# Presentation: 263587

## Efficacy and Safety

**Martin P. Lefkowitz, MD**
**Director, Clinical Research**

## 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**

## 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%), ****	****	****	****Canada****	**
**Phase 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%), ****	****	****	****Canada****	**
**Long-term safety****	****	****	**
**     ****B209****	****4-12****	****579****	****Europe (50%), US (41%), ****	****	****	****Canada**

**1**

***Divided into 2 daily doses.**

## Efficacy Presentation 

**Phase II**
**Phase III**
**Design and endpoints**
**Results**
**Summary**

## Phase II Study Design (B251)

**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 12**

**Week 0**

**Phase II Study Design (B251)**

**1**

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

**1**

## Phase III Design ConsiderationsOutcome Measures in IBS Trials (1)

**Phase III Design Considerations****Outcome 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)**

## Outcome Measures in IBS Trials (2)

**Outcome Measures in IBS Trials (2)**

**	****	****General consensus**
**Responder approach for primary efficacy variable**
**Frequency: at least weekly**
**Self-administered by patient**

## Phase III Study Designs

**1**

## Inclusion Criteria

**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 months**
**Discomfort/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**

## Exclusion Criteria

**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**

## Randomization Criteria

**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.**

## Primary Efficacy VariableSGA of Relief (B351)

**Primary Efficacy Variable****SGA 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**

## Primary Efficacy VariableSGA of Abdominal Discomfort/Pain (B351)

**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**	**Very**	**	**mild**	**	**	**	**severe*

**100 mm**

**Primary Efficacy Variable****SGA of Abdominal Discomfort/Pain (B351)**

**1**

## Statistical Methodology for Primary Efficacy Variables

**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**

## Adjustment Rules

**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**

## 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 scale**
**0 = none**
**1 = very mild**
**2 = mild**
**3 = moderate**
**4 = severe**
**5 = very severe**

**Stool consistency scale**
**1 = watery**
**2 = loose**
**3 = somewhat loose**
**4 = neither loose nor hard**
**5 = somewhat hard**
**6 = hard**
**7 = very hard**

## 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 (%)**

## Demographics

**	****Variable (mean)****	****B351****	****B301****	****B307**
**Age, years****	****43****	****46****	****45**
**Gender, % female ****	****87****	****83****	****84**
**Race, % Caucasian****	****88****	****98****	****91**
**Weight, kg****	****71****	****68****	****70**
**Smoking, %****	****21****	****26****	****22**
**Duration of IBS, years ****	****14****	****13****	****14**
**Use of bulking agents, %****	****18****	****11****	****17**
**Fiber score, g****	****  9****	****11****	****  9**

**1**

## Baseline Characteristics

**	****Variable (mean)**** ****	****B351****	****B301****	****B307**
**Abdominal discomfort/pain****	****63****	****60****	****61****VAS score, mm**
**Bowel habit VAS score, mm****	****64****	****60****	****62**
**Days with significant****	****87****	****84****	****86****abdominal discomfort/pain, %****	****	**
**Days with significant bloating, % ****	****88****	****83****	****86**
**Number of bowel movements/week****	****5.7****	****5.4****	****6.2**
**Days without bowel movements, % ****	****46****	****44****	****41**
**Days with hard stools, %****	****31****	****28****	****29**
**Stool consistency score****	****4.7****	****4.7****	****4.6**

**1**

## Efficacy ResultsPresentation 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**

## SGA Data Presentation

**SGA Data Presentation**

**1**

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**12**

**Response, %**

**Weekly response**

**Monthly response**

**Endpoint:**
**Last 4 available SGA values**
**Adjustment rules***

**1**

**Week**

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

## Primary Efficacy Variables at Endpoint (B351)

***P***** = .05**

**.27**

***P***** = .19**

**.08**

**1**

## Complete or Considerable Relief by Week (B351)

**1**

**†**

*****

*****

*****

*****

*****

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

**†**

**†**

## SGA of Abdominal Discomfort/Pain by Week (B351)

**9**

*****

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

## SGA of Bowel Habit (B351)

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

*****

**Weekly**

*****

**†**

*****

## Daily Diary: Abdominal Discomfort/Pain (B351)

**Improvement**

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

*****

*****

*****

*****

*****

*****

*****

**†**

**†**

**†**

**Pain score**

## Daily Diary: Bloating (B351)

**Improvement**

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

**†**

*****

*****

*****

*****

*****

*****

*****

*****

*****

**†**

**†**

**Bloating score**

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

**1**

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

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**Bowel movements**

**Stool consistency**

## Summary (B351)

**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**

## 	
	B351
Original SGA of relief
Complete or considerable relief at least 50% of the time at study endpoint	

**	****B351**
**Original**** SGA of relief**
**Complete or considerable relief at least 50% of the time at study endpoint****	**

**	**
**	****B301/B307**
**SGA of relief**
**Complete or considerable relief at least 50% of the time at study endpoint**
**	****	****OR**
**At least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint**

**1**

**Modification of Primary Efficacy Variables**

## 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****	****   3**
**Daily bloating score****	****–38****	**** –2**
**VAS score: SGA bowel habit****	****–47****	**** –6**
**Days 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.**

## 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****	****8****discomfort/pain ****	**
**Days with significant pain****  ****	****–73****	****–40****	****  –7****	****18****	****3**
**Daily pain score**** ****	****–72****	****–44****	****–16****	****  4****	****8**
**Days with significant ****	****–61****	****–37****	****  –7****	****  6****	****3**** bloating**** **
**Daily bloating score**** ****	****–64****	****–41****	****–16****	****  1****	****7**
**VAS score: SGA bowel ****	****–75****	****–50****	****–23****	****–3****	****6**** habit**
**Days 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**

## 	
	B351
Original SGA of relief
Complete or considerable relief at least 50% of the time at study endpoint

**	****B351**
**Original**** SGA of relief**
**Complete or considerable relief at least 50% of the time at study endpoint**

**	**
**	****B301/B307**
**SGA of relief**
**Complete or considerable relief at least 50% of the time at study endpoint**
**	****	****OR**
**At 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**

## Efficacy Results SGA of Relief (B351)

***P***** = .05**

**.27**

***P***** = .16**

**.004**

**1**

**SGA of relief**
**(retrospective analysis)**

**Original**** SGA of relief**

## Study B301Efficacy Results

## Study Design (B351 and B301)

**4 mg/d**

**12 mg/d**

**Placebo**

**Baseline**

**Week –4**

**Randomization**

**Week 4**

**Week 8**

**Week 12**

**Week 0**

**1**

**Study Design (B351 and B301)**

## SGA of Relief at Endpoint (B301)

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

**1**

***P***** = .018*****	****.033***

## SGA of Relief at Endpoint

**B301 **

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

**1**

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

## Monthly SGA of Relief

**B301 **

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

**1**

## At Least Somewhat Relief by Week

**1**

**B301**

*****

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*****

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

## SGA of Abdominal Discomfort/Pain (B301)

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

*****

**Weekly**

## SGA of Bowel Habit (B301)

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

**Weekly**

## Daily Diary: Abdominal Discomfort/Pain (B301)

**Improvement**

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

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**Pain score**

## Daily Diary: Bloating (B301)

**Improvement**

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

*****

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**Bloating score**

## Number of Bowel Movements and Stool Consistency by Week (B301)

**1**

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

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**Bowel movements**

**Stool consistency**

## Summary Study B301

**Clear evidence of efficacy**
**Significant treatment differences for SGA of relief **
**Consistent positive findings on secondary efficacy variables**

## Study B307Efficacy Results

## Study Design (B307)

**Nonresponder: 12 mg/d (65%)**

**4 mg/d**

**Placebo**

**Baseline**

**Week –4**

**Randomization**

**Week 4**

**Week 8**

**Week 12**

**Week 0**

**1**

**Study Design (B307)**

**4 mg/d**

**Responder: 4 mg/d (35%)**

## SGA of Relief (B307)

**1**

**Endpoint**

**Monthly**

**†**

*****

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

## At Least Somewhat Relief by Week (B307)

**1**

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

*****

**†**
*****

**†**

**†**
*****

## SGA of Abdominal Discomfort/Pain (B307)

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

**Weekly**

## SGA of Bowel Habit (B307)

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

**Weekly**

## Number of Bowel Movements and Stool Consistency by Week (B307)

**1**

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

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**Bowel movements**

**Stool consistency**

## Summary Study B307

**Favorable effects for tegaserod at Months ****1 and 2 with mixed results at endpoint**
**Not statistically significant for primary efficacy variable**

## Comparative EfficacySummary

## Phase III StudiesAt Least Somewhat Relief

**B351**

**B301**

**B307**

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

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## Phase III StudiesComplete/Considerable Relief

**B351**

**B301**

**B307**

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

*****

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*****

*****

*****

*****

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## 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.**

## Additional Analyses

## 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****	**
**	****	****	****	**

## 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.**

## % Weeks With At Least Somewhat Relief

**Placebo**

**4 mg/d**

**12 mg/d**

**4-12 mg/d**

**4**

***P***** = .021  < .001**

***P***** = .005   < .001**

***P***** = .278    .003**

## SGA of Relief by GenderPooled Results: B351/B301/B307

**1**

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

**Male**

**Female**

********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.**

*****

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**†**

**†**

## SGA of Relief at EndpointPlacebo-Subtracted Values by Gender

**SGA of Relief at Endpoint****Placebo-Subtracted Values by Gender**

**B351**

**B301**

**B307**

*****

**†**

**†**

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

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

## 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**

## Summary of Efficacy (2)

**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**

## Summary of Efficacy (3)

**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**

## Safety

**2**

## Safety Overview

**Exposure**
**Adverse events**
**Laboratory evaluations**
**ECG**
**Summary**

## 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**

## 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**

## Reasons for Discontinuations (Phase III)

**2**

## Overall Adverse Events (Phase III)

**2**

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

**2**

## Time to First Episode of Diarrhea (Phase III)

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

**2**

## 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**

## 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 **

## 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)**

## 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)**

## 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**

## ECG Recording and Analysis

**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)**

## Safety Summary

**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**

## 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**