ce-1 zelnorm ® (tegaserod maleate) efficacy and safety in chronic constipation eslie dennis, md...
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CE-1CE-1
Zelnorm®
(tegaserod maleate)
Efficacy and Safety in Chronic Constipation
Zelnorm®
(tegaserod maleate)
Efficacy and Safety in Chronic Constipation
Eslie Dennis, MD
Senior Medical Director: Gastroenterology Clinical Development and Medical Affairs
Novartis Pharmaceuticals Corporation
Eslie Dennis, MD
Senior Medical Director: Gastroenterology Clinical Development and Medical Affairs
Novartis Pharmaceuticals Corporation
C
CE-2CE-2
OutlineOutline
Rationale Study objectives Study design Patient population Efficacy
– Primary
– Secondary Safety and tolerability
– 12-wk double-blind, placebo-controlled
– 13 months extension, double-blind, uncontrolled
Rationale Study objectives Study design Patient population Efficacy
– Primary
– Secondary Safety and tolerability
– 12-wk double-blind, placebo-controlled
– 13 months extension, double-blind, uncontrolled
C
CE-3CE-3
NH
NH2
OH
Serotonin Tegaserod
C
Rationale for Drug DesignSimilarity to Serotonin (5-HT)Rationale for Drug DesignSimilarity to Serotonin (5-HT)
An aminoguanidine indole, designed to act specifically at 5-HT4 receptors in the GI tract
An aminoguanidine indole, designed to act specifically at 5-HT4 receptors in the GI tract
NH
NNH
ONH
NH
CE-4CE-4
Rationale for Zelnorm® in Chronic Constipation ProgramRationale for Zelnorm® in Chronic Constipation Program
#Nguyen A, et al. J Pharmacol Exp Ther. 1997;280:1270-1276.§Weber E, et al. Gastroenterology. 2004; 126(Suppl 2):A147-A148.‡Novick J et al. Aliment Pharmacol Ther. 2002;16:1877-1888.
#Nguyen A, et al. J Pharmacol Exp Ther. 1997;280:1270-1276.§Weber E, et al. Gastroenterology. 2004; 126(Suppl 2):A147-A148.‡Novick J et al. Aliment Pharmacol Ther. 2002;16:1877-1888.
In IBS-C clinical studies: Increases stool frequency‡
Improves stool consistency‡
Improves straining‡
In IBS-C clinical studies: Increases stool frequency‡
Improves stool consistency‡
Improves straining‡
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Mechanism of action: Enhances gut motility#
Decreases transit time#
Increases chloride and water secretion§
Mechanism of action: Enhances gut motility#
Decreases transit time#
Increases chloride and water secretion§
CE-5CE-5
Phase III Chronic ConstipationPhase III Chronic Constipation
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CE-6CE-6
Study ObjectivesPivotal Studies E2301, E2302Study ObjectivesPivotal Studies E2301, E2302
To evaluate efficacy, tolerability, and safety of Zelnorm® in patients with chronic constipation
– 2 mg and 6 mg BID vs placebo
– 12-wk treatment period
To evaluate efficacy, tolerability, and safety of Zelnorm® in patients with chronic constipation
– 2 mg and 6 mg BID vs placebo
– 12-wk treatment period
19 CSRs E2301, E2302; Sections 2
CE-7CE-7
Study DesignsStudy Designs
C
CE-8CE-8
Study DesignStudy E2301Study E2301Study DesignStudy E2301Study E2301
11 2.5 Clinical Overview F1-1
12-wkTreatment periodScreening
Zelnorm® 2 mg BID
Placebo
Zelnorm 6 mg BID
N = 1264
Europe, Australia, South AfricaEurope, Australia, South Africa
2-wkBaseline
Nostudy drug
CE-9CE-9
Study DesignStudies E2301, E2301EStudies E2301, E2301EStudy DesignStudies E2301, E2301EStudies E2301, E2301E
11 2.5 Clinical Overview F1-1
12-wkTreatment periodScreening
Nostudy drug
Zelnorm® 2 mg BID
Placebo
Zelnorm 6 mg BID
N = 1264
Europe, Australia, South AfricaEurope, Australia, South Africa
n = 842
Zelnorm 2 mg BID
Zelnorm 6 mg BID
13-moExtension period
E2301E1
2-wkBaseline
Zelnorm 6 mg BID
CE-10CE-10
Study DesignStudy E2302Study E2302Study DesignStudy E2302Study E2302
11 2.5 Clinical Overview F1-1
12-wkTreatment periodScreening
Zelnorm® 2 mg BID
Placebo
Zelnorm 6 mg BID
N = 1348
North and South AmericaNorth and South America
4-wkWithdrawal
Nostudy drug
2-wkBaseline
Nostudy drug
CE-11CE-11
CSBM Is the Basis for Patient Inclusion and Endpoints CSBM Is the Basis for Patient Inclusion and Endpoints
BM: Bowel Movement SBM: Spontaneous Bowel Movement
– Spontaneous: non–laxative-induced stool; no laxative or enema in 24 hr preceding BM
CSBM: Complete Spontaneous Bowel Movement– Complete: BM that results in sensation of
complete evacuation– Measure of quality and frequency
BM: Bowel Movement SBM: Spontaneous Bowel Movement
– Spontaneous: non–laxative-induced stool; no laxative or enema in 24 hr preceding BM
CSBM: Complete Spontaneous Bowel Movement– Complete: BM that results in sensation of
complete evacuation– Measure of quality and frequency
C Protocol CSR E2301, E2302, Sections 2, Pages 8 -9
CE-12CE-12
Current Concepts: Chronic ConstipationLembo, Camilleri N Engl J Med 2003; 349:1360-8Current Concepts: Chronic ConstipationLembo, Camilleri N Engl J Med 2003; 349:1360-8
“An epidemiologic study of constipation in the United States identified it as an inability to evacuate stool completely and spontaneously three or more times per week”‡
“An epidemiologic study of constipation in the United States identified it as an inability to evacuate stool completely and spontaneously three or more times per week”‡
‡Stewart et al. Am J Gastroenterol. 1999;94;3530-3540
CE-13CE-13
Main Inclusion CriteriaPivotal Studies E2301, E2302Main Inclusion CriteriaPivotal Studies E2301, E2302
Male or female, ≥ 18 yr of age Chronic constipation#
– Chronic: ≥ 6 months of constipation symptoms– Constipation: < 3 CSBM/wk and ≥ 1 of the following
(≥ 25% of occurrences):• Hard/very hard stools • Sensation of incomplete evacuation• Straining
Normal endoscopic/radiologic bowel evaluation within past 5 yr and after onset of symptoms– No alarm features
Male or female, ≥ 18 yr of age Chronic constipation#
– Chronic: ≥ 6 months of constipation symptoms– Constipation: < 3 CSBM/wk and ≥ 1 of the following
(≥ 25% of occurrences):• Hard/very hard stools • Sensation of incomplete evacuation• Straining
Normal endoscopic/radiologic bowel evaluation within past 5 yr and after onset of symptoms– No alarm features
1919 CSRs E2301, E2302; Sections 3.3.2; 2.5 Clinical Overview, Section 4.3
CSBM = Complete spontaneous bowel movement.#Modified Rome II criteria.
CE-14CE-14
Main Exclusion CriteriaPivotal Studies E2301, E2302Main Exclusion CriteriaPivotal Studies E2301, E2302
Constipation due to:– Organic disease of the colon– Known mechanical outlet dysfunction– Bowel or gynecologic surgery– Metabolic disturbances– Neurologic disturbances
Concomitant medications Fecal impaction requiring surgical or
manual intervention Significant medical disorder that could interfere with
completion of study
Constipation due to:– Organic disease of the colon– Known mechanical outlet dysfunction– Bowel or gynecologic surgery– Metabolic disturbances– Neurologic disturbances
Concomitant medications Fecal impaction requiring surgical or
manual intervention Significant medical disorder that could interfere with
completion of study
1919CSRs E2301, E2302; Section 3.3.2
CE-15CE-15
Exclusion Criteria at RandomizationPivotal Studies E2301, E2302Exclusion Criteria at RandomizationPivotal Studies E2301, E2302
Patients excluded if
During the 14-day baseline period
– Constipation not confirmed by diary data
– Loose or watery stools > 3 days
– Laxatives > 2 days outside of guidelines
– Noncompliant with completion of diary (< 11 days)
Patients excluded if
During the 14-day baseline period
– Constipation not confirmed by diary data
– Loose or watery stools > 3 days
– Laxatives > 2 days outside of guidelines
– Noncompliant with completion of diary (< 11 days)
C Protocol E2301, E2302; Sections 3.3.2
CE-16CE-16
Data CollectedPivotal Studies E2301, E2302Data CollectedPivotal Studies E2301, E2302
Daily per bowel movement– Straining – Stool frequency– Stool form– Complete/incomplete evacuation
Weekly – Satisfaction with bowel habits – Bothersomeness of
• Constipation • Distension/bloating• Abdominal discomfort/pain
Daily per bowel movement– Straining – Stool frequency– Stool form– Complete/incomplete evacuation
Weekly – Satisfaction with bowel habits – Bothersomeness of
• Constipation • Distension/bloating• Abdominal discomfort/pain
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CE-17CE-17
Patient DispositionPatient Disposition
CE-18CE-18
Patient Disposition—ITT PopulationPivotal Studies E2301, E2302—Pooled Patient Disposition—ITT PopulationPivotal Studies E2301, E2302—Pooled
Patients, %
Placebon = 863
Zelnorm®
2 mg BIDn = 867
Zelnorm6 mg BIDn = 882
Completed 81.5 84.2 83.1
Discontinued 18.5 15.8 16.9
Reason for discontinuation
Unsatisfactory therapeutic effect
7.2 4.4 3.7
Adverse event(s) 3.7 3.2 5.3
Withdrew consent 3.0 3.3 4.3
Other 4.6 4.8 3.5
Summary of Clinical Efficacy T 3-8C
CE-19CE-19
ResultsResults
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CE-20CE-20
Demographic InformationPivotal Studies E2301, E2302Demographic InformationPivotal Studies E2301, E2302
CSR E2301, PTT 7.3-1, 7.6-5; CSR E2302, PTT 7.3-1, 7.6-5
E2301N = 1264
E2302N = 1348
Female 86% 90%
Age (mean, yr) 46 47
Range, yr 18 - 86 18 - 88
≥ 65 yr 14% 12%
Postmenopausal# 43% 48%
Caucasians 98% 85%
C
#Female population (E2301, n = 1091; E2302, n = 1213).
CE-21CE-21
Constipation Symptoms Prior to Start of TreatmentConstipation Symptoms Prior to Start of Treatment
E2301 (N = 1264) E2302 (N = 1348)
Mean MeanHistory
Duration of symptoms, yr 14.7 19.5
Hard/very hard stools 73.9% 77.0%
Average SBM/wk, n 1.4 1.4
Diary data (14-day baseline)
CSBM/wk, n 0.5 0.6
SBM/wk, n 3.1 3.6
SBM with straining/wk, n 2.6 3.1
Stool form 2.6 2.9
C CRS E2301,E2302 PTTS 7.5-1, 7.6-5
CE-22CE-22
Constipation Symptoms Prior to Start of TreatmentConstipation Symptoms Prior to Start of Treatment
E2301 (N = 1264) E2302 (N = 1348)
Mean Median Mean MedianHistory
Duration of symptoms, yr 14.7 10.0 19.5 15.3Hard/very hard stools 73.9% 90% 77.0% 90%Average SBM/wk, n 1.4 1 1.4 1
Diary data (14-day baseline)
CSBM/wk, n 0.5 0 0.6 0SBM/wk, n 3.1 2.5 3.6 2.9SBM with straining/wk, n 2.6 2.0 3.1 2.5Stool form 2.6 2.5 2.9 2.8
CCRS E2301,E2302 PTTS 7.5-1, 7.6-5
CE-23CE-23
Primary Efficacy VariablePrimary Efficacy Variable
CE-24CE-24
Primary Efficacy VariablePivotal Studies E2301, E2302Primary Efficacy VariablePivotal Studies E2301, E2302
Wk 1 - 4Wk 1 - 4 Wk 5 - 8Wk 5 - 8 Wk 9 - 12Wk 9 - 12
2-wkdrug-freebaseline 12-wk treatment
Responder
– Increase of ≥ 1 CSBM/wk during the first 4 wk of treatment compared with baseline
– ≥ 7 days of treatment
Responder
– Increase of ≥ 1 CSBM/wk during the first 4 wk of treatment compared with baseline
– ≥ 7 days of treatment
CSBM = Complete spontaneous bowel movement.
19CSR E2301, F 3-1; E2302 pages 22-23
CE-25CE-25
26.7
35.640.2
0
10
20
30
40
50
Placebo Zelnorm® 2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
Primary Efficacy VariablePivotal Studies E2301, E2302Primary Efficacy VariablePivotal Studies E2301, E2302
*P < .05, ***P < .0001Responder = Increase of ≥ 1 CSBM/wk during Wk 1- 4 and ≥ 7 days of treatment.CSBM = Complete spontaneous bowel movement.
C
E2301
****
CSRs E2301, E2302 PTT 9.1-1
n = 416
25.1
41.4 43.2
0
10
20
30
40
50
Placebo Zelnorm® 2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
E2302*** ***
n = 450n = 447 n = 451n = 417 n = 431
CE-26CE-26Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1 - 12Pivotal Studies E2301, E2302
Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1 - 12Pivotal Studies E2301, E2302
Responder – Increase of ≥ 1 CSBM/wk during the
entire 12-wk treatment period compared with baseline#
Responder – Increase of ≥ 1 CSBM/wk during the
entire 12-wk treatment period compared with baseline#
18
CSBM = Complete spontaneous bowel movement.# ≥ 7 days of treatment.
Protocol E2301 Amendment 3, Sections 1, 2
Wk 1 - 4Wk 1 - 4 Wk 5 - 8Wk 5 - 8 Wk 9 - 12Wk 9 - 12
2-wk drug-freebaseline
12-wk treatment
CE-27CE-27Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1- 12 Pivotal Studies E2301, E2302
Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1- 12 Pivotal Studies E2301, E2302
***P < .0001Responder = Increase of ≥ 1 CSBM/wk during Wk 1 - 12 and ≥ 7 days of treatment.CSBM = Complete spontaneous bowel movement.
C
30.6
35.9
43.2
0
10
20
30
40
50
Placebo Zelnorm® 2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
26.9
40.344.8
0
10
20
30
40
50
Placebo Zelnorm® 2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
E2301 E2302***
******
CSRs E2301, E2302 PTT 9.1-5
n = 416 n = 450n = 447 n = 451n = 417 n = 431
CE-28CE-28
0
10
20
30
40
50
60
70
1 2 3 4 5 6 7 8 9 10 11 12
Time, wk
Re
sp
on
de
rs, %
1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4
Time, wk
Weekly Responder RatePivotal Studies E2301, E2302Weekly Responder RatePivotal Studies E2301, E2302
CSR E2301, PTT 9.1-4; CSR E2302, PTT 9.1-4
E2301N = 1264
E2302N = 1348
48
P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo,Cochran-Mantel-Haenszel test.Responder = Increase of ≥ 1 CSBM/wk and ≥ 7 days of treatment.EOT = End of treatment; W = Withdrawal.
Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID
CE-29CE-29
0
10
20
30
40
50
60
70
1 2 3 4 5 6 7 8 9 10 11 12
Time, wk
Re
sp
on
de
rs, %
1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4
Time, wk
Weekly Responder RatePivotal Studies E2301, E2302Weekly Responder RatePivotal Studies E2301, E2302
CSR E2301, PTT 9.1-4; CSR E2302, PTT 9.1-4
E2301N = 1264
E2302N = 1348
48
P < .05 vs placebo, Cochran-Mantel-Haenszel test.Responder = Increase of ≥ 1 CSBM/wk and ≥ 7 days of treatment.EOT = End of treatment; W = Withdrawal.
Placebo Zelnorm 6 mg BID
CE-30CE-30
0.0
0.5
1.0
1.5
2.0
2.5
3.0
–2 –1 1 2 3 4 5 6 7 8 9 10 11 12
Time, wk
Nu
mb
er
of
CS
BM
/wk
–2 –1 1 2 3 4 5 6 7 8 9 10 11 12 EOTW1W2W3W4
Time, wk
Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302
E2301N = 1264
E2302N = 1348
48
P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo, van Elteren test.Mean data.CSBM = Complete spontaneous bowel movement; EOT = End of treatment; W = Withdrawal.
Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID
CSR E2301, E2302, PTTs 9.2-2
CE-31CE-31
0.0
0.5
1.0
1.5
2.0
2.5
3.0
–2 –1 1 2 3 4 5 6 7 8 9 10 11 12
Time, wk
Nu
mb
er
of
CS
BM
/wk
–2 –1 1 2 3 4 5 6 7 8 9 10 11 12 EOTW1W2W3W4
Time, wk
Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302
E2301N = 1264
E2302N = 1348
48
Placebo Zelnorm® 6 mg BID
P < .05 vs placebo, van Elteren test.Mean data.CSBM = Complete spontaneous bowel movement; EOT = End of treatment; W = Withdrawal.
CSR E2301, E2302, PTTs 9.2-2
CE-32CE-32
Further a priori Secondary VariablesFurther a priori Secondary Variables
CE-33CE-33Satisfaction With Bowel HabitsWk 1 - 12Pivotal Studies E2301, E2302
Satisfaction With Bowel HabitsWk 1 - 12Pivotal Studies E2301, E2302
31.7 30.6
39.443.5
40.642.9
0
10
20
30
40
50
E2301 E2302
Re
sp
on
de
rs,
%
Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID
*P < .05; **P < .001Responder = Mean decrease of ≥ 1 point on a 5-point scale compared with baseline, Wk 1 - 12.Scale 0 - 4, 0 = a very great deal satisfied, 4 = not at all satisfied.
* *** **
48
n = 416 417 431 447 450 451
SCE T 3-18
CE-34CE-34Stool FormChange From BaselinePivotal Studies E2301, E2302
Stool FormChange From BaselinePivotal Studies E2301, E2302
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1 2 3 4 5 6 7 8 9 10 11 12
Time, wk
Ch
an
ge
fro
m b
as
elin
e s
co
re
1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4
Time, wk
P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo.Mean data.EOT = End of treatment; W = Withdrawal.Scale 1- 7, 1 = hard, 7 = watery.
CSRs E2301, E2302 PTTs 9.2-532
Placebo
Zelnorm® 2 mg BID
Zelnorm 6 mg BID
E2301N = 1264
E2302N = 1348
CE-35CE-35Straining Score of Spontaneous Bowel Movements—Change From BaselinePivotal Studies E2301, E2302
Straining Score of Spontaneous Bowel Movements—Change From BaselinePivotal Studies E2301, E2302
0.0
0.1
0.2
0.3
0.4
0.5
1 2 3 4 5 6 7 8 9 10 11 12
Time, wk
De
cre
as
e in
sc
ore
1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4
Time, wk
P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo.Mean data.EOT = End of treatment; W = Withdrawal.Scale 0 - 2, 0 = no straining, 1 = acceptable straining, 2 = too much straining.
CSRs E2301, E2302 PTTs 9.2-6
IIMMPPRROOVVEEMMEENNTT
32
Placebo
Zelnorm® 2 mg BID
Zelnorm 6 mg BID
E2301N = 1264
E2302N = 1348
CE-36CE-36Response Rates by Reduction of Bothersomeness - Wk 1 - 12Pivotal Studies E2301, E2302
Response Rates by Reduction of Bothersomeness - Wk 1 - 12Pivotal Studies E2301, E2302
Patients, %
Study E2301 Study E2302
Placebon = 416
Zelnorm®
2 mg BIDn = 417
Zelnorm6 mg BIDn = 431
Placebon = 447
Zelnorm®
2 mg BIDn = 450
Zelnorm6 mg BIDn = 451
Constipation 27.7 34.6* 40.9*** 25.7 35.1* 37.5**
Abdominal Distension/bloating
27.1 30.8 32.3 27.6 36.0* 35.4*
Abdominaldiscomfort/pain
22.5 27.8 28.3 21.4 31.8** 30.5*
*P < .05; **P < .001; ***P < .0001; Responder = Mean decrease of ≥ 1 point on a 5-point scale compared with baseline.Scale 0 to 4, where a lower score indicates less bother and greater satisfaction.
Summary of Clinical Efficacy T 3-18C
CE-37CE-37Association of CSBM and Improvement of Symptoms (Wk 1 - 4)Pivotal Studies E2301, E2302—Pooled
Association of CSBM and Improvement of Symptoms (Wk 1 - 4)Pivotal Studies E2301, E2302—Pooled
Median % change from baseline
Variable Responder Non-responder P value
Stool form of SBM 41.6 12.5 < .0001
Satisfaction with bowel habit –40.0 –6.7 < .0001
Constipation score –37.5 –8.3 < .0001
Straining score –37.6 –9.4 < .0001
Days with too much straining –50.0 –25.0 < .0001
Abdominal pain score –33.3 0 < .0001
Bloating score –33.3 –8.3 < .0001
C
No DV
CE-38CE-38
Additional AnalysesAdditional Analyses
CE-39CE-39
Responder – ≥ 3 CSBM/wk during the first 4 wk of treatment‡ – No comparison with baseline
Responder – ≥ 3 CSBM/wk during the first 4 wk of treatment‡ – No comparison with baseline
CSBM = Complete spontaneous bowel movement.#FDA responder definition #1.‡ ≥ 7 days of treatment.
Protocol E2301 Amendment 3, Sections 1, 218
Wk 1 - 4Wk 1 - 4 Wk 5 - 8Wk 5 - 8 Wk 9 - 12Wk 9 - 12
2-wk drug-freebaseline
12-wk treatment
≥ ≥ 3 CSBM/wk3 CSBM/wk
Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#
Pivotal Studies E2301, E2302
Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#
Pivotal Studies E2301, E2302
CE-40CE-40Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#
Pivotal Studies E2301, E2302
Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#
Pivotal Studies E2301, E2302
C
12.9
18.8
22.2
0
5
10
15
20
25
30
Placebo Zelnorm® 2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
12.9
23.021.8
0
5
10
15
20
25
30
Placebo Zelnorm® 2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
**
*
E2301 E2302
******
*P < .05; **P < .001; ***P < .0001.#FDA responder definition #1.
CSRs E2301, E2302 PTT 9.2-16
n = 412 n = 444n = 442 n = 449n = 410 n = 428
CE-41CE-41Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 12# Pivotal Studies E2301, E2302
Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 12# Pivotal Studies E2301, E2302
14.3
17.1
25.2
0
5
10
15
20
25
30
Placebo Zelnorm®2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
13.1
22.7 22.0
0
5
10
15
20
25
Placebo Zelnorm®2 mg BID
Zelnorm 6 mg BID
Re
sp
on
de
rs,
%
****** ***
***P < .0001#FDA responder definition #2.
E2301 E2302
CCSRs E2301, E2302 PTT 9.2-17
CE-42CE-42
Responders by Baseline Bowel Movements/Wk
Responders by Baseline Bowel Movements/Wk
C
CE-43CE-43
Responders by Baseline Bowel Movements/wk Primary Efficacy VariablePivotal Studies E2301, E2302—Pooled
Responders by Baseline Bowel Movements/wk Primary Efficacy VariablePivotal Studies E2301, E2302—Pooled
25.3 26.2
37.6 39.238.643.4
0
10
20
30
40
50
< 3 ≥ 3
BM/wk at baseline
Res
po
nd
ers,
%
Placebo Zelnorm® 2 mg Zelnorm 6 mg
*P < .05; **P < .01; ***P < .0001Responder = increase of ≥ 1 CSBM/wk, Wk 1 - 4, and ≥ 7 days of treatment.BM = Bowel movement; CSBM = Complete spontaneous bowel movement.
n = 890 (34.4%) n = 1695 (65.6%)
SCE PTT 9.1-1c
***********
20
CE-44CE-44
0.1 1 10
Overall
< 65 yr
≥ 65 yr
Male
Female
Caucasian
Black
No baseline laxatives
Baseline laxatives
Responders by Subgroup Primary Efficacy Variable Pivotal Studies E2301, E2302—Pooled
Responders by Subgroup Primary Efficacy Variable Pivotal Studies E2301, E2302—Pooled
Patients, n
Zelnorm6 mg BIDPlacebo
32
805
771
106
88
789
877
33
780
761
93
117
737
854
Odds ratio
Zelnorm® 6 mg BID versus placebo, Wk 1 - 4
Responder = Increase of ≥ 1 CSBM/wk; CSBM = Complete spontaneous bowel movement.
470
407
438
416
CSCE Ts 3.12-13.13-1, 3.14-1, 3.15-1, 3.16-1, 3.17-1, 3.24-1
CE-45CE-45
Patients With IBS-Like Features Pivotal Studies E2301, E2302—PooledPatients With IBS-Like Features Pivotal Studies E2301, E2302—Pooled
Addendum to SCE T 3-1, ED June 8, 2004
Patients, n (%)
CriteriaPlacebon = 863
Zelnorm®
2 mg BIDn = 867
Zelnorm6 mg BIDn = 882
a. History of diagnosisof IBS
21 (2) 29 (3) 39 (4)
b. Abdominal discomfort/pain asmain complaint
102 (12) 108 (12) 109 (12)
c. Abdominal discomfort/pain > 0 and diarrhea#
82 (10) 89 (10) 78 (9)
d. Meets any of the above criteria
185 (21) 201 (23) 197 (22)
#Patients with ≥ 25% of SBM loose or watery (stool form 6 or 7) or> 3 SBM/day for ≥ 25% of days.SBM = Spontaneous bowel movement.
54
-1
CE-46CE-46Responders Without IBS-Like FeaturesPrimary Efficacy VariablePivotal Studies E2301, E2302—Pooled
Responders Without IBS-Like FeaturesPrimary Efficacy VariablePivotal Studies E2301, E2302—Pooled
*P < .05; ***P < .0001Responder = increase of ≥ 1 CSBM/wk, Wk 1 - 4, and ≥ 7 days of treatment.CSBM = Complete spontaneous bowel movement.
Addendum to Summary of Clinical Efficacy T 3-3C
Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID
CC patients without IBS-like features
n = 666n = 666 n = 651n = 651 n = 675n = 6750
10
20
30
40
50
Pat
ien
ts,
%
******
26
4044
CE-47CE-47
Efficacy SummaryEfficacy Summary
Efficacy demonstrated in patients who were chronically constipated
– Early onset of relief
– Sustained
– No rebound Efficacy demonstrated for the treatment of the
multiple symptoms of chronic constipation Zelnorm® 6 mg BID consistently more
efficacious than Zelnorm 2 mg BID
Efficacy demonstrated in patients who were chronically constipated
– Early onset of relief
– Sustained
– No rebound Efficacy demonstrated for the treatment of the
multiple symptoms of chronic constipation Zelnorm® 6 mg BID consistently more
efficacious than Zelnorm 2 mg BID
C
CE-48CE-48
Zelnorm®
(tegaserod maleate)Safety in Chronic Constipation
Zelnorm®
(tegaserod maleate)Safety in Chronic Constipation
C
CE-49CE-49
OverviewOverview
12-wk safety profile
– Exposure
– Adverse events profile
– Serious adverse events
– Laboratory evaluations
Long-term safety profile (16 months)
12-wk safety profile
– Exposure
– Adverse events profile
– Serious adverse events
– Laboratory evaluations
Long-term safety profile (16 months)
C
CE-50CE-50
Overall Exposure Pivotal Studies E2301, E2302—PooledOverall Exposure Pivotal Studies E2301, E2302—Pooled
Summary of Clinical Safety PTT 2.1-114
Placebon = 861
Zelnorm®
2 mg BIDn = 861
Zelnorm6 mg BIDn = 881
Mean duration,days ± SD
79 ± 23 81 ± 21 80 ± 23
≥ 77 days, n 712 738 740
≥ 85 days, n 603 604 585
CE-51CE-51
Most Frequent Adverse Events Pivotal Studies E2301, E2302—PooledMost Frequent Adverse Events Pivotal Studies E2301, E2302—Pooled
5.2 3.7
10.1
5.1 4.2 6.0 4.8
11.07.2 6.6 4.7 4.7
7.23.0
59.6
13.2
56.3 57.1
0
10
20
30
40
50
60
Any AE Headache Nasopharyngitis Diarrhea Abdominal pain Nausea
Patie
nts,
%
Placebo (n = 861)Zelnorm® 2 mg BID (n = 861)Zelnorm 6 mg BID (n = 881)
Clinical Overview T5-2C
CE-52CE-52Most Frequent Adverse Events#
Leading to Discontinuation Pivotal Studies E2301, E2302—Pooled
Most Frequent Adverse Events#
Leading to Discontinuation Pivotal Studies E2301, E2302—Pooled
SCS Table 4-1218
Patients, %
Placebon = 861
Zelnorm®
2 mg BIDn = 861
Zelnorm6 mg BIDn = 881
Any AE 3.7 3.4 5.7
Abdominal pain NOS 0.6 1.0 0.8
Diarrhea NOS 0.2 0.3 0.9
Abdominal distension 0.2 0.2 0.6
Nausea 0.6 0.3 0.3
Headache NOS 0.2 0.2 0.3
NOS = Not otherwise specified.#≥ 5 patients treated with Zelnorm® any dose.
CE-53CE-53
Diarrhea EvaluationPivotal Studies E2301, E2302—PooledDiarrhea EvaluationPivotal Studies E2301, E2302—Pooled
Placebon = 861
Zelnorm®2 mg BIDn = 861
Zelnorm 6 mg BIDn = 881
Patients with diarrhea, n (%) 26 (3.0) 36 (4.2) 58 (6.6)
Diarrhea episodes per patient
1 episode, n (% of patients with diarrhea)
22 (84.6) 29 (80.6) 48 (82.8)
Duration of first episode, days (median)
2.0 2.0 2.5
Stool characteristics, first day of diarrhea (median)
Bowel movements 3.0 2.0 3.0
Stool form score# 5.7 6.0 6.3
SCS Table 8-1C
E2301&E2301 Diarrhea data.xls
#Bristol stool form scale.
CE-54CE-54
Diarrhea ManagementPivotal Studies E2301, E2302—PooledDiarrhea ManagementPivotal Studies E2301, E2302—Pooled
Patients, n
Placebon = 861
Zelnorm® 2 mg BIDn = 861
Zelnorm6 mg BIDn = 881
Diarrhea, n (%) 26 (3.0) 36 (4.2) 58 (6.6)
No action taken 19 24 30
Concomitant medication taken 3 5 6
Dose adjusted/interrupted 3 6 21
Dose permanently discontinued 2 3 8
Each AE occurrence counted.
C SCS T8-1 and SCS PTT 4.28-1
CE-55CE-55Diarrhea—No Clinically Significant ConsequencesPivotal Studies E2301, E2302
Diarrhea—No Clinically Significant ConsequencesPivotal Studies E2301, E2302
No clinically significant consequencesof diarrhea
None required IV hydration orelectrolyte replacement
No clinically significant consequencesof diarrhea
None required IV hydration orelectrolyte replacement
C
CE-56CE-56
Serious Adverse EventsPivotal Studies E2301, E2302—PooledSerious Adverse EventsPivotal Studies E2301, E2302—Pooled
Patients, n (%)
Placebon = 861
Zelnorm®
2 mg BIDn = 861
Zelnorm6 mg BIDn = 881
SAEs# 14 (1.6) 11 (1.3) 12 (1.4)
Discontinuations due to SAEs
3 (0.3) 4 (0.5) 3 (0.3)
Deaths‡ 0 1 (0.1) 0
Clinical Overview T5-3; SCS P13
#Excluding deaths.‡Patient 2521-9: 85-yr-old male with mesothelioma; died 67 days after last dose of Zelnorm 2 mg.
C
CE-57CE-57
Laboratory EvaluationsPivotal Studies E2301, E2302Laboratory EvaluationsPivotal Studies E2301, E2302
Low frequency of notable abnormalities
– Hematology
– Chemistry
– Liver function
– Renal function
Similar between Zelnorm® and placebo
Low frequency of notable abnormalities
– Hematology
– Chemistry
– Liver function
– Renal function
Similar between Zelnorm® and placebo
C Summary of Clinical Safety T 6-1
CE-58CE-58
Abdominal and Pelvic SurgeriesPivotal Studies E2301, E2302—PooledAbdominal and Pelvic SurgeriesPivotal Studies E2301, E2302—Pooled
Placebon = 861
Zelnorm®
2 mg BIDn = 861
Zelnorm6 mg BIDn = 881
All abdominal and pelvic surgeries, n (%)
8 (0.9) 3 (0.3) 6 (0.7)
Cholecystectomies, n 0 0 1
Other, n 8 3 5
C Clinical overview T 5-4, p 23
CE-59CE-59
Long-term Safety Studies E2301, E2301E1 (Long-term Safety Population)Long-term Safety Studies E2301, E2301E1 (Long-term Safety Population)
842 patients entered the extension trial Exposure
– 518 patients (61.7%) exposed to Zelnorm® ≥ 12 months
Discontinuation – 46% of patients discontinued
• 19% Unsatisfactory therapeutic response• 11% Withdrew consent• 10% Other (lost to follow-up, administrative
reasons, etc.)• 6% AE
842 patients entered the extension trial Exposure
– 518 patients (61.7%) exposed to Zelnorm® ≥ 12 months
Discontinuation – 46% of patients discontinued
• 19% Unsatisfactory therapeutic response• 11% Withdrew consent• 10% Other (lost to follow-up, administrative
reasons, etc.)• 6% AE
C CSR E2301E1 T 7-1, 8-1
CE-60CE-60
Adverse Events ≥ 5%Study E2301E1 (Long-term Safety Population)Adverse Events ≥ 5%Study E2301E1 (Long-term Safety Population)
Patients, %
Placebo -Zelnorm®
6 mg BIDn = 274
Zelnorm2 mg BID -2 mg BIDn = 283
Zelnorm6 mg BID -6 mg BIDn = 283
Headache 16.1 24.0 21.2Abdominal pain NOS 10.9 14.8 11.3Diarrhea NOS 10.6 8.1 9.9Nasopharyngitis 6.9 9.5 11.0Nausea 4.4 12.4 9.2Influenza 5.8 6.7 10.2Back pain 5.1 6.0 7.1Abdominal distension 4.0 5.7 7.8Abdominal pain upper 4.4 6.4 6.7Constipation 4.0 4.6 6.4Dyspepsia 3.3 7.4 3.9Flatulence 5.8 3.9 4.9Sinusitis NOS 2.2 5.7 4.9
C Summary of Clinical Safety T 4-5
CE-61CE-61
Conclusions—SafetyConclusions—Safety
Incidence of AEs on Zelnorm® similarto placebo
– Except diarrhea
Low discontinuation rate due to AEs
Long-term safety similar to pivotal studies
Zelnorm is safe and well tolerated in patients with chronic constipation
Incidence of AEs on Zelnorm® similarto placebo
– Except diarrhea
Low discontinuation rate due to AEs
Long-term safety similar to pivotal studies
Zelnorm is safe and well tolerated in patients with chronic constipation
C
CE-62CE-62
Final ConclusionsChronic ConstipationFinal ConclusionsChronic Constipation
Zelnorm® is effective in the treatment of multiple symptoms of chronic constipation
– 6 mg BID consistently more efficacious than 2 mg BID
Zelnorm improves
– Satisfaction with bowel habits
– Straining
– Stool form
– Stool frequency Zelnorm has a favorable safety profile
Zelnorm® is effective in the treatment of multiple symptoms of chronic constipation
– 6 mg BID consistently more efficacious than 2 mg BID
Zelnorm improves
– Satisfaction with bowel habits
– Straining
– Stool form
– Stool frequency Zelnorm has a favorable safety profile
C
CE-63CE-63
Proposed IndicationProposed Indication
Zelnorm® (tegaserod maleate) is indicated for the treatment of patients with chronic constipation and relief of associated symptoms of straining, hard or lumpy stools, and infrequent defecation.
Zelnorm® (tegaserod maleate) is indicated for the treatment of patients with chronic constipation and relief of associated symptoms of straining, hard or lumpy stools, and infrequent defecation.
C Proposed Package Insert, 1 Oct 2003, p 8