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TESPI (Thrombolysis in Elderly Stroke Patients in Italy):a randomized controlled trial of alteplase (rt-PA) versusstandard treatment in acute ischaemic stroke inpatients aged more than 80 years where thrombolysis isinitiated within three hours after stroke onset

Svetlana Lorenzano*, and Danilo Toni for the TESPI trial Investigators

Rationale Intravenous (i.v.) thrombolysis with recombinant

tissue-Plasminogen Activator (rt-PA) (alteplase) within three

hours from symptom onset is the only approved treatment

of pharmacological revascularization in acute ischaemic

stroke. However, the current license limits the use of rt-PA to

patients aged80 years due to the lack of evidence of safety

and efficacy of this treatment in the elderly from rand-

omized clinical trials. This article describes the design of the

Thrombolysis in Elderly Stroke Patients in Italy (TESPI) trial

planned to fill the lack of controlled data on i.v. thrombolysis

in this age category of stroke patients.

Aims To collect efficacy and safety data on i.v. alteplase

(rt-PA) in patients aged more than 80 years, to demonstrate

that the treatment of these patients within three hours ofsymptoms onset of an acute ischaemic stroke with i.v. rt-PA,

compared to patients receiving standard treatment (accord-

ing to the national guidelines), will result in an improved

clinical outcome with a favourable benefit/risk ratio.

Design TESPI is a prospective, multicenter, national, open-

label, controlled (non-treated group as control), randomized,

parallel group trial with blinded evaluation of outcome in

patients older than 80 years treated with i.v. rt-PA within

three hours after ischaemic stroke onset. The randomization

procedure assigns patients to the treatment group with

IV alteplase (0·9 mg/kg of body weight) or to standard

treatment group with a 1 : 1 basis. A three-month follow-up,

when applicable, is performed by a blind assessor. Sixhundred patients will be enrolled (300 patients per arm) The

study period has been planned to be of three years.

Study Outcomes The primary efficacy end-point is the dis-

ability at day 90, dichotomized as a favourable outcome

(modified Rankin Scale 0–2) or unfavourable outcome (modi-

fied Rankin Scale 3–6). The main primary safety end-point

is symptomatic intracerebral haemorrhage defined as any

hemorrhage at the 22–36 h post-treatment scan combined

with neurological deterioration leading to an increase of

one or more points at the National Institutes of Health

Stroke Scale. The TESPI trial, with the protocol number

FARM65KNKY, is registered in the European Union Drug

Regulating Authorities Clinical Trials database with the

number 2007-006177-88 and in the Stroke Trials Registry of

the Washington University Internet Stroke Center.

Key words: elderly, intravenous thrombolysis, ischaemic

stroke, rt-PA

Introduction

Thrombolysis with intravenous (i.v.) rt-PA administered

within three hours of symptom onset is the only proven effec-

tive pharmacological reperfusion treatment for acute ischae-

mic stroke. The current license defined strict eligibility criteria

which limit the use of rt-PA to patients aged 80 years. This is

properly due to the lack of clear evidence of safety and efficacy

of this treatment in the elderly as most randomized clinical

trials (RCTs) on thrombolysis in acute ischaemic stroke arbi-

trarily excluded or underrepresented patients over 80 years,

having frequently empirically fixed age limit of 80 years. The

likely reasons for this exclusion are several: the highest preva-

lence in the elderly patients of comorbidities with relative

contraindications to thrombolysis, their presumed poorer

outcome, and major risk of symptomatic intracerebral haem-

orrhage (SICH) occurrence that could outweigh the benefits

Correspondence: Svetlana Lorenzano*, Unità di Trattamento

Neurovascolare, Department of Neurological Sciences, Policlinico

Umberto I Sapienza University, Viale del Policlinico 155, 00161 Rome,

Italy.

E-mail: [email protected]

Conflict of interest: None declared.

Funding: TESPI is a non-profit study and it was approved and funded by

AIFA – Agenzia Italiana del Farmaco (Italian Medicines Agency, for the

Drug approval and vigilance), with the protocol number FARM65KNKY.

DOI: 10.1111/j.1747-4949.2011.00747.x

Protocols

© 2012 The Authors.

International Journal of Stroke © 2012 World Stroke Organization250 Vol 7, April 2012, 250–257


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of the therapy. But the incidence of stroke increases exponen-

tially with age (1). Life expectancy has increased over the past

few decades, and the elderly is the fastest-growing component

of the population worldwide and particularly in the Western

world, and it is expected to further increase in the next few

years. Moreover, age is an important independent predictor

for poor outcome after ischaemic stroke, and among olderpatients, there is a larger proportion discharged to long-term

institutional care, with relevant financial implications on both

health and social care system. For all these reasons, this sub-

group of patients might benefit more from thrombolysis.

Hence, safe implementation of this therapeutic approach even

in the elderly would be an issue of great relevance for which

clearer data are urgently required.

No evidences from RCTs on the efficacy/safety ratio of i.v

thrombolysis in elderly patients are available. The Neurologi-

cal Institute of Neurological Disorders and Stroke (NINDS)

rt-PA Stroke Trial (2) part I had an age limit that was subse-

quently removed in the second part of the study. Since then,

only 42 patients over 80 years of age were included, and nocomparison with younger patients was performed. Analysis of

data from NINDS trial reported the efficacy of rt-PA for acute

ischaemic stroke regardless of the subgroups, and, therefore,

no threshold value for age was identified (3). Most of phase IV

studies on thrombolysis (4) included elderly patients without

an age limit. None, however, stressed specifically the issue of

the thrombolytic treatment in the elderly.

In the last few years, some open studies on i.v. thrombolysis

have addressed the issue of treatment in older patients, with

controversial results (5–13). In a few studies, the older patients

were less likely to recover favourably as compared with the

young patients (6,9–12). In other studies, there was no differ-ence among age groups (5,7,8,13). A recent systematic review

(14) selected some of these cohort studies collecting data on

2244 patients, of whom 477 (ranging from 12 to 31% in the

different studies) were aged 80 years. All these studies have

discrepancies due to the lack of homogenous baseline charac-

teristics between the two age groups, and, furthermore, the

definition of SICH varied among the studies. Therefore, these

studies do not allow to draw any conclusion about the safety

and effectiveness of thrombolysis in the elderly. However, they

seem to suggest that older patients have less likely a favourable

functional outcome (odds ratio (OR) 0·53; 95% confidence

interval (CI) 0·42–0·66, P < 0·001), a higher mortality rate

(OR 3·09; 95% CI 2·37–4·03; P < 0·001), and similar risk of

SICH (OR 1·22, 95% CI 0·77–1·94; P = 0·34) as compared to

younger patients. Data from an Italian cohort of patients con-

firmed these results (13), showing a threefold higher mortality

(34·1% vs. 10·6%, P < 0·001), a non-significantly lower rate of

three-month good outcome (modified Rankin Scale (mRS)

0–2) (44% vs. 58·5%, P = 0·897), and the same rate of SICH

(both non-fatal and fatal) (4·8% vs. 4·8%) in the elderly com-

pared to younger patients. The results would indicate an

overall beneficial effect of t-PA in the elderly group. As base-

line National Institutes of Health Stroke Scale (NIHSS) was

the only statistically significant predictor of both mortality

and poor outcome in the >80 group, the increased mortality

was not explained by a higher rate of SICH. Therefore, it is

likely that alteplase exhibits an age-independent safety profile

despite the alleged higher risk of SICH in the older patients.

It has been suggested that new neuroimaging methods could

be useful for a better and safer selection of the elderly patientslikely to benefit from thrombolysis. In fact, in a recent study,

none of the patients aged over 80 years selected by multipara-

metric magnetic resonance imaging (MRI) for thrombolysis

had a SICH, even if there was no decrease in the in-hospital

mortality or improvement of the clinical outcome compared

with the patients not screened with MRI (12).

All the data discussed above may be useful to understand

more about the issue of thrombolysis in the elderly, but are

neither evidence based nor conclusive. Hence, RCTs are nec-

essary before definitive recommendations on i.v. thrombolysis

in elderly patients can be given. The Third International

Stroke Trial (IST-3) (The Third International Stroke Trial,

unpublished data) is a prospective, randomized, open-label,blinded end-point study of rt-PA in ischaemic stroke patients

aimed at defining the risk/benefit ratio of i.v. thrombolysis

among patients who do not exactly meet the current license

criteria. Hence, the study allows inclusion of patients older

than 80 years, within a six-hour window. However, the six-

hour time window will likely result in fewer patients being

treated within three-hours of symptom onset, while the evi-

dence that the shorter the time to treatment the better the

outcome (15) might be particularly true in elderly patients.

We herein present the design of the trial Thrombolysis in

Elderly Stroke Patients in Italy (TESPI), which we planned to

hopefully fill the lack of controlled data on i.v. thrombolysis inthis age category of patients.

Objectives

The primary objective is to collect efficacy and safety data on

i.v. alteplase (rt-PA) in patients aged more than 80 years, to

demonstrate that the treatment of these patients with IV rt-PA

within three hours of symptoms onset of an acute ischaemic

stroke, compared to patients receiving standard treatment

according to the national guidelines (Stroke Prevention and

Educational Awareness Diffusion, SPREAD) (16), will result in

an improved clinical outcome with a favourable benefit/

risk ratio. The secondary objectives are: to study efficacy meas-ures along 90 days and prognostic factors, and to set, in this

patient population, a neurological severity cut-off point, if

any, below which benefit/risk ratio of thrombolytic therapy is

advantageous.

Methods

Design

The TESPI study is a prospective, multicenter, national,

open-label, controlled (standard treatment group as control),

ProtocolsS. Lorenzano et al .


International Journal of Stroke © 2012 World Stroke OrganizationVol 7, April 2012, 250–257 251


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The clinical evaluation at day 90 is done by blinded central

assessor through a telephone interview. Besides the baseline

CT, a second scan must be performed 22 to 36 h after starting

the infusion of trial medication. Other CT scans are optional

and must be performed only in case of clinical deterioration.

Outcome measures are listed in Table 3. The primary

outcome consists in evaluating disability at day 90 dichot-

omized as a favourable outcome (mRS 0–2) or unfavourable

outcome (mRS 3–6). The secondary outcomes are a global

outcome analysis combining four neurological and disability

scores. The assessment of safety, incidences, and severity of

adverse events (AEs) as per system organ class, including

mortality at day 90, stroke-related and neurological, cerebral

herniation rate, symptomatic oedema, and symptomatic cer-

ebral bleedings, will be evaluated. Intracranial haemorrhages

will be assessed separately. SICH is defined as any haemor-

rhage on the 22–36 h post-treatment imaging scan combined

with a neurological deterioration leading to an increase of one

Table 1 Inclusion and exclusion criteria

Inclusion criteria

Female or male inpatients

Age >80 years.

Clinical diagnosis of ischaemic stroke causing a measurable neurological deficit defined as impairment of language, motor function, cognition

and/or gaze, vision, or neglect. Ischaemic stroke is defined as an event characterized by the sudden onset of an acute focal neurologic

deficit presumed to be due to cerebral ischaemia after CT scan excludes haemorrhage.Onset of symptoms 17) and/or by appropriate imaging techniques.Epileptic seizure at onset of stroke.

Symptoms suggestive of subarachnoid haemorrhage, even if the CT scan is normal.

Administration of heparin within the previous 48 h and a thromboplastin time exceeding the upper limit of normal for laboratory.

Prior stroke within the last 3 months.

Patients with any history of prior stroke and concomitant diabetes.

Platelet count of below 100 000/mm3.

Systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg, or aggressive management (IV medication) necessary to reduce

BP below these limits.

Blood glucose 200 mg/dl; values up to 300 mg/dl are allowed, if they can be reduced to


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or more points on the NIHSS or leading to death. Hemor-

rhagic events will be classified as haemorrhagic infarction type

I or II or as parenchymal haemorrhage type I or II (19).

Data monitoring body

A Steering Committee consisting of four neurologists is estab-

lished. The Steering Committee’s functions include the review

of enrolment and trial conduct at the sites, recommendation

of remedial actions (if necessary), recommendation of pro-

tocol amendments, review of the results, preparation of the

scientific publication(s), and validation of the Data Safety

Monitoring Board (DSMB) charts.

In addition to the safety monitoring by the Promoter’s

Medical Monitors and Safety Officers, an independent DSMB

is established to periodically review all safety issues during

the course of the trial. No interim analysis is foreseen. DSMB

will give recommendations about the study conduction and

an eventual early interruption of the trial. It will review

the results of the study and evaluate the risk/benefit ratio

of the treatment. DSMB consists of one neurologist, one

neuroradiologist, and one biostatistician. DSMB periodically

receives and analyses blinded data from the Trial Data Center

and from the centralized CT reading panel. Safety reviews

are conducted on all data available on a regular basis. The

procedures and guidelines of the DSMB were reviewed by

the Steering Committee before the beginning of the trial.

The procedures for reporting the AEs are advanced and not

time consuming. All AEs, whether or not considered to be

Table 2 Flow chart of trial procedures

Visit 1A 1B 2 3 4

Hour/day window

Baseline (within

three hours) D0

Trial drug

admin† 2 h§ 15 min

24 h§ 1 h

D1

7 days§ 1 day

D7

90 days§ 14 day

D90

rt-PA† /standard treatment ←x→

60 minsDemographics x

Medical history x

Inclusion/exclusion criteria x

Informed consent and

subject information

x

IVRS contact x

Physical exam x

Vital signs x x x x

Concomitant therapy x x x

Adverse events x x x x x

12-Lead EKG x x

CT scan x x * x ‡

NIHSS x x x * x

Glasgow outcome score x ¶

Modified Rankin Scale x x

¶

Barthel index x ¶

Pat. termination record x

*CT: between 22 and 36 h, NIHSS closely before or after CT. †Only for patients receiving rt-PA. ‡ Optional in case of clinical deterioration. § Time after

the end of infusion of study drug. ¶ Clinical evaluation by a co-investigator not involved in the acute treatment phase for a specific patient.

Table 3 Outcome measures

Primary end-points

Patients (%) with favourable outcome at day 90, according to:

modified Rankin Scale (mRS) 0–2

Secondary end-points

At days: 0 (2 h after treatment), 1, 7

NIHSS (total score), mean/median change from baseline

At day: 7

NIHSS: improvement of 4 points or score 0–1

At day 90:

mRS 0–1; Barthel Index 95; Glasgow Outcome Scale 1–2

Stratified end-point of NIHSS and mRS

Baseline NIHSS


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related to the treatment by the investigator, must be docu-

mented in the appropriate ‘adverse event’ case report form

from the admission until the hospital discharge. Any serious

adverse event (SAE), whether or not considered related to

the investigational product, and whether or not the investiga-

tional product has been administered, must be immediately

reported. The SAE notification is sent electronically via emailto the Clinical Research Organization (CRO) and another

copy to the responsible of the Scientific Board, which have the

role to communicate the SAE to the Authority. Thereafter, the

Clinical Monitor must provide a written report of the AE and

any sequelae to CRO.

The e-CRF allows monitors and data managers to check

through a password all the entered data for each centre involv-

ing in the trial.

The Promoter reserves the right to discontinue this trial at

any time for failure to meet expected enrolment goals, for

safety or any other administrative reasons.

Quality assurance

A quality assurance audit of this trial may be conducted by

the Promoter or Promoter’s designees. The quality assurance

auditor willhave accessto all medical records,the investigator’s

trial related filesand correspondence,and thewritteninformed

consent documentation that is relevant to this clinical trial.

Therefore, case report forms, progress notes, and copies of

laboratory andmedical test results must be available at all times

for inspection by the Promoter’s clinical trial monitor and

health authorities (e.g. European Medicines Agency, Food and

DrugAdministration). The accuracy of thedata will be verified

by reviewing the above-referenced documents.

Sample size

Sample size calculation is based on the following assumptions.

The proportion in group 1 (treatment group) is assumed to be

0·44 under the null hypothesis and 0·58 under the alternative

hypothesis. Group sample sizes of 280 in group 1 and 280 in

group 2 achieve 90% power to detect a difference between the

group proportions of 0·14 with regard to the percentage

of patients with a favourable outcome (mRS 0–2). The test

statistic used is the two-sample chi-square. The significance

level of the test was targeted at 0·05.

Statistical analysis

The primary null hypothesis of interest is that the magnitude

of response with regard to the primary end-point (mRS 0–2)

is not different between the two groups; the alternative is that

rt-PA is superior over non-treated group.

An intent-to-treat analyses (ITT) of all patients randomized

as well as an explanatory analyses of all patients randomized

and treated according to protocol (PP) will be carried out

considering a descriptive presentation and an exploratory

evaluation of all efficacy data. Baseline characteristics will be

tabulated; counts and percentages for categorical data and

continuous data will be summarized by means of the follow-

ing statistics: the number of observations, means, standard

deviations, median, minimum, and maximum. To assess base-

line comparability of the two groups, we perform appropriate

statistical tests.As regard the primary analyses, the ITT analyses on mRS

0–2 at day 90 will be carried out by the chi-square test on

proportions (alpha level 5%, two-sided). The proportion of

response rate will be estimated with 95% CI, using both tra-

ditional method and the Wilson method. Also the relative risk

(RR) will be presented. For secondary analyses, descriptive

analyses and data set exploratory, survival analyses (Kaplan–

Meier), and regression analyses (Cox) will be carried out.

As regard the safety analyses, incidence and severity of AEs

willbe described for all treated patientsby treatment group. An

explanatory analysis of all patients randomized and treated

according to protocol will be carried out considering a descrip-

tive presentation and an exploratory evaluation of all safety data. This population will be fixed by the Steering Committee

under blinded conditions before database lock. All (dichot-

omized) safety end-points (including intracranial haemor-

rhages) will be analysed by chi-square test on proportions. In

addition,the RRswith 95%CIs willbe presented. Furthermore,

the lower limits of the 95% CIs will be compared with the

observed RR in NINDS (2) and the combined analyses of

European Cooperative Acute Stroke Study (ECASS) II (20)

and Alteplase Thrombolysis for Acute Noninterventional

Therapy in Ischemic Stroke (ATLANTIS) (21). In general, RRs

reduction will be associated to absolute risk differences for

an overall assessment of the treatment differences; further-more, the number needed to treat (the number of patients

who need to be treated to prevent one adverse outcome) will

be evaluated.The Kaplan–Meiermethodwill be used to analyse

time to event (progression, mortality). Incidence and severity

of the (serious) AEs as per system organ class will be descrip-

tively analysed.

No interim analysis is foreseen. A continuous safety

monitoring will be done by the DSMB in a blinded fashion.

All efforts will be made to collect complete CRF information

according to the protocol. This refers to all randomized

patients, treated or not treated with study drug. No missing

values regarding survival status and intracranial bleeds are

expected. However, for functional outcome parameters of

surviving patients. missing values might occur. The last-

observation carried-forward method will be applied in the

sense that data from the last available visit or measurement

will substitute the missing data. In case of missing values due

to death, the worst score principal will be applied.

Data management

The study uses an e-CRF available by password without a

specific online software for collecting and imputing efficacy

ProtocolsS. Lorenzano et al .


International Journal of Stroke © 2012 World Stroke OrganizationVol 7, April 2012, 250–257 255


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5 Tanne D, Gorman MJ, Bates VE et al . tPA Stroke Survey Group.

Intravenous tissue plasminogen activator for acute ischemic stroke in

patients aged 80 years and older. The tPA stroke survey experience.

Stroke 2000; 31:370–5.

6 Berrouschot J, Röther J, Glahn J et al . Outcome and severe hemor-

rhagic complications of intravenous thrombolysis with tissue plas-

minogen activator in very old (80 years) stroke patients. Stroke 2005;

36:2421–5.

7 Engelter ST, Reichhart M, Sekoranja L et al . Thrombolysis in stroke

patients aged 80 years and older: Swiss survey of iv thrombolysis.

Neurology 2005; 65:1–4.

8 Chen CI, Iguchi Y, Grotta JC et al . Intravenous tPA for very old stroke

patients. Europ Neurol 2005; 54:140–4.

9 Mouradian MS, Senthilselvan A, Jickling G et al . Intravenous rt-PA

for acute ischemic stroke: comparing its effectiveness in younger

and older patients. J Neurol Neurosurg Psychiatry 2005; 76:1234–7.

10 Van Oostenbrugge RJ, Hupperts RMM, Lodder J. Thrombolysis

for acute stroke with special emphasis on the very old: experience

from a single Dutch centre. J Neurol Neurosurg Psychiatry 2006; 77:

375–7.

11 Sylaja PN, Cote R, Buchan AM, Hill MD and on behalf of Canadian

Alteplase for Stroke effectiveness Study (CASES) Investigators.

Thrombolysis in patients older than 80 years with acute ischemic

stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol

Neurosurg Psychiatry 2006; 77:826–9.

12 Ringleb PA, Schwark CH, Köhrmann M et al . Thrombolytic therapy

for acute ischemic stroke in octagenarians. MRI selection improves

safety but does not improves outcome. J Neurol Neurosurg Psychiatry

2007; 78:690–3.

13 Toni D, Lorenzano S, Agnelli GC et al . Intravenous thrombolysis with

rt-PA in acute ischemic stroke patients aged older than 80 years in

Italy. Cerebrovasc Dis 2008; 25(1–2):129–35.

14 Engelter ST, Bonati LH, Lyrer PA. Intravenous thrombolysis in stroke

patients of 80 versus


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