Therapy with glatiramer acetate for MS

Summary

From Dr Douglas L A (November 2004)

I believe that the review of Copaxone therapy by Munari et al may have been excessively negative and could benefit from revision and

updating taking into account in particular the report of Boneschi et al (2003) which was published shortly after the cut-off date for

the original review and included more complete data from the relevant clinical trials

I am a physician involved with clinical research in MS and have received financial support for research consultancy and educational

activities from multiple pharmaceutical companies including TEVA

(Dr Munari may wish to consider revising his conflict of interest declaration as well not only to reflect recent pharmaceutical industry

sponsored activities but also to declare a potential bias due to his job as a hospital administrator)

Reply

Authorrsquos reply (February 2005)

The Cochrane review has been updated taking into account the re-analysis of RRMS glatiramer trials published by Boneschi et al as

Dr Arnold suggested

Contributors

Dr Douglas L Arnold Canada

W H A T rsquo S N E W

Last assessed as up-to-date 14 September 2009

Date Event Description

7 October 2009 New citation required but conclusions have not changed The review title has been modified from ldquoTherapy with

Glatiramer acetate for multiple sclerosisrdquo to ldquoGlatiramer

acetate for multiple sclerosisrdquo

Dr L La Mantia joined the review team She updated

the review and integrated new data and co-authors com-

ments

The outcome measures did not change however a better



(Continued)

description of the outcomes has been performed Fur-

thermore the type of analysis changed substantially ac-

cording to the grouping of included patients

26 March 2009 New search has been performed searches were re-run

H I S T O R Y

Protocol first published Issue 3 2001

Review first published Issue 1 2004


28 August 2008 Amended Converted to new review format

23 February 2005 New search has been performed Searches updated to 31 December 2004

19 February 2005 Feedback has been incorporated Feedback and reply added

C O N T R I B U T I O N S O F A U T H O R S

RL LM LLM carried out double-checked data extraction LM wrote the protocol and text of the review integrating AB and RL

comments and remarks LLM was charged for updating the review and wrote the final version integrating new data and co-authors

comments

L Munari who wrote the first published version of this review Neurologist and Statistician has been Chief Medical Officer at the

Azienda Ospedaliera Niguarda Carsquo Granda Milan Italy

R Lovati is an independent practicing physician participating in the activities of the Neuroepidemiology Unit and MS Cochrane

Review Group at the Ist Nazionale Neurologico C Besta Milan Italy Dr Lovati is at present working in Oncology Department of S

Paolo Hospital Milan

LLa Mantia is a senior neurologist involved in MS diagnosis and treatment within the MS center of Neurological Instute C Besta

from many years She participated to many national and international trials and clinical -immunological studies in MS patients



D E C L A R A T I O N S O F I N T E R E S T

L Munari held a number of conferences on its methodology and results Some of these meetings were sponsored by Biogen Idec

Canada

I N D E X T E R M SMedical Subject Headings (MeSH)

Disease Progression Immunosuppressive Agents [lowasttherapeutic use] Multiple Sclerosis Chronic Progressive [lowastdrug therapy] Multiple

Sclerosis Relapsing-Remitting [lowastdrug therapy] Peptides [lowasttherapeutic use] Randomized Controlled Trials as Topic Recurrence

Treatment Outcome

MeSH check words

Humans



T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON

6BACKGROUND

6OBJECTIVES

6METHODS

8RESULTS

Figure 1 11

Figure 2 12

Figure 3 13

Figure 4 14

Figure 5 15

Figure 6 16

Figure 7 17

Figure 8 18

Figure 9 19

Figure 10 19

19DISCUSSION

21AUTHORSrsquo CONCLUSIONS

21ACKNOWLEDGEMENTS

21REFERENCES

29CHARACTERISTICS OF STUDIES

46DATA AND ANALYSES

47ADDITIONAL TABLES

49FEEDBACK

49WHATrsquoS NEW

50HISTORY

50CONTRIBUTIONS OF AUTHORS

50DECLARATIONS OF INTEREST

51INDEX TERMS

iGlatiramer acetate for multiple sclerosis (Review)















A B S T R A C T

Background


No CD004678 DOI 10100214651858CD004678)



Objectives


course

Search methods




Selection criteria






Main results

















No CD004678 DOI 10100214651858CD004678)















Settings



(95 CI)

No of Participants

(studies)


(GRADE)

Comments




remitting patient


- at 2 years


(051 to 112)

299

(2)282 per 1000 212 per 1000

(144 to 316)


362 per 1000 272 per 1000

(185 to 405)


- at 35 months


(05 to 129)

203

(1)

See comment

288 per 1000 233 per 1000

(144 to 372)


289 per 1000 234 per 1000

(144 to 373)

3G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td




follow-up





tion groups was

033 lower

(058 to 008 lower)

301

(2)




follow-up





vention groups was

045 lower

(077 to 013 lower)

203

(1)

See comment

Mean number of re-


follow-up




vention groups was

035 lower

(053 to 016 lower)

287

(2)

Mean number of re-


low-up




tion groups was

051 lower

(081 to 022 lower)

298

(2)




4G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td






5G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

B A C K G R O U N D



























sive information

O B J E C T I V E S













gression




M E T H O D S


Types of studies























in both arms




up period






















the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51

Le 008 published data only















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans
















A B S T R A C T

Background


No CD004678 DOI 10100214651858CD004678)



Objectives


course

Search methods




Selection criteria






Main results

















No CD004678 DOI 10100214651858CD004678)















Settings



(95 CI)

No of Participants

(studies)


(GRADE)

Comments




remitting patient


- at 2 years


(051 to 112)

299

(2)282 per 1000 212 per 1000

(144 to 316)


362 per 1000 272 per 1000

(185 to 405)


- at 35 months


(05 to 129)

203

(1)

See comment

288 per 1000 233 per 1000

(144 to 372)


289 per 1000 234 per 1000

(144 to 373)

3G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td




follow-up





tion groups was

033 lower

(058 to 008 lower)

301

(2)




follow-up





vention groups was

045 lower

(077 to 013 lower)

203

(1)

See comment

Mean number of re-


follow-up




vention groups was

035 lower

(053 to 016 lower)

287

(2)

Mean number of re-


low-up




tion groups was

051 lower

(081 to 022 lower)

298

(2)




4G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td






5G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

B A C K G R O U N D



























sive information

O B J E C T I V E S













gression




M E T H O D S


Types of studies























in both arms




up period






















the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans













No CD004678 DOI 10100214651858CD004678)















Settings



(95 CI)

No of Participants

(studies)


(GRADE)

Comments




remitting patient


- at 2 years


(051 to 112)

299

(2)282 per 1000 212 per 1000

(144 to 316)


362 per 1000 272 per 1000

(185 to 405)


- at 35 months


(05 to 129)

203

(1)

See comment

288 per 1000 233 per 1000

(144 to 372)


289 per 1000 234 per 1000

(144 to 373)

3G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td




follow-up





tion groups was

033 lower

(058 to 008 lower)

301

(2)




follow-up





vention groups was

045 lower

(077 to 013 lower)

203

(1)

See comment

Mean number of re-


follow-up




vention groups was

035 lower

(053 to 016 lower)

287

(2)

Mean number of re-


low-up




tion groups was

051 lower

(081 to 022 lower)

298

(2)




4G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td






5G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

B A C K G R O U N D



























sive information

O B J E C T I V E S













gression




M E T H O D S


Types of studies























in both arms




up period






















the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans






Settings



(95 CI)

No of Participants

(studies)


(GRADE)

Comments




remitting patient


- at 2 years


(051 to 112)

299

(2)282 per 1000 212 per 1000

(144 to 316)


362 per 1000 272 per 1000

(185 to 405)


- at 35 months


(05 to 129)

203

(1)

See comment

288 per 1000 233 per 1000

(144 to 372)


289 per 1000 234 per 1000

(144 to 373)

3G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td




follow-up





tion groups was

033 lower

(058 to 008 lower)

301

(2)




follow-up





vention groups was

045 lower

(077 to 013 lower)

203

(1)

See comment

Mean number of re-


follow-up




vention groups was

035 lower

(053 to 016 lower)

287

(2)

Mean number of re-


low-up




tion groups was

051 lower

(081 to 022 lower)

298

(2)




4G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td






5G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

B A C K G R O U N D



























sive information

O B J E C T I V E S













gression




M E T H O D S


Types of studies























in both arms




up period






















the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans






follow-up





tion groups was

033 lower

(058 to 008 lower)

301

(2)




follow-up





vention groups was

045 lower

(077 to 013 lower)

203

(1)

See comment

Mean number of re-


follow-up




vention groups was

035 lower

(053 to 016 lower)

287

(2)

Mean number of re-


low-up




tion groups was

051 lower

(081 to 022 lower)

298

(2)




4G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td






5G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

B A C K G R O U N D



























sive information

O B J E C T I V E S













gression




M E T H O D S


Types of studies























in both arms




up period






















the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans








5G

latira

mer

aceta

tefo

rm

ultip

lesc

lero

sis(R

evie

w)

Co

pyrig

ht

copy2010

Th

eC

och

ran

eC

olla

bo

ratio

nP

ub

lished

by

Joh

nW

iley

ampS

on

sL

td

B A C K G R O U N D



























sive information

O B J E C T I V E S













gression




M E T H O D S


Types of studies























in both arms




up period






















the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



B A C K G R O U N D



























sive information

O B J E C T I V E S













gression




M E T H O D S


Types of studies























in both arms




up period






















the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans










the trial












Electronic searches



March 2009)



(Appendix 1)


(Appendix 2)


(Appendix 3)





Europe and America


GA





DATA EXTRACTION




























































needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans






needed

R E S U L T S































































daily in RR MS


RRMS




























































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans































trial














study exit

































outcome




CLINICAL OUTCOMES






















































sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans






























sures















not be calculated




SECONDARY ENDPOINTS








MRI PARAMETERS

































RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans









RANDOMISATION









BLINDING
































































VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans















VALIDITY SCORE











sclerosis

PRIMARY OUTCOMES














(95 CI [050 to 129] (Figure 3)











(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans









(WMD= -033 95 CI [-058 to -008] p = 0009) and at 35


4)




















ative risk = 064 (95 CI [031 to 134] p= 02)



























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans


























predefined protocol







points

Progressive MS





















measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans













measure

ADVERSE EFFECTS



















patients





risk = 246 [205 295] p lt000001])



















SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans










SECONDARY OUTCOMES






p = 002]) ( Figure 9)















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51

Le 08 published data only















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans















D I S C U S S I O N















(McFarland 2008)



























































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans

















































points













covariates













































system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans








system







ramer acetate
























progression
















the paper

R E F E R E N C E S






























Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans





Suppl 2A289




200157(4)731ndash3


























20082551378ndash83















19961(6)325ndash6













701ndash8










20039585ndash91





242S38






















Markowitzhtm 2000




































407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans
























407ndash10




69ndash72









406270ndash5











101ndash10









1370ndash1






115(1-2)152ndash60






























25658ndash73

























200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans







200768 939ndash44










371ndash5












44ndash50













141266ndash74










967ndash76





Brain 2001124(4)705ndash19


















200225(1)11ndash5






2)51ndash5






309ndash20












































1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans




















1122












20039585ndash91
















(5)641ndash9








349ndash53












200818314ndash9










4585)476ndash80





Mass) 200627(2)143ndash51
















199850(4)1127ndash33












20082551378ndash83










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans










20087903ndash14






































281ndash90






















2000108(1-2)201ndash6








































786ndash7























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans























447ndash9











116207ndash10






























754ndash62











































































14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans




























14 issue suppl 1S38



S9ndash11


Boneschi 2003






Brocke 1996





Caramanos 2005



74ndash5

Comi 2005



20054(2)75ndash6

Drago 1999





Ebers 2008




Edgar 2004




(1)58ndash63

Ge 2000





Higgins 2008





Hwang 2001




Jadad 1996




Kurtzke 1983




Lefebvre 2008






handbookorg

Mancardi 2000




(3)220ndash1

McFarland 2008



826ndash28

Munari 2004a



20043(11)641



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



Munari 2005




Poser 1983





Prentice 1989



431ndash40

RevMan 2008




Rio 2002






Rio 2006





Teitelbaum 1997




Wisniewski 1977




Yusuf 1985




27(5)335ndash71


Munari 2004









Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans





Bornstein 1987



either patient










Israel 1 centre

Sex both

Age 20-35







58 female











to progression












Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans





Risk of bias






Blinding

All outcomes










All outcomes


data (2 placebo)









Bornstein 1991


Two center


Double blind











20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans




20-60 years of age

2-65 EDSS










Risk of bias




greaterrdquo

pg 534




Blinding

All outcomes





fectsrdquo


All outcomes







Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



Comi 2001


Double -blind

placebo controlled




Drop-outs







Sex both

Age 18-50



























weighted images





















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans

















Risk of bias





Blinding

All outcomes










All outcomes














Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



Filippi 2006









(5 mg) 548 placebo









fied)


period

Secondary


change


lesions







Risk of bias




Teva rdquo pg 214


Blinding

All outcomes











All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans








All outcomes



(placebo)




ported

Johnson 1995











study 135


USA 11 centres

Sex both

Age 18-45











73 female































Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans




























Risk of bias





Blinding

All outcomes


were blinded rdquo

pg 1270


All outcomes




specified) 15










yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans






yses



Wolinsky 2007


Allocation 21











Drop out GA 170 (27) Plac 91 (29)



Age 30-65

EDSS 30-65















Secondary outcome


mean MSFC scores






volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans





volume loss





Risk of bias




Blinding

All outcomes






All outcomes



(22)

Drop out GA 170 (27) Plac 91 (29)


equated





































(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans






























(Continued)




alone























(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



(Continued)












agents









treatment effect








(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



(Continued)




























(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



(Continued)
















Comi 2008












Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans




Notes






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans






studies

No of






end of follow-up














studies

No of






end of follow-up




studies

No of



























withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



















withdrawal




studies

No of







Table 1 Jadad score


Was the study

described as ran-

domized

1 1 1 1 1 1

Was the study

described as dou-

ble blind

1 1 1 1 1 1

Was there a de-

scription of

withdrawals and

dropouts

1 1 1 1 1 1




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans




Appropriate ran-

domization +-

-1 1 1 1 1 -1

Appropriate

Blinding+-

-1 1 1 1 1 -1

Score 3 5 5 5 5 3



Alloca-

tion (GA

Placebo)


Ndeg 25 25 125 126 119 120 543 553 548

Sex (

Males)

44 40 296 238 not

reported

not

reported

25 25 27

Mean age 30 311 not

reported

not

reported

341+74 34+75 368-73 361-8 366-77

Dis-

ease dura-

tion(years)

49 61 73+49 66+51 79+55 83+55 79+61 74-62 77-62

EDSS 29 32 28+12 24+13 23+11 24+12 23-11- 22-11 23-12

Pre 1 year

RF

19 19 145 145 14 125 15 15 15




Ndeg 627 316 51 55

Sex ( Females) 472 519 549 545

Mean age 504+84 502+81 416 423





EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans




EDSS 49+12 49+12 57 55


F E E D B A C K


Summary









Reply



Dr Arnold suggested

Contributors










ments




(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans



(Continued)





H I S T O R Y










comments












Canada




Treatment Outcome

MeSH check words

Humans





Canada




Treatment Outcome

MeSH check words

Humans



Cochrane Database of Systematic Reviews (Reviews) || Glatiramer acetate for multiple sclerosis

Documents

Transcript of Cochrane Database of Systematic Reviews (Reviews) || Glatiramer acetate for multiple sclerosis