ef 1 efficacy and safety martin p. lefkowitz, md director, clinical research martin p. lefkowitz, md...

EF 1

Efficacy and Safety

Martin P. Lefkowitz, MDDirector, Clinical Research

EF 2

Overview of Clinical Results

Totality of data provides convincing evidence of efficacy for tegaserod 12 mg/d on global relief measure and secondary parameters of efficacy

Safe and well tolerated Favorable benefit-to-risk profile in constipation-

predominant IBS, a disorder with no proven therapeutic options

EF 3

Tegaserod Clinical Program in Constipation-Predominant IBS

Study Dose, mg/d* N Location (% of patients)

Phase II dose-ranging B251 1-24 547 US (54%), Europe (43%), CanadaPhase III efficacy/safety B351 4, 12 799 US (97%), Canada B301 4, 12 881 Europe (90%), US, S Africa B307 4, 4-12 845 US (66%), Europe (32%), CanadaLong-term safety B209 4-12 579 Europe (50%), US (41%), Canada

1

*Divided into 2 daily doses.

EF 4

Efficacy Presentation

Phase II Phase III– Design and endpoints– Results

Summary

EF 5

24 mg/d; n = 110

12 mg/d; n = 110

4 mg/d; n = 108

1 mg/d; n = 107

Placebo; n = 113

Baseline

Week –4

Randomization

Week 4 Week 8 Week 12Week 0

Phase II Study Design (B251)1

EF 6

Phase II Subject’s Global Assessment (SGA) of Overall GI Symptoms (B251)

0

10

20

30

40

50

Endpoint

Res

pons

e, %

Placebo 1 mg 4 mg 12 mg 24 mg

1

EF 71

Phase III Design ConsiderationsOutcome Measures in IBS Trials (1)

No consensus No consensus on primary outcome measure Assessment variable– Overall measure that integrates

IBS symptoms– Specific symptom measure:

abdominal discomfort/pain Measurement– Ordinal and visual analog scales (VAS)

EF 81

Outcome Measures in IBS Trials (2)

General consensus Responder approach for primary efficacy

variable Frequency: at least weekly Self-administered by patient

EF 9

Phase III Study Designs1

B351

4 mg/d

12 mg/d

Placebo

12 weeks4 weeks

Baseline

4 mg/d

12 mg/d

Placebo

12 weeks4 weeks

B301

Baseline

B3074 mg/d

12 mg/d

Placebo

12 weeks4 weeks

4 mg/d4 mg/dBaseline

EF 101

Inclusion Criteria

Males and females 18 years of age (B351: 12 years) Colon evaluated within last 5 years Rome criteria

Continuous or recurrent discomfort/pain in lower abdomen in last 3 monthsDiscomfort/pain • Relieved by BM(1 of 3) • Associated with change in frequency of BMs

• Associated with change in consistency of stool

25% of the time • < 3 BMs/week(2 of 3) • Hard or lumpy stool

• Straining

EF 111

Exclusion Criteria

Diarrhea associated with IBS 25% of the time

Other relevant GI conditions Concurrent use of

– Narcotics, motility agents

– Laxative use except as rescue

EF 121

Randomization Criteria

Abdominal discomfort/pain – Mean baseline score 35 mm on 100-mm VAS– No upper limit cutoff for pain severity

Stool consistency– No specific mean score

Eligibility based on clinical history• Abdominal discomfort/pain• Constipation

VAS = Visual analogue scale.

EF 13

Primary Efficacy VariableSGA of Relief (B351)

Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain, and altered bowel habit.Compared to the way you usually felt before entering the study, how would you rate your relief symptoms during the past week: Completely relieved Considerably relieved Somewhat relieved Unchanged Worse

Response: 50% complete/considerable relief at study endpoint

1

EF 14

Response: 40% reduction and at least 20-mm absolute reduction from baseline at study endpoint

“How much of a problem was your abdominal discomfort/pain over the last week?”

Absent Very Mild Moderate Severe Verymild severe

100 mm

Primary Efficacy VariableSGA of Abdominal Discomfort/Pain (B351)

1

EF 151

Statistical Methodology for Primary Efficacy Variables

Study endpoint: last 4 available weekly scores

Treatment comparisons by Mantel-Haenszel test stratified by center

A multiple comparison procedure was used to ensure the overall 2-sided type I error rate of < .05

EF 16

Adjustment Rules

Applied to primary efficacy variables at endpoint: Patient defined as nonresponder if

– No postrandomization SGA assessment

– < 28 days treatment

– Laxative intake > 5 days overall or any use in last 4 weeks of study

1

EF 17

Secondary Efficacy Assessments

Weekly: • SGA of bowel habit (VAS)Daily: • Intensity of abdominal

discomfort/pain (6-point scale)• Intensity of bloating (6-point scale)• Number of bowel movements• Stool consistency (7-point scale)

Intensity scale0 = none1 = very mild2 = mild3 = moderate4 = severe5 = very severe

Stool consistency scale1 = watery2 = loose3 = somewhat loose4 = neither loose nor hard5 = somewhat hard6 = hard7 = very hard

EF 18

Patient Disposition

B351 B301 B307

Enrolled 1,093 1,122 1,163

Discontinued 292 (27) 240 (21) 313 (27)during baseline

Randomized 799 881 845

Completed 633 (79) 751 (85) 680 (80)

Discontinued during 166 (21) 130 (15) 165 (20)double-blind period

1

Patients, n (%)

EF 19

Demographics

Variable (mean) B351 B301 B307

Age, years 43 46 45Gender, % female 87 83 84Race, % Caucasian 88 98 91Weight, kg 71 68 70Smoking, % 21 26 22Duration of IBS, years 14 13 14Use of bulking agents, % 18 11 17Fiber score, g 9 11 9

1

EF 20

Baseline Characteristics

Variable (mean) B351 B301 B307

Abdominal discomfort/pain 63 60 61VAS score, mmBowel habit VAS score, mm 64 60 62Days with significant 87 84 86abdominal discomfort/pain, %Days with significant bloating, % 88 83 86Number of bowel movements/week 5.7 5.4 6.2Days without bowel movements, % 46 44 41Days with hard stools, % 31 28 29Stool consistency score 4.7 4.7 4.6

1

EF 21

Efficacy ResultsPresentation Overview

Efficacy results of study B351 Modification of primary efficacy variable

for studies B301 and B307 Efficacy results of study B301 Efficacy results of study B307 Summary

EF 22

SGA Data Presentation

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

Res

pons

e, %

Weekly responseWeekly response

Monthly responseMonthly response

Endpoint:Endpoint:Last 4 available SGA valuesLast 4 available SGA valuesAdjustment rules*Adjustment rules*

1

Week

*No SGAs, < 28 d treatment, laxative use.

EF 23

Primary Efficacy Variables at Endpoint (B351)

22.118.7

29.4

23.426.2 25.1

0

10

20

30

40

SGA of relief SGA of abdominaldiscomfort/pain

Res

pons

e, %

Placebo 4 mg/d 12 mg/d

P = .05 .27 P = .19 .08

1

EF 24

Complete or Considerable Relief by Week (B351)

0

10

20

30

40

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

Res

pons

e, %

1

†

*

* **

*

*P < .05 versus placebo.†P < .01 versus placebo.


†

†

EF 25

SGA of Abdominal Discomfort/Pain by Week (B351)

0

10

20

30

40

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

Week

Res

pons

e, %

9

*


*P < .05 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

EF 26

SGA of Bowel Habit (B351)

20.2

26.424.7

0

10

20

30

Endpoint

Resp

onse

, %

*P < .05 versus placebo.†P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

0

10

20

30

40

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

Week

Resp

onse

, %

*


Weekly

*†

*

EF 27

Daily Diary: Abdominal Discomfort/Pain (B351)

-3.9

15.216.9

-5

0

5

10

15

20Significant days at endpoint

Mea

n re

duct

ion

from

bas

elin

e, %

Impr

ovem

ent

Impr

ovem

ent

*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).Significant: at least mild; 2 on a 6-point scale.

*

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

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

Week

Mea

n pa

in s

core

*

* * * *

*


† †

†

Pain score

EF 28

Daily Diary: Bloating (B351)

5.6

14.9 15.1

-5

0

5

10

15


Mea

n re

duct

ion

from

bas

elin

e, %

Impr

ovem

ent

Impr

ovem

ent


†

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

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

Week

Mea

n bl

oatin

g sc

ore

**

* * * **

* *

† †

Bloating score


EF 29

Number of Bowel Movements and Stool Consistency by Week (B351)

3

4

5

6

7

8

9

10

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

Mea

n nu

mbe

r of b

owel

mov

emen

ts/w

eek

1


*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).

3.0

3.5

4.0

4.5

5.0

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

Mea

n st

ool c

onsi

sten

cy/w

eek

*†

†

****†††

†

*** †††

†

††

***† † ††

††

††††

††

†

† †* †

† †

† †††

††

Bowel movements Stool consistency

EF 301

Summary (B351)

No statistically significant differences in primary efficacy variables– Low placebo response rates:• SGA of relief 22%• SGA of abdominal discomfort/pain 19%

Significant treatment differences observed in daily diary variables

Consistent pattern of improvement for tegaserod across primary and secondary variables

EF 31

B351

Original SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint

B301/B307

SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint

ORAt least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint

1

Modification of Primary Efficacy Variables

EF 32

Associations Between SGA of Relief and Other Efficacy Variables (B351)

Efficacy variable % change from baseline Responder Nonresponder

VAS score: SGA abd discomfort/pain –48 –6 Days with significant pain –35 9 Daily pain score –40 –0.2 Days with significant bloating –32 3Daily bloating score –38 –2VAS score: SGA bowel habit –47 –6Days with no bowel movement –44 –15 Days with hard or very hard stool –66 –23

1

All comparisons significant (P < .001)

Response: 50% complete/considerable or 100% at least somewhat relief.

EF 33

Associations Between SGA of Relief and Other Efficacy Variables (B351)

Efficacy variable Complete Considerable Somewhat Unchanged Worse% change from baseline (n = 48) (n = 164) (n = 222) (n = 256) (n = 61)VAS score: SGA abd –79 –50 –23 –5 8discomfort/pain Days with significant pain –73 –40 –7 18 3Daily pain score –72 –44 –16 4 8Days with significant –61 –37 –7 6 3 bloating

Daily bloating score –64 –41 –16 1 7VAS score: SGA bowel –75 –50 –23 –3 6 habitDays with no bowel –62 –46 –28 –10 –16 movement

Days with hard or –71 –70 –50 –19 3 very hard stool

1

Last study week

EF 34

B351

Original SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint

B301/B307

SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint

ORAt least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint

1

Modification of Primary Efficacy Variables for Studies B301/B307

SGA of abdominal discomfort/pain 40% reduction and at least 20-mm absolute reduction from baseline Secondary efficacy variable

EF 35

Efficacy Results SGA of Relief (B351)

22.1

33.329.4

38.9

26.2

45.7

0

10

20

30

40

50

60

Res

pons

e, %

Placebo 4 mg 12 mg

P = .05 .27 P = .16 .004

1

SGA of relief(retrospective analysis)

Original SGA of relief

EF 36

Study B301Efficacy Results

EF 37

4 mg/d

12 mg/d

Placebo

Baseline

Week –4

Randomization


1

Study Design (B351 and B301)

EF 38

SGA of Relief at Endpoint (B301)

30.2

38.8 38.4

0

10

20

30

40

50

60

70R

espo

nse,

%Placebo 4 mg/d 12 mg/d

*Statistically significant.Response: 50% complete/considerable or 100% at least somewhat relief.

1

P = .018* .033*

EF 39

SGA of Relief at Endpoint

3033

3943

38

45

0

10

20

30

40

50

60

70

Adjusted Not laxativeadjusted

Resp

onse

, %

B301

*Statistically significant.Response: 50% complete/considerable or 100% at least somewhat relief.

1

P = .018* .033* P = .007* .003*

B351 (retrospective analysis)

333739

4246

49

0

10

20

30

40

50

60

70


Resp

onse

, %

P = .157 .004* P = .251 .006*


EF 40

Monthly SGA of Relief

21

3237

26

44 46

34

42

50

0

10

20

30

40

50

60

70

Month 1 Month 2 Month 3

Resp

onse

, %

B301

*P < .05 versus placebo; †P < 0.01 versus placebo.Response: 50% complete/considerable or 100% at least somewhat relief.

1

31

44 4239

424545

50

57

0

10

20

30

40

50

60

70


Resp

onse

, %

B351 (retrospective analysis)

†

†

†

† ††

*


EF 41

At Least Somewhat Relief by Week1


0

10

20

30

40

50

60

70

80

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

At le

ast s

omew

hat r

elie

f, %

B301

*

** **

††

† ††

† †† †

†† † † † †

0

10

20

30

40

50

60

70

80

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

B351

* **††

† † †


EF 42

SGA of Abdominal Discomfort/Pain (B301)

22.6

29.8 29.9

0

10

20

30

40

Endpoint

Resp

onse

, %

*P < .05 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

*

0

10

20

30

40

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

Weeks

Resp

onse

, % **

**

*


Weekly

EF 43


22.6

28.826.2

0

10

20

30

40

Endpoint

Resp

onse

, %

*P < .05 versus placebo.†P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

0

10

20

30

40

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

Weeks

Res

pons

e, %


**

* * *

**

*

** *

*†

Weekly

EF 44

Daily Diary: Abdominal Discomfort/Pain (B301)

10.4

18.9 18.6

0

5

10

15


Mea

n re

duct

ion

from

bas

elin

e, %

Impr

ovem

ent

Impr

ovem

ent


1.8

2.0

2.2

2.4

2.6

2.8

3.0

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

Week

Mea

n pa

in s

core

* * **

*

* *

†

††

† †

†

†

† †† †

†

†


Pain score

EF 45

Daily Diary: Bloating (B301)

-4.0

10.7

8.3

-5

0

5

10


Mea

n re

duct

ion

from

bas

elin

e, %

Impr

ovem

ent

Impr

ovem

ent


1.8

2.0

2.2

2.4

2.6

2.8

3.0

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

Week

Mea

n bl

oatin

g sc

ore

*

*

**

**

**

*

†

†

††

††

†

Bloating score


EF 46


3

4

5

6

7

8

9

10

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

Mea

n nu

mbe

r of b

owel

mov

emen

ts/w

eek

1


†

†

***

*†† † † † † †

††

††


3.0

3.5

4.0

4.5

5.0

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

Mea

n st

ool c

onsi

sten

cy/w

eek

†

† † † †† † † † †

†† † † † † † † ††

†† †

† † †

† †

*†


EF 47

Summary Study B301

Clear evidence of efficacy– Significant treatment differences for SGA

of relief – Consistent positive findings on secondary

efficacy variables

EF 48

Study B307Efficacy Results

EF 49

Nonresponder: 12 mg/d (65%)

4 mg/d

Placebo

Baseline

Week –4

Randomization


1

Study Design (B307)

4 mg/dResponder: 4 mg/d (35%)

EF 50

SGA of Relief (B307)

37 39

25

38

46

3842

32

39

50

4246

40

47 49

0

10

20

30

40

50

60

70



Resp

onse

, %

Placebo 4 mg/d 4-12 mg/d

1

Endpoint Monthly

†*

*P < .05 versus placebo; †P < .01 versus placebo.Response: 50% complete/considerable or 100% at least somewhat relief.

EF 51

At Least Somewhat Relief by Week (B307)

10

20

30

40

50

60

70

80

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

At l

east

som

ewha

t rel

ief,

%


1


*†

*†

†

*

EF 52

SGA of Abdominal Discomfort/Pain (B307)

30.6

25.527.6

0

10

20

30

40

Endpoint

Resp

onse

, %

*P < .05 versus placebo; †P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

0

10

20

30

40

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

Weeks

Resp

onse

, %

*

* †


Weekly

EF 53


2527

24

0

10

20

30

40

Endpoint

Resp

onse

, %

*P < .05 versus placebo; †P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

0

10

20

30

40

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

Weeks

Resp

onse

, %

*†

*


Weekly

EF 54


3

4

5

6

7

8

9

10

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

Mea

n nu

mbe

r of b

owel

mov

emen

ts

3.0

3.5

4.0

4.5

5.0

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

Mea

n st

ool c

onsi

sten

cy

1

*†

†

†

*† † †


*

†

*†*

†

† † *

† †

† †


† ††††

† ††

† † † †


EF 55

Summary Study B307

Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint

Not statistically significant for primary efficacy variable

EF 56

Comparative EfficacySummary

EF 57

Phase III StudiesAt Least Somewhat Relief

01020304050607080

0 2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8 10 12

Week

At l

east

som

ewha

t rel

ief,

%


B351 B301 B307


** * * † † †

** * * * * †

† * * †

*†

**

EF 58

Phase III StudiesComplete/Considerable Relief

0

10

20

30

40

0 2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8 10 12

Week

Com

plet

e/co

nsid

erab

le re

lief,

%


B351 B301 B307


*

†

***

*

†

** †

†

†† †

†† †

EF 59

Efficacy Variables at Endpoint B351 B301 B307

Efficacy variable 4 mg/d 12 mg/d 4 mg/d 12 mg/d 4 mg/d 4-12 mg/d

SGA efficacy variables SGA of relief + < .01 < .05 < .05 + + Original SGA of relief < .05 + < .05 + - - SGA of abdominal + + + < .05 - - discomfort/pain SGA of bowel habits + + + + + -Daily diary variables Days with significant: Abdominal pain + < .05 + + + + Abdominal bloating + < .01 + + - - Number of: Bowel movements < .01 < .001 < .001 < .01 < .05 < .001 Days without BMs + < .01 < .05 < .05 + < .05 % days with hard stools + < .01 + + + +

12

+ = Positive direction for tegaserod, P > .05 versus placebo.- = Negative direction for tegaserod, P > .05 versus placebo.

EF 60

Additional Analyses

EF 61

Pooled Analysis

Prespecified primary efficacy variables B351: Original SGA of relief and SGA of abdominal discomfort/pain

B301/B307: SGA of relief

Endpoint analysis Longitudinal analysis

P value versus placebo P value versus placebo

12 mg/d 12 mg/d 4 mg/d (4-12 mg/d) 4 mg/d (4-12 mg/d)

.0141 .0028 .0085 < .0001

EF 62

Number of Months With Positive Response for SGA of Relief§

P value versus placebo

12 mg/d Study 4 mg/d (4-12 mg/d)

B351 Original SGA of relief .107 .047

B351 SGA of relief .353 .013*

B301 SGA of relief .008* < .001*

B307 SGA of relief .479 .008*

1

* Statistically significant with adjustment for multiple comparisons.

§ Primary analysis of alosetron data. Gastrointestinal Drug Advisory Committee meeting, November 16, 1999.

EF 63

% Weeks With At Least Somewhat Relief

5346

5160

55 53

6556 60

0102030405060708090

B351 B301 B307

At l

east

som

ewha

t rel

ief,

%

Placebo 4 mg/d 12 mg/d 4-12 mg/d

4

P = .021 < .001 P = .005 < .001 P = .278 .003

EF 64

SGA of Relief by GenderPooled Results: B351/B301/B307

2633

24

3834

3933

384043

3236

0

10

20

30

40

50

Month 1 AdjustedEndpoint

Month 1 AdjustedEndpoint

Res

pons

e, %

Placebo 4 mg/d 12 or 4-12 mg/d

1

(n = 2,025) (n = 2,037) (n = 373) (n = 373)

MaleFemale

*P < .05 versus placebo; †P < .01 versus placebo. 4-12 mg/d group pooled with 4 mg/d group at Month 1 and with 12 mg/d group at endpoint.

*†

††

EF 65

SGA of Relief at EndpointPlacebo-Subtracted Values by Gender

-2

6.7

0.4

10.2

0.8 1.4

-1.1

14.2

-7.8

11.4

4.15.3

-10

-5

0

5

10

15

20

Male Female Male Female Male Female

Res

pons

e, %

4 mg/d 12 mg/d 4-12 mg/d

B351 B301 B307

*†

†


(n = 102) (n = 697) (n = 150) (n = 731) (n = 138) (n = 703)

EF 66

Summary of Efficacy (1)

Study B301: clear evidence of efficacy– Significant treatment differences for SGA of relief – Consistent positive findings on secondary

efficacy variables Study B351: although not statistically significant on

prespecified primary efficacy endpoints, overall results strongly supportive of efficacy– Daily diary variables statistically significant in

favor of tegaserod– Positive trends for all SGA assessments

EF 67


Studies B301 and B351– B351 results largely replicated in study B301– Consistent results between weekly SGA and daily diary

variables – Tegaserod 12 mg/d group had most consistent effect

across efficacy variables and over time Study B307

– Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint

– Not statistically significant for primary efficacy variable

EF 68


Additional analyses (pooled analyses, number of months with positive response, % weeks with relief) reinforce findings of a positive treatment effect

Positive treatment effect primarily due to efficacy in women

Totality of data across multiple efficacy variables provides convincing evidence that tegaserod is effective in treatment of constipation-predominant IBS

EF 69

Safety

2

EF 70

Safety Overview

Exposure Adverse events Laboratory evaluations ECG Summary

EF 71

Overall Exposure

3,510 healthy subjects or patients

– Maximum daily dose up to 200 mg in healthy subjects

1,874 IBS patients for 85 days 302 IBS patients for 335 days

EF 72

Serious Adverse Events

Database Placebo Tegaserod

Pooled phase II studies 5/151 3.3% 10/519 1.9%Pooled phase III studies 13/837 1.6% 30/1,679 1.8%Pooled phase II/III studies 18/988 1.8% 40/2,198 1.8%Long-term studies 28/675 4.1%

2

EF 73

Reasons for Discontinuations (Phase III)

0

5

10

15

20

25

Total Adverseevent

Consentwithdrawal

Lost tofollow up

Lack ofefficacy

Protocolviolation

Other

Patie

nts,

%

Placebo (n = 837)4 mg/d (n = 844)4-12 mg/d (n = 275)12 mg/d (n = 560)

2

EF 74

Overall Adverse Events (Phase III)

0

20

40

60

80

100

Any AE Any severe AE Serious AE Discontinuationdue to AE

Patie

nts,

%

Placebo (n = 837)4 mg/d (n = 844)4-12 mg/d (n = 275)12 mg/d (n = 560)

2

EF 75

Adverse Events > 5% (Phase III)

%

Placebo 4 mg/d 4-12 mg/d 12 mg/d(n = 837) (n = 844) (n = 275) (n = 560)

Headache 21 21 17 23Abdominal pain 18 20 22 19Diarrhea 5 11 12 12Nausea 9 9 8 10Flatulence 7 8 8 7Back pain 5 6 6 8Influenza-like symptoms 6 7 4 8Upper respiratory tract infections 8 6 10 5Dyspepsia 6 6 7 6Dizziness 6 6 3 6Pharyngitis 3 3 5 4

2

EF 76

Time to First Episode of Diarrhea (Phase III)

0.0

1.0

2.0

3.0

4.0

5.0

Day 1 Days 2 - 7 Days 8 - 29 Days 30 - 59 Days > 60

Patie

nts,

%


- Majority (75%) single episode - Median duration, 2 days; mean duration, 7 days

2

EF 77

Adverse Events ( 1%) Leading to Discontinuation (Phase III)

%

Placebo 4 mg/d 4-12 mg/d 12 mg/d Events (n = 837) (n = 844) (n = 275) (n = 560)

Total 5.7 7.7 7.6 6.6

Abdominal pain 1.9 1.5 2.5 1.3 Diarrhea 0.4 1.7 1.5 1.6 Flatulence 0.7 1.1 1.1 0.4 Headache 0.8 0.7 2.2 0.4 Dizziness 1.0 1.3 0.4 0.2

2

EF 78

Long-Term Safety Study (B209)

12-month, open label 4-12 mg/d dose titration

– 80% titrated to 12 mg/d Enrolled: 579 Completed: 304

EF 79

Adverse Events > 5% (Long-term Study: 12 Months)

Event

Headache 30%Abdominal pain 17%Upper respiratory 16%tract infection Diarrhea 15%Back pain 9%Sinusitis 8%Nausea 8%Flatulence 8%

2

Total patients, N = 567 (4-12 mg/d)

EF 80

Adverse Events (> 1%) Leading to Discontinuation (Long-term Study)

Events

Total 11% Diarrhea 4% Abdominal pain 3% Flatulence 3% Headache 1%

2

Total patients, N = 567 (4-12 mg/d)

EF 81

Laboratory Evaluations (Phase III)

Clinically relevant laboratory abnormalities in hematology and biochemistry values were rare and with similar frequency for tegaserod- and placebo-treated groups

Liver chemistries (LFTs)– ALT > 3-fold normal: tegaserod 0.4% versus placebo 0.2%– AST > 3-fold normal: tegaserod 0.1% versus placebo 0.1%– No simultaneous elevations in ALT/AST and bilirubin– No serious adverse event of hepatitis or elevated LFTs No evidence of tegaserod-induced hepatotoxicity was noted

EF 822

ECG Recording and Analysis

12-lead electrocardiograms (> 10,000 tracings) Timepoint recording – Phase III: baseline, first dose (2 h),

Months 1 and 3 (2 h) – Long-term: baseline; Months 2, 6, and 12

Analysis:– Central analysis by independent cardiologist– Intervals evaluated by SigmaScan technique

No effects on ECG (QTc intervals or arrhythmias)

EF 832

Safety Summary

Tegaserod 4 and 12 mg/d – Well tolerated– Similar safety profile

Diarrhea: – Only adverse event with higher frequency

than placebo– Low discontinuation rate (~ 2%)

No effects on ECG (QTc intervals or arrhythmias) or laboratory parameters

EF 84

Conclusions

Totality of data demonstrates that tegaserod is effective in the treatment of IBS in patients who identify abdominal pain/discomfort and constipation as their predominant symptoms

Tegaserod 12 mg/d improves:– Abdominal discomfort/pain– Bloating– Constipation (stool frequency and stool consistency)

Favorable safety profile Favorable benefit-to-risk profile

ef 1 efficacy and safety martin p. lefkowitz, md director, clinical research martin p. lefkowitz, md...

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