Efficacy of Zelnorm® for Chronic Constipation

Efficacy of ZelnormEfficacy of Zelnorm® ® for Chronic for Chronic Constipation Constipation

Efficacy of ZelnormEfficacy of Zelnorm® ® for Chronic for Chronic Constipation Constipation

Robert Prizont, MD, Medical OfficerRobert Prizont, MD, Medical OfficerRobert Prizont, MD, Medical OfficerRobert Prizont, MD, Medical Officer

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Division of Gastrointestinal and Coagulation Division of Gastrointestinal and Coagulation Drug Products Drug Products

July 14, 2004July 14, 2004

2Gastrointestinal Drugs Advisory Committee MeetingJuly 14, 2004

IndicationsIndicationsIndicationsIndications

• 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.

• In this application, Novartis is seeking approval of Zelnorm® 6 mg twice a day for the treatment of chronic constipation in males and females.

• 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.

• In this application, Novartis is seeking approval of Zelnorm® 6 mg twice a day for the treatment of chronic constipation in males and females.


OutlineOutlineOutlineOutline

• Definition of Constipation and Relevant Issues of the Prospective Protocol

• Brief Summary of Novartis’ Efficacy

• Patient Representation by Subtype of Constipation

• Primary Efficacy Endpoint

• Conclusion

• Definition of Constipation and Relevant Issues of the Prospective Protocol

• Brief Summary of Novartis’ Efficacy

• Patient Representation by Subtype of Constipation

• Primary Efficacy Endpoint

• Conclusion


Constipation Based on <3 Bowel Constipation Based on <3 Bowel Movements per Week (BM/w)Movements per Week (BM/w)

Constipation Based on <3 Bowel Constipation Based on <3 Bowel Movements per Week (BM/w)Movements per Week (BM/w)

• 1965. British study in 655 women and 400 men defines normal frequency between 3 BM/week to 3 BM/day

• 1975. Federal Register on OTC Laxatives

• 1988. Expert Group in Rome Publish Guidelines

• 1989. NHANES I and II (Survey of 14,407 US Subjects)

• 1999. Rome II Criteria

• 2000. AGA Technical Review on Constipation

• 1965. British study in 655 women and 400 men defines normal frequency between 3 BM/week to 3 BM/day

• 1975. Federal Register on OTC Laxatives

• 1988. Expert Group in Rome Publish Guidelines

• 1989. NHANES I and II (Survey of 14,407 US Subjects)

• 1999. Rome II Criteria

• 2000. AGA Technical Review on Constipation


• Eligibility was based on the Rome Criteria for constipation, i.e., < 3 spontaneous bowel movements per week plus sense of complete evacuation (CSBM/week).

• The primary efficacy endpoint was an increase of at least one CSBM/week.

• Response was limited to the 1st month of a 3-month study.

• Eligibility was based on the Rome Criteria for constipation, i.e., < 3 spontaneous bowel movements per week plus sense of complete evacuation (CSBM/week).

• The primary efficacy endpoint was an increase of at least one CSBM/week.

• Response was limited to the 1st month of a 3-month study.

Prospective ProtocolProspective ProtocolProspective ProtocolProspective Protocol


Prospective Protocol Prospective Protocol (continued)(continued) Prospective Protocol Prospective Protocol (continued)(continued)

• The aim of the studies was to determine Zelnorm® efficacy in chronic idiopathic or functional constipation.

• There was no provision to exclude patients with constipation-predominant Irritable Bowel Syndrome (C-IBS), for which Zelnorm® is already approved.

• The aim of the studies was to determine Zelnorm® efficacy in chronic idiopathic or functional constipation.

• There was no provision to exclude patients with constipation-predominant Irritable Bowel Syndrome (C-IBS), for which Zelnorm® is already approved.


Novartis’ Summary of Efficacy Novartis’ Summary of Efficacy Novartis’ Summary of Efficacy Novartis’ Summary of Efficacy • Study 2301 (Euro) and Study 2302 (US)

• 416 to 451 patients were enrolled in each treatment group

• The increase of ≥1 CSBM/wk resulted in 40% to 43% responders for Zelnorm 6 mg

• Superior to 25% to 27% responders for Placebo

• Study 2301 (Euro) and Study 2302 (US)

• 416 to 451 patients were enrolled in each treatment group

• The increase of ≥1 CSBM/wk resulted in 40% to 43% responders for Zelnorm 6 mg

• Superior to 25% to 27% responders for Placebo


Novartis’ Summary of Efficacy Novartis’ Summary of Efficacy Novartis’ Summary of Efficacy Novartis’ Summary of Efficacy

• The average efficacy in 12 wks revealed no dose response in study 2301 (2 mg vs 6 mg)

• Efficacy was translated in an increase of less than 1 CSBM per week over placebo

• 50-60% of patients used bisacodyl as rescue

• Between 12% to 20% of patients exceeded the protocol-specified use of the rescue laxative

• The average efficacy in 12 wks revealed no dose response in study 2301 (2 mg vs 6 mg)

• Efficacy was translated in an increase of less than 1 CSBM per week over placebo

• 50-60% of patients used bisacodyl as rescue

• Between 12% to 20% of patients exceeded the protocol-specified use of the rescue laxative


Was the Treated Patient Population Was the Treated Patient Population

Representative of Idiopathic Constipation ?Representative of Idiopathic Constipation ?

Was the Treated Patient Population Was the Treated Patient Population

Representative of Idiopathic Constipation ?Representative of Idiopathic Constipation ?


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FunctionalType

IBS Type Outlet Type IBS-Outlet Type

Pre

va

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pe

r 1

00

Females

Males

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FunctionalType

IBS Type Outlet Type IBS-Outlet Type

Pre

va

len

ce

pe

r 1

00

Females

Males

Stewart et al., EPOC Study in the U.S., American Journal of Gastroenterology, 96:3530-3540, 1999


Treated Patient Population in Treated Patient Population in ZelnormZelnorm®® StudiesStudies

Treated Patient Population in Treated Patient Population in ZelnormZelnorm®® StudiesStudies

• 90% Women, mean age 47 years (13% of patients were 65 years or older).

• About half of the patients had three or more SBMs/week at baseline

• Over 80% had less than 2 CSBM/week at baseline.

• Up to 45% had abdominal symptoms as main complaint prior to entry

• 90% Women, mean age 47 years (13% of patients were 65 years or older).

• About half of the patients had three or more SBMs/week at baseline

• Over 80% had less than 2 CSBM/week at baseline.

• Up to 45% had abdominal symptoms as main complaint prior to entry


Inclusion of IBS PatientsInclusion of IBS PatientsInclusion of IBS PatientsInclusion of IBS Patients• The lack of a protocol provision to exclude IBS

allowed entrance of IBS patients in both trials.

• At least 23% of patients had IBS-like symptoms. Some patients had an IBS diagnosis prior to entry.

• The proportion is higher if the main complaint of abdominal distention is part of IBS symptoms.

• The lack of a protocol provision to exclude IBS allowed entrance of IBS patients in both trials.

• At least 23% of patients had IBS-like symptoms. Some patients had an IBS diagnosis prior to entry.

• The proportion is higher if the main complaint of abdominal distention is part of IBS symptoms.

Gastrointestinal Drugs Advisory Committee MeetingJuly 14, 2004

Does the Chosen Primary Does the Chosen Primary Endpoint Represent Efficacy Endpoint Represent Efficacy

Based on the Rome Definition Based on the Rome Definition of Constipation ?of Constipation ?

Does the Chosen Primary Does the Chosen Primary Endpoint Represent Efficacy Endpoint Represent Efficacy

Based on the Rome Definition Based on the Rome Definition of Constipation ?of Constipation ?


Primary Endpoint IssuesPrimary Endpoint Issues Primary Endpoint IssuesPrimary Endpoint Issues

• The Rome Criteria defines constipation as < 3 SBM per week. A complete SBM is required in at least 25% of SBM.

• Efficacy based on the average increase of 1 or more CSBM/week from baseline may count constipated patients as responders.

• Efficacy analysis based on an average of > 3 CSBM/week resulted in fewer responders.

• The Rome Criteria defines constipation as < 3 SBM per week. A complete SBM is required in at least 25% of SBM.

• Efficacy based on the average increase of 1 or more CSBM/week from baseline may count constipated patients as responders.

• Efficacy analysis based on an average of > 3 CSBM/week resulted in fewer responders.


Responders Weeks 1-4 Responders Weeks 1-4 Mean Increase Mean Increase >>1 CSBM/wk or Mean Total 1 CSBM/wk or Mean Total >>3 CSBM/wk3 CSBM/wk

Responders Weeks 1-4 Responders Weeks 1-4 Mean Increase Mean Increase >>1 CSBM/wk or Mean Total 1 CSBM/wk or Mean Total >>3 CSBM/wk3 CSBM/wk

Study 2302Study 2302

Placebo Zel 2 mg* Zel 6 mg*

Increase >1 25% 41% 43%

Total >3 13% 23% 22%

*p<0.05


Primary Endpoint Primary Endpoint IssuesIssuesPrimary Endpoint Primary Endpoint IssuesIssues

• Chronic constipation efficacy in a 12-week study was a 1 CSBM increase from baseline during the initial 4 weeks.

• 12 week efficacy was the mean of CSBMs extended for 12 wks.

• Responders were not required to respond or participate for all 12-weeks

• Chronic constipation efficacy in a 12-week study was a 1 CSBM increase from baseline during the initial 4 weeks.

• 12 week efficacy was the mean of CSBMs extended for 12 wks.

• Responders were not required to respond or participate for all 12-weeks


12-Week Responders 12-Week Responders MMean Increase ean Increase >>1 CSBM/wk or Mean Total 1 CSBM/wk or Mean Total >>3 3

CSBM/wkCSBM/wk

12-Week Responders 12-Week Responders MMean Increase ean Increase >>1 CSBM/wk or Mean Total 1 CSBM/wk or Mean Total >>3 3

CSBM/wkCSBM/wk



Increase >1 27% 40% 45%

Total >3 13% 23% 22%

*p<0.05p


Responders in All 3 MonthsFDA Analysis

________________________

All 3 Month Participants

Responders in All 3 MonthsFDA Analysis

________________________

All 3 Month Participants


Responders in All 3 Months by Responders in All 3 Months by Protocol and by 3 or more CSBMs Protocol and by 3 or more CSBMs

Responders in All 3 Months by Responders in All 3 Months by Protocol and by 3 or more CSBMs Protocol and by 3 or more CSBMs



>1 CSBM/wk 15% 24% 26%

>3 CSBM/wk 7% 14% 12%

*p<0.05


Monthly Responders by the Monthly Responders by the FDA Analysis FDA Analysis ((>>3 CSBM/week)3 CSBM/week)

Monthly Responders by the Monthly Responders by the FDA Analysis FDA Analysis ((>>3 CSBM/week)3 CSBM/week)


Placebo Zel 2 mg Zel 6 mg

1 Month 10% 10% 15%

2 Months 7% 9% 11%

3 Months 7% 14% 12%


ConclusionsConclusionsConclusionsConclusions

• The clinical significance of an endpoint based on an increase of 1 CSBM/week is uncertain.

• Based on the definition of 3 or more CSBM/week, the proportion of responders for all 3 months was small.

• Use of a known laxative (bisacodyl) further confounds the assessment of effectiveness.

• The clinical significance of an endpoint based on an increase of 1 CSBM/week is uncertain.

• Based on the definition of 3 or more CSBM/week, the proportion of responders for all 3 months was small.

• Use of a known laxative (bisacodyl) further confounds the assessment of effectiveness.


Conclusions Conclusions (continued)(continued)Conclusions Conclusions (continued)(continued)

• There is a plethora of OTC laxatives, a few under prescription, all indicated for occasional constipation.

• 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.

• There is a plethora of OTC laxatives, a few under prescription, all indicated for occasional constipation.

• 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.



• 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.

• A benefit from Zelnorm® use to laxative abusers is unknown, for they were excluded from studies.

• 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.

• A benefit from Zelnorm® use to laxative abusers is unknown, for they were excluded from studies.



• Men were under-represented. No statistical differences between treatments were observed.

• Subjects > 65 years were also under-represented (about 10% of all pts). No statistical or numerical differences between treatments were seen.

• Men were under-represented. No statistical differences between treatments were observed.

• Subjects > 65 years were also under-represented (about 10% of all pts). No statistical or numerical differences between treatments were seen.

Efficacy of Zelnorm® for Chronic Constipation

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