# Presentation: 270276

## Zelnorm®(tegaserod maleate)Benefit/Risk

**Philip Schoenfeld, MD, MSEd, MSc (Epi)**
**Division of Gastroenterology**
**University of Michigan School of Medicine**

## Outline

**The Benefit/Risk Analysis for Constipation Therapies: An Evidence Based Medicine Approach**
**Based on RCT evidence, what is the efficacy of tegaserod & traditional therapies? **
**Based on clinical trial data, what is the safety of tegaserod & traditional therapies?**

## Epidemiology of Constipation

**Chronic constipation (CC) is common****1-3**
**CC has a negative impact on quality of life****4,5**
**Many constipation patients are not satisfied with available treatments ****4,6**

**1. Stewart WF, et al. *****Am J Gastroenterol*****. 1999;94:3530-3540.**
**2. Pare P, et al. *****Am J Gastroenterol*****. 2001;96:3130-3137. **
**3. Sandler RS, et al. *****Dig Dis Sci*****. 1987;32:841-845.**
**4. Irvine EJ, et al. *****Am J Gastroenterol*****. 2002;97:1986-1993.**
**5. Damon H, et al. *****Gastroenterol Clin Biol*****. 2004;28:16-20.****	****                                                                   6. Ferrazi S, et al. *****Can J Gastroenterol*****. 2002;16:159-164.**

## Efficacy

## Commonly Used Treatments*for Constipation

**Stimulant Laxatives**
**Surface-Acting Agents**
**Dioctyl Sodium Sulfosuccinate (e.g., Colace****®****)**
**Dioctyl Calcium Sulfosuccinate (e.g., Surfak****®****) **
**Diphenylmethane derivatives: Bisacodyl (e.g., Dulcolax****®****)**
**Anthraquinones: Senna (e.g., Senokot****®****)**
**Bulking Agents**
**Psyllium (e.g, Metamucil****®****)**
**Methylcellulose (e.g., Citrucel****®****)**
**Osmotic Laxatives**
**Poorly absorbed disaccharides: Lactulose**
**PEG-3350 (e.g., Miralax****®****)**
**Poorly absorbed ions: Magnesium Hydroxide (e.g., Milk of Magnesia)**

***Partial list: all treatments are FDA-approved for constipation.**

## Commonly Used Treatments* for Constipation 

**“****Randomized trials ... have been carried out, albeit many of them, under deficient designs”****1**
**“****Trials revealed little difference between laxatives, and modest improvement over placebo”****1**
**Lack of Objective Evidence of Efficacy of Laxatives in Chronic Constipation****2**

**1. Prizont R. Clinical Summary of Efficacy. FDA Briefing Document, 2004.  **
**2. Jones MP, Talley N, et al. *****Dig Dis Sci*****. 2002;47:2222-2230.**

## Lack of Objective Evidence of Efficacy of Laxatives* in Chronic Constipation 1 

**Change in Stool Frequency/week (compared to baseline) **
**Trials ≤ 4 weeks duration**
**Placebo: 1.0 (95% CI: -0.3 to 2.2)**
**Laxatives: 1.9 (95% CI: 1.0 to 2.8)**
**Trials 5-12 weeks duration:**
**Placebo: 1.5 (95% CI: 0.3 to 2.8)**
**Laxatives: 1.0 (95% CI: 0.3 to 1.6)**

***Laxatives in meta-analysis include senna, psyllium, lactulose, docusate, surfak, bran, calcium polycarbophil.**
**1. Jones MP, Talley N, et al. *****Dig Dis Sci*****. 2002;47:2222-2230.                        **

## The Treatment of Chronic Constipation in Adults: A Systematic Review1

**Change in Stool Frequency/week (compared to baseline)**
**Bulking Agents: 1.4 (95% CI: 0.6 to 2.2)**
**Laxatives: 1.5 (95% CI: 1.1 to 1.8)**
**Study Conclusions **
**Fiber and laxatives modestly increase stool frequency **
**Unknown if these agents improve global satisfaction or general well-being**

***Laxatives in review include psyllium, lactulose, docusate, cisapride, magnesium hydroxide, etc.**
**1. Tramonte S, Brand M, Mulrow C, et al for the San Antonio Veterans Affairs Cochrane Center. *****J Gen Int Med*****. 1997;12:15-24.                         **

## Efficacy of Commonly Used Treatments for Constipation

**RCT evidence indicates that psyllium, PEG-3350  (e.g., Miralax****®****), and lactulose increase stool frequency  **
**RCT evidence does not demonstrate increases in stool frequency for other treatments**
**Most of these RCTs suffer from “deficient designs” and do not meet Rome criteria****1**

**1. Van Zanten et al. *****Gut*****. 1999; 5:II69-II77 (Suppl II).**

## The Clinical Trial Data Are Adequate for the CC Population Likely to be Treated With Tegaserod

**#Loose stools are not present, and there are insufficient criteria for IBS. These criteria may not apply when the patient is taking laxatives. **
**§ > 25% of defecations.**
**BM = Bowel movement; CSBM = Complete spontaneous bowel movement.**
**1. Thompson WG, et al. Gut 1999; 45 (Suppl II): II43-II47**

**Addendum to SCE T 2-7**

**43**

## 78% of RCT Patients Had Chronic Constipation

** ****Up to 22% of patients may have had IBS-C**
**“****Responder rates for the non-IBS-like patients were similar to the overall rates”****1**
**Some patients with slow transit constipation may have been enrolled**
**Treatment recommendations for normal transit & slow transit constipation are quite similar****2**

**1. Mele J. Statistical Review & Evaluation. FDA Briefing Document. July 14, 2004, p. 29     2. American Gastroenterological Association Medical Position Statement on Constipation. *****Gastroenterology*****. 2000;119:1761-1778.**

## Appropriateness of a Primary Efficacy Endpoint of  ≥ 1 CSBM/wk (Compared to Baseline) Vs % of CC Patients Achieving ≥ 3 CSBM/wk 

**ROME II Consensus Document****1**
**Multiple symptoms are present in functional constipation and IBS**
**Multiple endpoints may be used to assess efficacy in these disorders**
**Global improvement in satisfaction may be the most appropriate endpoint****1,2**

**1. Whitehead WE, Corazziari E, Prizont R, et al. *****Gut*****. 1999;45:II78-II79.**
**2. Van Zanten et al. *****Gut*****. 1999;45:II69-II77 (Suppl II).**

## Global Satisfaction With Bowel Habits

***p < 0.05 for both analyses**

**Responder: mean decrease ≥ 1 point on 5-point likert scale, compared with baseline on week 1 - 12.**

*****

*****

## Appropriateness of Efficacy Endpoints 

***A priori***** secondary endpoints demonstrate significant improvement for tegaserod 6 mg bid vs placebo:**
**Average number of spontaneous BM/wk**
**1.9 - 2.0/wk vs 0.9 - 1.0/wk **
**Tegaserod has demonstrated significant improvement vs placebo for proportion of patients with ≥ 3 CSBM/week:**

**p < 0.05 for all analyses**

|  | Tegaserod | Placebo |
| --- | --- | --- |
| Weeks 1 - 4 | 22% | 13% |
| Weeks 1 - 12 | 22 – 25% | 13 – 14% |

## Conclusions: Efficacy

**RCT data of tegaserod efficacy is robust and precise **
**The study population reflects patients with chronic constipation**
**The *****a priori***** primary and secondary endpoints are reflect the multiple symptoms of chronic constipation**
**RCT data demonstrate that tegaserod produces significant and clinically important improvement in the multiple symptoms of chronic constipation**

## Safety

## Commonly Used Treatments for Constipation: Safety

**The Treatment of Chronic Constipation in Adults****1**
**“****Few studies used standardized techniques for assessing adverse effects”**
**For laxatives vs placebo, no significant differences in adverse events were identified**
**Conclusion: “Although there is no evidence that laxatives are unduly harmful, data are very limited and short-term”**

***Laxatives in review include psyllium, lactulose, docusate, cisapride, magnesium hydroxide, etc.**
**Tramonte S, Brand M, Mulrow C, et al for the San Antonio Veterans Affairs Cochrane Center. *****J Gen Int Med*****. 1997;12:15-24.                         **

##  *Reported Adverse Effects of Laxatives1

**Bulking Agents**
**Acute esophageal obstruction (with or without esophageal disease)**
**Fecal impaction and large bowel obstruction**
**Anaphylaxis**
**Osmotic Agents**
**Magnesium-based agents: hypermagnesemia**
**Phospate-based agents: hyperphosphatemia**
**Lactulose: hypernatremia**
**Stimulant Laxatives**
**Anthraquinones: electrolyte imbalances, abdominal pain, allergic reaction, and potential hepatotoxicity.**

***Partial list: all treatments are FDA-approved for constipation.**
**1. Xing JH, Soffer E. Adverse Effects of Laxatives. *****Dis Colon Rectum*****. 2001;44:1201-1209.**

## The clinical trials & post-marketing surveillance data provide adequate evidence of safety

**Over 2600 patients enrolled in two placebo-controlled RCTs of patients with chronic constipation **
**1742 tegaserod-using pts vs 861 placebo-using pts**
**Clinical trial data on over 11,640 tegaserod-treated pts**
**3456 patient-years of tegaserod use in clinical trials **
**Clinical trial safety data for tegaserod is more robust and precise than for any other constipation treatment**

## RCT Data about Frequency of Serious Adverse Events in Constipation Patients

**Serious adverse events leading to discontinuation was 0.3% in both groups. **

**n = 1742**

**n = 861**

## Diarrhea: Adverse Events

***Clinical trial data on % of patients with diarrhea adverse event or discontinuation**
**due to diarrhea comes from studies E2301 and E2302. **
****Clinical trial data on clinically significant consequences of diarrhea comes from the entire ****completed clinical trial database.**

**CSC = Clinically significant consequences of diarrhea**

## Background on Ischemic Colitis: Alosetron Data 

***17 cases (0.16%) of ischemic colitis among 10,805 alosetron-treated patients in clinical trials**
**Alosetron: 5.9 cases per 1000 patient-years**
**Placebo: 1.1 cases per 1000 patient-years**

**Briefing Document on Lotronex (alosetron HCL) for the FDA Joint GI Drugs Advisory Committee and Drug Safety and Risk Management Sub-Committee. April 23, 2002.**

## Reported Rate of Ischemic Colitis from Clinical Trial Data of PEG-3350

**PEG-3350 (MiraLax****®****) NDA-Clinical Trial Data****1**
**3 cases per 1000 patient-years**

**1.Gallo-Torres H. NDA 20-698. Division of Gastrointestinal and Coagulation Drug Products Medical Officer’s Review. MiraLax****®****. Aug 26, 1998. 1 case of ischemic colitis/~300 patient-years**
**CDER/CBER Pharmacovigilance Working Group. Concept Paper: Risk Assessment of Observational Data. FDA Center for Drug Research and Evaluation. March 3, 2003. Lines 278-280: FDA recognizes the value of comparisons of reporting rates across... different product classes prescribed for the same indication.**

## Ischemic Colitis: Controlled Clinical Trial Data

**Zero cases among 11,640 tegaserod-treated patients**
**Zero cases over 3456 patient-years of exposure**
**One probable IC case among 4267 placebo-treated patients**
**One probable IC case over 780 patient-years of exposure**

**Chronic constipation RCT Data: 0 cases of ischemic colitis among 1742 tegaserod-using patients (e.g., ~ 430 patient-years)**

## Maximum Rate (95% CI) of Ischemic Colitis Based on Clinical Trial Data

| Clinical Trial Patient Population | Maximal IC Rate |
| --- | --- |
| ~7000 Tegaserod patients
(Preliminary analysis) | 1 in ~2000 |
| 11,640 Tegaserod patients | 1 in 3883 |
| 4267 Placebo patients | 1 in 867 |

## US Post-Marketing Surveillance Data

**Over 2 million prescriptions of tegaserod **
**Over 233,000 patient-years of tegaserod use**
**26 reported cases of possible IC cases in US**
**~12 cases/100,000 patient-years in US**

## Ischemic Colitis IsMore Common in IBS

**C**

|  | Non-IBS | IBS |
| --- | --- | --- |
| Medi-Cal#1 (1995 - 2002) | 47 | 179 |
| United Health Care#2 (1995 - 1999) |   7 |   43 |
|  |  |   53 (IBS > 1 year)3 |
| CORI, ASGE‡ (2000 - 2003) | 21 |   93 |

**#Per 100,000 patient-yr.**
**‡****Per 100,000 colonoscopies.**
**1. Singh et al. *****Gastroenterology***** 2004;126:A349;A41**
**2. Cole et al. *****American Journal of Gastro.***** 2004;486-491**
**3. Brinker A et al. *****Clinical Pharmacology and Therapeutics*****, 2003 vol 73, p 33 Abstract.**

## Ischemic Colitis IsMore Common in IBS

**C**

|  | Non-IBS | IBS |
| --- | --- | --- |
| Medi-Cal#1 (1995 - 2002) | 47 | 179 |
| United Health Care#2 (1995 - 1999) |   7 |   43 |
|  |  |   53 (IBS > 1 year)3 |
| CORI, ASGE‡ (2000 - 2003) | 21 |   93 |
| Post-marketing surveillanceof tegaserod-using patients |  |   12 |

**#Per 100,000 patient-yr.**
**‡****Per 100,000 colonoscopies.**
**1. Singh et al. *****Gastroenterology***** 2004;126:A349;A41**
**2. Cole et al. *****American Journal of Gastro.***** 2004;486-491**
**3. Brinker A et al. *****Clinical Pharmacology and Therapeutics*****, 2003 vol 73, p 33 Abstract.**

## Conclusions: Safety

**More robust & precise clinical trial safety data for tegaserod than for other constipation therapies  **
**Safety data demonstrates a low rate of serious consequences of diarrhea**
**Evidence does not support an association between tegaserod and ischemic colitis**

## Global Benefit/Risk Assessment of Tegaserod

**Robust efficacy data from two largest RCTs of CC patients**
**Significant improvement in multiple symptoms of constipation:**
**Global satisfaction**
**CSBM****	****-SBM**
**Robust safety data from clinical trials:**
**1742 CC patients**
**Over 11,000 patients (total)**

**Diarrhea:**
**5.4% vs 3% in CC patients**
**D/C due to diarrhea: 0.6%**
**CSC of diarrhea: 0.04%**
**Evidence does not support an association with ischemic colitis**

**Benefits**

**Risks**

## Global Benefit/Risk Assessment of Tegaserod 

**This analysis demonstrates a favorable risk-benefit profile for tegaserod in the management of chronic constipation**
**The risk-benefit analysis for tegaserod compares favorably with risk-benefit analyses of traditional therapies of constipation**