Efficacy of Zelnorm ®  for Chronic Constipation  Robert Prizont, MD, Medical Officer Center for Drug Evaluation and Resear...
Indications <ul><li>Zelnorm ®  (tegaserod maleate), 6 mg twice a day, is currently approved for the treatment of women wit...
Outline <ul><li>Definition of Constipation and Relevant Issues of the Prospective Protocol </li></ul><ul><li>Brief Summary...
Constipation Based on <3 Bowel Movements per Week (BM/w) <ul><li>1965. British study in 655 women and 400 men defines  nor...
<ul><li>Eligibility was based on the Rome Criteria  for constipation, i.e., < 3 spontaneous bowel movements per week plus ...
Prospective Protocol  (continued)   <ul><li>The aim of the studies was to determine Zelnorm ®  efficacy in chronic idiopat...
Novartis’ Summary of Efficacy  <ul><li>Study 2301 (Euro) and Study 2302 (US)  </li></ul><ul><li>416 to 451 patients were e...
Novartis’ Summary of Efficacy  <ul><li>The average efficacy in 12 wks revealed no dose response in study 2301 (2 mg vs 6 m...
Was the Treated Patient Population    Representative of Idiopathic Constipation ?
Stewart  et al.,  EPOC Study in the U.S., American Journal of Gastroenterology, 96:3530-3540, 1999
Treated Patient Population in Zelnorm ®   Studies <ul><li>90% Women, mean age 47 years (13% of patients were 65 years or o...
Inclusion of IBS Patients <ul><li>The lack of a protocol provision to exclude IBS allowed entrance of IBS patients in both...
Does the Chosen Primary  Endpoint Represent Efficacy Based on the Rome Definition of Constipation ?
Primary Endpoint Issues <ul><li>The Rome Criteria defines constipation  as < 3 SBM per week. A complete SBM is required in...
Responders Weeks 1-4  Mean Increase  > 1 CSBM/wk or Mean Total  > 3 CSBM/wk <ul><li>Study 2302 </li></ul>*p < 0.05  22% 2...
Primary Endpoint  Issues <ul><li>Chronic constipation efficacy in a 12-week study was a 1 CSBM increase from baseline duri...
12-Week Responders  M ean Increase  > 1 CSBM/wk or Mean Total  > 3 CSBM/wk <ul><li>Study 2302 </li></ul>*p<0.05p 22% 23% 1...
<ul><li>Responders in All 3 Months </li></ul><ul><li>FDA Analysis </li></ul><ul><li>________________________ </li></ul><ul...
Responders in All 3 Months by Protocol and by 3 or more CSBMs  <ul><li>Study 2302 </li></ul>*p < 0.05 12% 14% 7% > 3 CSBM/...
Monthly Responders by the   FDA Analysis  ( > 3 CSBM/week) <ul><li>Study 2302 </li></ul>12% 14% 7% 3 Months 11% 9% 7% 2 Mo...
Conclusions <ul><li>The clinical significance of an endpoint based on an increase of  1  CSBM/week is uncertain. </li></ul...
Conclusions  (continued) <ul><li>There is a plethora of OTC laxatives, a few under  prescription, all indicated for occasi...
Conclusions  (continued) <ul><li>It is unclear which constipation subtype benefited from Zelnorm ® . The contribution to e...
Conclusions  (continued) <ul><li>Men were under-represented.  No statistical differences between treatments were observed....
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Efficacy of Zelnorm® for Chronic Constipation

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Efficacy of Zelnorm® for Chronic Constipation

  1. 1. Efficacy of Zelnorm ® for Chronic Constipation Robert Prizont, MD, Medical Officer Center for Drug Evaluation and Research Division of Gastrointestinal and Coagulation Drug Products July 14, 2004
  2. 2. Indications <ul><li>Zelnorm ® (tegaserod maleate), 6 mg twice a day, is currently approved for the treatment of women with irritable bowel syndrome-constipation predominant . Zelnorm ® is not approved for males. </li></ul><ul><li>In this application, Novartis is seeking approval of Zelnorm ® 6 mg twice a day for the treatment of chronic constipation in males and females. </li></ul>
  3. 3. Outline <ul><li>Definition of Constipation and Relevant Issues of the Prospective Protocol </li></ul><ul><li>Brief Summary of Novartis’ Efficacy </li></ul><ul><li>Patient Representation by Subtype of Constipation </li></ul><ul><li>Primary Efficacy Endpoint </li></ul><ul><li>Conclusion </li></ul>
  4. 4. Constipation Based on <3 Bowel Movements per Week (BM/w) <ul><li>1965. British study in 655 women and 400 men defines normal frequency between 3 BM/week to 3 BM/day </li></ul><ul><li>1975. Federal Register on OTC Laxatives </li></ul><ul><li>1988. Expert Group in Rome Publish Guidelines </li></ul><ul><li>1989. NHANES I and II (Survey of 14,407 US Subjects) </li></ul><ul><li>1999. Rome II Criteria </li></ul><ul><li>2000. AGA Technical Review on Constipation </li></ul>
  5. 5. <ul><li>Eligibility was based on the Rome Criteria for constipation, i.e., < 3 spontaneous bowel movements per week plus sense of complete evacuation (CSBM/week). </li></ul><ul><li>The primary efficacy endpoint was an increase of at least one CSBM/week. </li></ul><ul><li>Response was limited to the 1 st month of a 3-month study. </li></ul>Prospective Protocol
  6. 6. Prospective Protocol (continued) <ul><li>The aim of the studies was to determine Zelnorm ® efficacy in chronic idiopathic or functional constipation. </li></ul><ul><li>There was no provision to exclude patients with constipation-predominant Irritable Bowel Syndrome (C-IBS), for which Zelnorm ® is already approved. </li></ul>
  7. 7. Novartis’ Summary of Efficacy <ul><li>Study 2301 (Euro) and Study 2302 (US) </li></ul><ul><li>416 to 451 patients were enrolled in each treatment group </li></ul><ul><li>The increase of ≥ 1 CSBM/wk resulted in 40% to 43% responders for Zelnorm 6 mg </li></ul><ul><li>Superior to 25% to 27% responders for Placebo </li></ul>
  8. 8. Novartis’ Summary of Efficacy <ul><li>The average efficacy in 12 wks revealed no dose response in study 2301 (2 mg vs 6 mg) </li></ul><ul><li>Efficacy was translated in an increase of less than 1 CSBM per week over placebo </li></ul><ul><li>50-60% of patients used bisacodyl as rescue </li></ul><ul><li>Between 12% to 20% of patients exceeded the protocol-specified use of the rescue laxative </li></ul>
  9. 9. Was the Treated Patient Population Representative of Idiopathic Constipation ?
  10. 10. Stewart et al., EPOC Study in the U.S., American Journal of Gastroenterology, 96:3530-3540, 1999
  11. 11. Treated Patient Population in Zelnorm ® Studies <ul><li>90% Women, mean age 47 years (13% of patients were 65 years or older). </li></ul><ul><li>About half of the patients had three or more SBMs/week at baseline </li></ul><ul><li>Over 80% had less than 2 CSBM/week at baseline. </li></ul><ul><li>Up to 45% had abdominal symptoms as main complaint prior to entry </li></ul>
  12. 12. Inclusion of IBS Patients <ul><li>The lack of a protocol provision to exclude IBS allowed entrance of IBS patients in both trials. </li></ul><ul><li>At least 23% of patients had IBS-like symptoms. Some patients had an IBS diagnosis prior to entry. </li></ul><ul><li>The proportion is higher if the main complaint of abdominal distention is part of IBS symptoms. </li></ul>
  13. 13. Does the Chosen Primary Endpoint Represent Efficacy Based on the Rome Definition of Constipation ?
  14. 14. Primary Endpoint Issues <ul><li>The Rome Criteria defines constipation as < 3 SBM per week. A complete SBM is required in at least 25% of SBM. </li></ul><ul><li>Efficacy based on the average increase of 1 or more CSBM/week from baseline may count constipated patients as responders. </li></ul><ul><li>Efficacy analysis based on an average of > 3 CSBM/week resulted in fewer responders. </li></ul>
  15. 15. Responders Weeks 1-4 Mean Increase > 1 CSBM/wk or Mean Total > 3 CSBM/wk <ul><li>Study 2302 </li></ul>*p < 0.05  22% 23% 13% Total > 3 43% 41% 25% Increase > 1 Zel 6 mg* Zel 2 mg* Placebo
  16. 16. Primary Endpoint Issues <ul><li>Chronic constipation efficacy in a 12-week study was a 1 CSBM increase from baseline during the initial 4 weeks. </li></ul><ul><li>12 week efficacy was the mean of CSBMs extended for 12 wks. </li></ul><ul><li>Responders were not required to respond or participate for all 12-weeks </li></ul>
  17. 17. 12-Week Responders M ean Increase > 1 CSBM/wk or Mean Total > 3 CSBM/wk <ul><li>Study 2302 </li></ul>*p<0.05p 22% 23% 13% Total > 3 45% 40% 27% Increase > 1 Zel 6 mg* Zel 2 mg* Placebo
  18. 18. <ul><li>Responders in All 3 Months </li></ul><ul><li>FDA Analysis </li></ul><ul><li>________________________ </li></ul><ul><li>All 3 Month Participants </li></ul>
  19. 19. Responders in All 3 Months by Protocol and by 3 or more CSBMs <ul><li>Study 2302 </li></ul>*p < 0.05 12% 14% 7% > 3 CSBM/wk 26% 24% 15% >1 CSBM/wk Zel 6 mg* Zel 2 mg* Placebo
  20. 20. Monthly Responders by the FDA Analysis ( > 3 CSBM/week) <ul><li>Study 2302 </li></ul>12% 14% 7% 3 Months 11% 9% 7% 2 Months 15% 10% 10% 1 Month Zel 6 mg Zel 2 mg Placebo
  21. 21. Conclusions <ul><li>The clinical significance of an endpoint based on an increase of 1 CSBM/week is uncertain. </li></ul><ul><li>Based on the definition of 3 or more CSBM/week, the proportion of responders for all 3 months was small. </li></ul><ul><li>Use of a known laxative (bisacodyl) further confounds the assessment of effectiveness. </li></ul>
  22. 22. Conclusions (continued) <ul><li>There is a plethora of OTC laxatives, a few under prescription, all indicated for occasional constipation. </li></ul><ul><li>The proposed indication is for the use of Zelnorm ® in chronic constipation of all subtypes. However, the aim of the studies was to demonstrate the effect of Zelnorm on the idiopathic subtype of chronic constipation. </li></ul>
  23. 23. Conclusions (continued) <ul><li>It is unclear which constipation subtype benefited from Zelnorm ® . The contribution to efficacy by C-IBS and outlet obstruction patients is unresolved, because 90% were women, many with a predominance of abdominal symptoms. </li></ul><ul><li>A benefit from Zelnorm ® use to laxative abusers is unknown, for they were excluded from studies. </li></ul>
  24. 24. Conclusions (continued) <ul><li>Men were under-represented. No statistical differences between treatments were observed. </li></ul><ul><li>Subjects > 65 years were also under-represented (about 10% of all pts). No statistical or numerical differences between treatments were seen. </li></ul>

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