# Presentation: 247502

## ZELMAC (tegaserod)  

**Presentation to**
**GI Advisory Committee**
**June 26, 2000**

**Raymond E. Joseph MD**
**Medical Officer**
**HFD-180**

## Zelmac Background

**Proposed Indication:**
**Indicated for the treatment of irritable bowel syndrome (IBS) in patients who identify abdominal pain/discomfort and constipation as their predominant symptoms**

**Notes:**
Zelmac-this is the indication in the labeling
the subset of IBS with constipation -predominant IBS

## Zelmac NDA Submission

**2 Phase II-double-blind trials:**
**Study 251****:**** (n=547) 45 sites in North America and Europe; dose-ranging with 4 dose levels of tegaserod or PL for 12 weeks**
**Study 202****: ****(n=123) 16 sites in Europe and Canada; dose-titration with 4 dose levels of tegaserod or PL for 20 weeks**

**Notes:**
There were 670 pts. In the phase II trials
study 251 an. Amer. &europe study
	dose-ranging(1,4,12,&24mg/d)
		no dose response curve
study202 europe &can. Used a dose-titration arm -after 4 wks. Of 4mg-no respond(old criteria) increase dose to 12mg/d
large PL response at time of pseudo-titration;sustained till the end of the study

## Summary of Phase II Studies

**Study 251**** **
**	****	****	****1mg/d =PL; 4mg/d most effective dose**
**	****	****	****No dose response seen over the range of **
**	****	****	****4 to 24 mg/d**
**Study 202**** **
**	****	****	****Increased response rates observed during **
**	****	****	****dose-titration from 4 to 12 mg/d**
** ****Doses of 4 and 12 mg/d chosen for Phase III trials**

## Phase III Trials -2521 PtsSimilarities

**PL-controlled, double-blind, randomized, three parallel groups with dose levels of 4, 12 mg vs placebo with 4 week baseline and 12 -week treatment period**

**Study 351**
**Study 301**
**Study 307**

**      ****(Dose titration- **
**      ****4 to 12 mg/d at 1   **
**      ****mo)**

**Notes:**
Study 351 was completed first
def. Of responder thought to be too restrictive;added “somewhat relieved” (100% of the time)
this new def. Of responder was then used for the other 2 studies 

## Phase III Trials

**Study 351(n=799)**
**First of the three Phase III studies to be completed**
**The protocol pre-specified analysis failed to demonstrate efficacy**
**Subsequently **
**a) the definition of responder in the SGA of relief was   **
**    ****changed to incorporate “somewhat” relieved 100% of   **
**    ****the time**
**b) the SGA of abd. discomfort/pain was changed to a **
**    ****secondary efficacy variable**
**Post-hoc analyses incorporating the above changes demonstrated efficacy for the 12 mg/d dose level**

**Led to protocol amendments for studies 301 and 307**

**Notes:**
Study 351 was completed first
def. Of responder thought to be too restrictive;added “somewhat relieved” (100% of the time)
this new def. Of responder was then used for the other 2 studies 

## Responder Rates for SGA of Relief 

## Efficacy Issues

**	****1. ****Pain ****not adequately assessed as an efficacy**
**    ****endpoint**
**2. Overall difference between drug and PL group is 8%**
**3. Efficacy in males not established**
**4. Potential affect of laxatives**

**Notes:**
These issues will be discussed in following slides

## Abdominal Pain

**Pain is an essential component of IBS**
**When analyzed as a component of SGA of relief along with well-being and altered bowel function was statistically significant for studies 351 and 301**
**However, when analyzed independently no statistical difference was seen in studies 301 and 307**

**Notes:**
1
2
3 pain is still somewhat represented in the SGA of Relief
4 abd. Pain reaches stat. Sig. For the 12mg. Dose only(301)

## Responder Rates for SGA of Abdominal Discomfort/Pain 

## Overall Efficacy 8-11 %

**Discussion Factors:**
**  ****	****a) effect of gender in this study group**
**  ****	****b) effect of long-standing disease**
**Are results clinically meaningful?**

**Notes:**
Pts. With long duration of disease-more recalcitrant to therapy

(this slide not done)
small # of males makes it difficult to evaluate

## Efficacy in Males

**Studies included 15% males **
**Response to Zelmac in males was not different compared to placebo**
**Lack of differentiation from placebo**
**inadequate sample size **
**may raise the question whether the disease is different in males**

**Notes:**
Pts. With long duration of disease-more recalcitrant to therapy

(this slide not done)
small # of males makes it difficult to evaluate

## Laxative Use

**1. In the clinical trails, laxative use including bulking-agents was allowed**
**2. The use and timing of laxatives may influence the response of the SGA of relief **
**3. There was similar qualitative consumption between groups**
** ****Quantitative differences not assessed may be affecting outcome in constipation study patients**

**Notes:**
Pts. With constipation feel generally relieved with a BM brought on by a laxative

better if no laxative use allowed in responders

#of tsps. Etc. of bulking agents in each arm not known

## Efficacy Summary

**1. Overall efficacy was shown in one of the pivotal studies (301) for both the 4 mg and 12 mg dose levels ; supportive study 351 showed efficacy for the 12 mg dose level only; efficacy not replicated in 307**
**2. Efficacy in males not demonstrated **
**3. Laxative usage may have had an affect on efficacy **

**Notes:**
Read & elaborate on the 5 points

## Most Frequently Reported AEs in Phase III

- In Phase II and long term results are similar

## Most Frequently AEs Led to Discontinuation in Phase II & III

## Duration of Exposure 

**Duration of Exposure **
**Pooled L-T Studies**

## Safety in Generaln =1679

**Approx. 72% phase III pts experienced one AE Only ****diarrhea**** was statistically significantly different from PL 11.7% vs 5.4%**
**	****(p <0.0001)**
**AEs only marginally greater in tegaserod groups vs placebo **
**SAEs incidence-tegaserod (1.8%) = PL**
**profiles  were similar**

**Notes:**
Mention study 209
review most common AEs

Even thought syncope is 5X more frequent in the tegaserod group than PL;changes in vital signs & orthostatic hypotension are the same in all groups

## Safety (Cont.)

**One death- in study 301-Patient with 14y Hx of depression; committed suicide on day 36 of drug**
**5 SAEs in tegaserod pts-possibly related to test medication**
**abdominal pain ****	**** [n=2]**
**gastritis****	****	**** [n=1]**
**SVT ****	****	****	**** [n=1]**
**hypoglycemia****	**** [n=1]**

**Notes:**
This death is not thought to be related to drug

overall SAEs the same in all treatment groups(1.8%)

## Safety Issues

**. ****Diarrhea (> 3 BMs/d, loose, watery **
**   ****with a sense of urgency) **
**. ****Syncope **
**tegaserod (n=8) vs PL (n=1) p=(NS) **
** ****3.”Ovarian Cysts”**

## Diarrhea

**Incidence: 11.7% tegaserod vs***** *****5.4% **_**PL**_
**p value <0.0001 **
**In alternators (18-36% at baseline) 21%**
**Discontinuation secondary to diarrhea was 2.1% in tegaserod vs 0.6% in PL **
**	****p value = 0.002**
**50% occurred during the first week; contributing factors?**
**In long-term ****study 209****, 14.6% experienced diarrhea leading to discontinuation in 3.5 %**

**Notes:**
P==

diarrhea predom. Occurred early;no definite contributing factor/s identified

best method to treat ? stop the drug

## Possible Ovarian Cysts

**Notes:**
State facts from slide

## Pts Undergoing Surgery

**All**** 5 cases on 12 mg/d dose of drug**
**3 in study 209 ( ie. long- term)**
**1 in study 307**
**1 in study 351**
**None**** from placebo groups**

**Notes:**
Read slide

## Case No. 1 (12 mg)

**50y WF 10y Hx. of ovarian cyst**
**	****no abdominal pain**
**Elective surgery performed on day **
**	****334 of drug**
**Surgery: benign tumor; no cyst**
** ****Not associated with test med**.

## Case No. 2 (12 mg)

**45y WF with past Hx. of hysterectomy experienced abdominal pain; **
**went to OR on day 261 of drug **
**Surgery:**
**bilateral salpingo-oophorectomy**
**post-op diagnosis:**** ****adhesions**
**there is no mention of a cyst**

## Case No. 3 (12 mg)

**37y BF with past Hx. of hysterectomy abdominal pain on day 100 of drug**
**CT scan:**** ****2.7 cm right ovarian cyst**
**Surgery:**** ****due to continue pain  **
**(performed 5 weeks later) **
**	****right salpingo-oophorectomy, **
**lysis of**** ****adhesions****, appendectomy**
**Pathology****: 1cm peritubal cyst, adhesions, normal appendix**

**Notes:**
May have been a small functional cyst at time of CT or peritubal cyst was confused

## Case No. 4 (12 mg)

**35y F presented with unknown Hx **
**Surgery: day 306 of drug**
**Pathology: multiple ovarian cysts, **
**including 3.5cm partially luteinized follicle cyst and adenomyosis of the uterus**

**Notes:**
This is consistent with a functional ovarian cyst

## Case No. 5 (12mg)

**13y WF with past Hx. of bilateral ovarian cysts Presented on day 87 of drug **
**	****with right-sided abdominal pain**
**Surgery: laparoscopic resection of a right ovarian cyst (4 to 5cm) and appendectomy. **
**Ovarian cyst seen at surgery-lysed and drained**
**Pathology:**** ****early appendicitis**

## Surgery Summary

**Relationship between drug and ovarian cysts is unknown **
**3 of the 5 had previous pelvic surgery**
**	****Adhesion were seen in 2**
**One had early appendicitis**
**Pharmacologic effects - **
**lower abdomen and pelvis**

## Ovarian Cysts In Ongoing Studies

**One case****- ****(Tx. group=blinded)**
**43y F with Hx. of tubal ligation with reversal **
**Diagnosed with ovarian cyst via sonogram on day 23 of drug**
**Discontinued from the trial due to nausea and flatulence**

**Notes:**
No further info.

?’ Common thread’  previous surgery

## Safety Summary

**AEs occurring more frequently in the tegaserod group**
**Syncope p=(NS)**
**Diarrhea p< 0.0001**
**Ovarian cyst - the significance of which  is unclear at present**
**Relationship of Zelmac to risk of abdominal  pathology  leading to surgery unknown**

**Notes:**
Read & elaborate on the 5 points