Treat Algorith Uc

8/2/2019 Treat Algorith Uc

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Treatment Algorithms in Ulcerative Colitis

Gary R. Lichtenstein, M.D.Professor of Medicine

University of Pennsylvania School of Medicine

Hospital of the University of PA

PhiladelphiaPennsylvania


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Premise and Preview

In Most Clinical Scenarios ofUlcerative Colitis

Therapy is Sequential


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Goals of Therapy for IBD

Inducing remission

Maintaining remission

Restoring and maintaining nutrition Maintaining patients quality of life

Surgical intervention (selection of optimal

time for surgery)


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Referral Population Cohort:Disease Distribution at Presentation

n=1116

37%

17%

46%

Farmer RG, Easley KA, Ranking GB. Dig Dis Sci1993;38(6):1137-1146


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> 30> 30< 30ESR

Transfusion required 90> 90NormalPulse

> 37.5> 37.5NormalTemperature (C)

ContinuousFrequentIntermittentBlood in stool

>10>6


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UC: Natural History

0

20

40

60

80

100

Disease Activity

PatientswithUC(%)

Disease Severity at Presentation

Mild Activity(20%)

ModerateActivity(71%)

Severe Activity(9%)

Mild Activity: < 4 stools dailyNo systemic disturbanceESR: Nl

Moderate Activity: > 4 stools dailyMinimal systemic effects

Severe Activity: > 6 stools dailyBloody stoolsFever

TachycardiaAnemiaESR > 30 mm/hr

Hendriksen C, Kreiner S, Binder V. Gut1985;26:158-163


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UC Natural History

0%

10%

20%

30%

40%

0 5 10 15 20

Years

ColectomyRa

te(

0%

20%

40%

60%

80%

100%

Disease Activity

PatientswithUC

(%)

No Symptoms

(50%)

Low Activity

(30%)

Moderate-High

Activity (20%)

10%

23%

31%

Disease course one year after diagnosis


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Natural Course of Ulcerative Colitis

Langholz E et al.Scand J Gastroenterol. 1996;31:260-266.Based on a multivariate analysis.

Proctitis Left-Sided Pan-colitis

Progression

Surgery

Regression


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Therapeutic Pyramid for

Active UC

Severe

Moderate

Mild

Systemic Corticosteroids

Aminosalicylates

Surgery

Oral Steroids

AZA/6-MP

Cyclosporine

Infliximab


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Sequential Indications

Induction of remission Treatment of acute disease

Maintenance of remission Medical maintenance

Steroid-sparing


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Ulcerative Colitis:Induction of Remission

Mild disease

Aminosalicylate Topical therapy (distal disease)

Oral therapy (extensive disease)


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Chemical Structure of 5-Aminosalicylate(Mesalamine) and Its Pro-Drugs: Sulfasalazine,

Balsalazide, and Olsalazine

5-aminosalicylic acid Sulfasalazine

Balsalazide Olsalazine


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Oral 5-ASA Release Sites

Stomach

Small

Intestine

Large

Intestine

Azo bond

AZO-

COMPOUNDS

Mesalamine in

microgranules

Pentasa

Mesalamine

w/ eudragit-S

Asacol


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Comparative Doses:

Mild to Moderate UC

Recommended

Treatment Dose

Equivalent

5-ASA dose

Sulfasalazine 3-4 grams 1.2-1.6 grams

Mesalamine 2.4 grams 2.4 grams

Balsalazide 6.75 grams 2.4 grams


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5-ASA Delivery Systems

PENTASA

ASACOL

SASP/OLS/BALS

ENEMA

SUPP

JEJUNUM / ILEUM / ASC / DES / SIG / RECT


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SPD476 uses MMX technology to deliver

5-ASA to the entire colon

Gastro-resistant layer Hydrophilic polymers

5-ASA Lipophilic excipients

Delayed and extendeddrug release formulationcontaining 1.2g 5-ASA

Highest 5-ASA drugloading per tablet

MMX = MMX Multi Matrix System


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Sulfasalazine Dose/Toxicity

1G 2G 3G 4G

100%

Response

Toxicity


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Aminosalicylate Dosing for Reduction

of Signs/Symptoms

Dose-Response without Intolerance

%Response

Schroeder, Tremaine, Ilstrup, 1997; Hanauer, 1993; Sninsky, 1991

0

10

20

30

40

50

60

70

80

PLACEBO 1.6G 2G 2.4G 4G 4.8G


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ASCEND I & II:

Pooled Data

Two Phase III, multi-center, randomized, double-blind controlled studies

423 analyzable patients with moderately active UC

randomized to oral mesalamine 4.8 g/day (800 mgtablets) or 2.4 g/day (400 mg tablets) x 6 weeks

Treatment with 4.8 g/day provided a statisticallysignificant efficacy benefit over 2.4 g/day in

moderately active disease

Both doses of mesalamine had similar safetyprofiles, and both were well tolerated

Hanauer et al. DDW 2005


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ASCEND I & II:

Treatment Success at Weeks 3 & 6

P=0.0034P=0.058

n=223 n=223n=198 n=200

*

Pooled Data: Moderately Active UC

58%53%

72%

62%

0

20

40

60

80

Week 3 Week 6

%o

fPatientsImprov

ed

2.4 g/day

4.8 g/day


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Oral (2.4 g) vs. Rectal (4 g)

Mesalamine for Distal UC

%Response

Safdi. Am J Gastroenterol1997

0

1020

30

40

50

60

70

80

90

100

1 week 2 weeks 3 weeks 6 weeks

Oral

Rectal

Combined


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Addition of Rectal Mesalamine to Oral

Mesalamine in Pancolitis

Marteau, P et al. Gut 2005;54:960-965

Percentage of patients achieving remission (ulcerativecolitis disease activity index (UCDAI) of 0 or 1) or

improvement (decrease in UCDAI >2 points).


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Marteau, P et al. Gut 2005;54:960-965

Remission and improvement rates


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Maintenance Therapies for

Ulcerative Colitis

Aminosalicylates

Azathioprine/6-MP


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Aminosalicylate:

Maintenance Therapy

Sulfasalazine

Dose-response limited by intolerance

Conventional dose-reduction basedon balance of efficacy/toxicity


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Oral Mesalamine Dosing

for UC Maintenance

%Remiss

ion

Months

Hanauer. Ann Intern Med1996

PLCB

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10 11 12

1.6 g

0.8 g


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Oral vs. Topical Mesalamine

for Maintenance of Distal UC

%Remission

Months

DAlbasio. Am J Gastroenterol1997

4 g QOD enema

1.6 g/day oral

0

20

40

60

80

100

120

2 4 6 8 10 12 14 16 18 20 22 24


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Frequency of Topical Mesalamine for

Maintenance of Distal UC

Miner. Gastroenterol1994;106:A736

%Remissi

on

0

1020

30

40

50

60

70

80

90

6 wks 12 wks 24 wks

QHS

QOD

Q3D

Placebo


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Combined Oral + Topical Mesalamine for

Maintenance of Distal UC

DAlbasio. Am J Gastroenterol1997

Months

%Remission

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10 12

Oral 1.6 g + topical

2/wk

Oral 1.6 g

AZA i S UC 1 Y Pl b


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Outcome Azathioprinen=25

Placebon=25

Remission

Complete

Partial

17

14

3

16

10

6

Relapse 3* 6

Withdrawn

Side effects

Poor compliance

5

3*

2

3

0

3

*P


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Controlled Trial of AZA in Managementof Chronic UC - Results

Rosenberg J, et al. Gastroenterology. 1975;65:96-99.

P=NS17.6

15.8

13.9

7.9

02

4

6

8

10

1214

16

18

20

First 3 Months Last 3 Months

Placebo N=14 Azathio rine N=16

**P


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Controlled Trial of AZA in Managementof Chronic UC - Results

23.222.2

13.6

2.3

0

5

10

15

20

25

30

Placebon=20

Azathioprinen=24

MeanActivityScore

P


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Methotrexate for Active UC andInduction of Remission

Oren R, et al. Gastroenterology. 1996;110:1416.

0

1020

30

40

50

60

7080

90

100

Percent of Patients in 1st Remission

Placebo

Methotrexate 12.5 mg/wk PO

%Patients

49% 47%

n=37

n=30P=NS

Time to first remission for MTX was 4.1 months vs. placebo (3.4 months)

C li ti f S Il l P h


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Complications of Surgery: Ileal Pouch-Anal Anastomosis (IPAA)

Pelvic sepsis

Leakage

Incontinence

Intestinal obstruction

Anastomotic strictures

Sexual dysfunction

Pouchitis

Female infertility

Lichtenstein G. The Clinicians Guide to Inflammatory Bowel Disease. SLACK;2003:127129.

Potential short-term complications

Potential long-term complications


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Complications of UC Surgery

Mortality (


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Delaney CP, et al. Ann Surg. 2003;238:221-228.

Ileal PouchFunctional Outcome

Age in Years

10 year postoperative 65

# of BM / 24 Hours 5.5 5.7 6.2 4.6

Never Incontinent (%) 56 46 42 33

Nocturnal Seepage (%) 39 48 39 60

Majority of patients had UC other diseases included Crohns disease,

indeterminate colitis, familial polyposis, and cancer

Ileal Po ch: C m lati e Incidences


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Ileal Pouch: Cumulative IncidencesPregnancy

MonthsControls(n=914)

BeforeColectomy

(n=84)

AfterIPAA

(n=149)

12 75% 78% 18%*24 82% 85% 27%*

60 88% 90% 36%**P


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20Patients

2

81

9

11

Cyclosporine in Patients with

Severe Ulcerative Colitis

Cyclosporine

No Response:

surgery

Response

Electivecolectomy

OralCyclosporine

Lichtiger S et al. NEJM1994


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IV Cyclosporine: Major Toxicity

Renal insufficiency 23%

Infection 20%

Seizures 3%

Deaths 2%

Anaphylaxis 1%

Sternthal J et al. Gastroenterol1996

ACT 1


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Study Design

Multicenter, randomized, double-blind,placebo-controlled, parallel-treatment grouptrial

Conducted globally at 62 sites 364 subjects with moderately to severely

active ulcerative colitis were randomizedand treated:

121 in the placebo treatment group

121 in the REMICADE (infliximab) 5 mg/kgtreatment group

122 in the REMICADE 10 mg/kg treatment group

ACT 1

Data on File, Centocor, Inc.

ACT 1


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Patient Population

Subjects with: Moderately to severely active ulcerative colitis

(UC): Mayo score 6 points (on 12 point scale) Endoscopy subscore 2 points

Subjects must meet at least 1 of thefollowing criteria: Current treatment with 1 of the following:

Oral corticosteroids, 6-mercaptopurine (6-MP), or

azathioprine (AZA) Have failed to successfully taper, tolerate, or

respond to corticosteroids within the past 18months

Have failed to tolerate or respond to 6-MP or

AZA within the previous 5 years

ACT 1


ACT 1


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Study Design

Infusions

ACT 1

Randomization of patients

Final Evaluation

Week 0

Week 2

Week 6

Week 8

Week 14

Week 22

Week 30

Visits

Week 46

Week 54

REMICADE(infliximab)

5 mg/kgPlacebo

REMICADE10 mg/kg

Primary endpoint (clinical response)Major secondary endpoints (clinical remission, mucosal healing)

Major secondary endpoints (clinical response, clinical remission)

Week 38


ACT 1


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Clinical Response at Week 8 and Week 30

ACT 1

Intent-to-treat Analysis

Patients in all groups with baseline medication were continued on stable dosesREMICADE US Packa e Insert.

3730

69

52

62

51

0

10

20

30

4050

60

70

80

90100

Week 8 Week 30

Proportionof

Patients(%)

Placebo Infusion 5 mg/kg REMICADE (infliximab) 10 mg/kg REMICADE

*p


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Clinical Response at Week 8 by

Corticosteroid Refractory Status

ACT 1

Data on File, Centocor, Inc.Data on File, Centocor, Inc.

Placebo infusions

5 mg/kg REMICADE (infliximab)

10 mg/kg REMICADE

Placebo Infusion

5 mg/kg REMICADE (infliximab)

10 mg/kg REMICADE

p=0.010p=0.005*p


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Clinical Remission at Week 8 and Week 30ACT 1

REMICADE US Package Insert.


Patients in all groups with baseline medication were continued on stable doses

15 16

393432

37

0

10

20

30

40

50

60

70

80

90100

Week 8 Week 30

Proportionof

Patients(%)


*

*

*p


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Mucosal Healing at Week 8 and Week 30

ACT 1

REMICADE US Package Insert.


Patients in all groups with baseline medication were continued on stable doses

34

25

62

50

59

49

0

10

20

30

4050

60

70

80

90100

Week 8 Week 30

Proportionof

Patients(%)


**

*

*p


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Clinical Remission

Without Corticosteroids at Week 30

ACT 1


10

22

0

5

10

15

20

25

30

Pro

portionofPatients(%)

Placebo Combined REMICADE (infliximab)

*p = 0.039

*

Ulcerative Colitis: Mild to Moderate


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Ulcerative Colitis: Mild to ModerateAcute flare

Exclude entericpathogen

Extensive

Oral 5-ASA

Responseadequate

Responseinadequate

Maintainoral 5-ASA

Responseadequate Consider

increased dose

Responseinadequate

Oral steroid

Responseinadequate

Oral 5-ASA Responseinadequate

Consider rectal therapy(5-ASA and/or steroid)

Patient willing totake rectal therapyPatient unwillingto take rectaltherapy

Responseadequate

Maintain

L sided

Ulcerative Colitis: Moderate to Severe


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Ulcerative Colitis: Moderate to Severe

Moderate

Oral steroid

Taper

Successful

Maintain on5-ASA and

observe

Inadequate response

Adequate response

Unsuccessful

IV Steroid

6MP/AZA

Success

Maintain6-MP/AZA

Response

Failure

ConsiderCyA

Noresponse

Colectomy

Inadequate response

Severe

Infliximab

Response

Maintaininfliximab

Noresponse


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Final Points

There is no one size fits all to IBDtherapy

Therapy and decision making are tailored tothe individual

Algorithms are based upon availableevidence

Evidence is in constant flux

Success of algorithms depends uponoptimization of each step of therapy andconsiderable judgment about eachoutcome

Treat Algorith Uc

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