CB1

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Zelnorm(tegaserod maleate)Benefit/Risk

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

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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?

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Epidemiology of Constipation

• Chronic constipation (CC) is common1-3
• CC has a negative impact on quality of life4,5
• Many constipation patients are not satisfied with
  available treatments 4,6

1. Stewart WF, et al. Am J Gastroenterol.
1999943530-3540. 2. Pare P, et al. Am J
Gastroenterol. 2001963130-3137. 3. Sandler RS,
et al. Dig Dis Sci. 198732841-845. 4. Irvine
EJ, et al. Am J Gastroenterol. 2002971986-1993.
5. Damon H, et al. Gastroenterol Clin Biol.
20042816-20.
6. Ferrazi S, et
al. Can J Gastroenterol. 200216159-164.
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Efficacy
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Commonly Used Treatmentsfor 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.
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Commonly Used Treatments for Constipation

• Randomized trials have been carried out,
  albeit many of them, under deficient designs1
• Trials revealed little difference between
  laxatives, and modest improvement over placebo1
• Lack of Objective Evidence of Efficacy of
  Laxatives in Chronic Constipation2

1. Prizont R. Clinical Summary of Efficacy. FDA
Briefing Document, 2004. 2. Jones MP, Talley N,
et al. Dig Dis Sci. 2002472222-2230.
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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. 2002472222-2230.

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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. 19971215-24.
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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 criteria1

1. Van Zanten et al. Gut. 1999 5II69-II77
(Suppl II).
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The Clinical Trial Data Are Adequate for the CC
Population Likely to be Treated With Tegaserod
Addendum to SCE T 2-7
43
Loose stools are not present, and there are
insufficient criteria for IBS. These criteria may
not apply when the patient is taking laxatives.
gt 25 of defecations. BM Bowel movement
CSBM Complete spontaneous bowel movement. 1.
Thompson WG, et al. Gut 1999 45 (Suppl II)
II43-II47
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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 rates1
• Some patients with slow transit constipation may
  have been enrolled
• Treatment recommendations for normal transit
  slow transit constipation are quite similar2

1. Mele J. Statistical Review Evaluation. FDA
Briefing Document. July 14, 2004, p. 29 2.
American Gastroenterological Association Medical
Position Statement on Constipation.
Gastroenterology. 20001191761-1778.
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Appropriateness of a Primary Efficacy Endpoint of
1 CSBM/wk (Compared to Baseline) Vs of CC
Patients Achieving 3 CSBM/wk

• ROME II Consensus Document1
• 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 endpoint1,2

1. Whitehead WE, Corazziari E, Prizont R, et al.
Gut. 199945II78-II79. 2. Van Zanten et al. Gut.
199945II69-II77 (Suppl II).
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Global Satisfaction With Bowel Habits

p lt 0.05 for both analyses

Responder mean decrease 1 point on 5-point
likert scale, compared with baseline on week 1 -
12.
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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 lt 0.05 for all analyses
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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

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Safety
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Commonly Used Treatments for Constipation Safety

• The Treatment of Chronic Constipation in Adults1
• 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. 19971215-24.

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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.
2001441201-1209.
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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

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RCT Data about Frequency of Serious Adverse
Events in Constipation Patients
n 1742
n 861
Serious adverse events leading to discontinuation
was 0.3 in both groups.
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Diarrhea Adverse Events
CSC Clinically significant consequences of
diarrhea
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.
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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.
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Reported Rate of Ischemic Colitis from Clinical
Trial Data of PEG-3350

• PEG-3350 (MiraLax) NDA-Clinical Trial Data1
• 3 cases per 1000 patient-years

1.Gallo-Torres H. NDA 20-698. Division of
Gastrointestinal and Coagulation Drug Products
Medical Officers 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.
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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)
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Maximum Rate (95 CI) of Ischemic Colitis Based
on Clinical Trial Data
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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

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Ischemic Colitis IsMore Common in IBS
C
Per 100,000 patient-yr. Per 100,000
colonoscopies. 1. Singh et al. Gastroenterology
2004126A349A41 2. Cole et al. American Journal
of Gastro. 2004486-491 3. Brinker A et al.
Clinical Pharmacology and Therapeutics, 2003 vol
73, p 33 Abstract.
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Ischemic Colitis IsMore Common in IBS
C
Per 100,000 patient-yr. Per 100,000
colonoscopies. 1. Singh et al. Gastroenterology
2004126A349A41 2. Cole et al. American Journal
of Gastro. 2004486-491 3. Brinker A et al.
Clinical Pharmacology and Therapeutics, 2003 vol
73, p 33 Abstract.
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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

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Global Benefit/Risk Assessment of Tegaserod
Benefits
Risks

• 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

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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