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EF 3 Tegaserod Clinical Program in Constipation-Predominant IBS StudyDose, mg/d*NLocation (% of patients) Phase II dose-ranging B US (54%), Europe (43%), Canada Phase III efficacy/safety B3514, 12799US (97%), Canada B3014, 12881Europe (90%), US, S Africa B307 4, US (66%), Europe (32%), Canada Long-term safety B Europe (50%), US (41%), Canada StudyDose, mg/d*NLocation (% of patients) Phase II dose-ranging B US (54%), Europe (43%), Canada Phase III efficacy/safety B3514, 12799US (97%), Canada B3014, 12881Europe (90%), US, S Africa B307 4, US (66%), Europe (32%), Canada Long-term safety B Europe (50%), US (41%), Canada 1 *Divided into 2 daily doses.
Citation preview
EF 1
Efficacy and Safety
Martin P. Lefkowitz, MDDirector, Clinical Research
EF 2
Overview of Clinical Results
Totality of data provides convincing evidence of efficacy for tegaserod 12 mg/d on global relief measure and secondary parameters of efficacy
Safe and well tolerated Favorable benefit-to-risk profile in constipation-
predominant IBS, a disorder with no proven therapeutic options
EF 3
Tegaserod Clinical Program in Constipation-Predominant IBS
Study Dose, mg/d* N Location (% of patients)
Phase II dose-ranging B251 1-24 547 US (54%), Europe (43%), CanadaPhase III efficacy/safety B351 4, 12 799 US (97%), Canada B301 4, 12 881 Europe (90%), US, S Africa B307 4, 4-12 845 US (66%), Europe (32%), CanadaLong-term safety B209 4-12 579 Europe (50%), US (41%), Canada
1
*Divided into 2 daily doses.
EF 4
Efficacy Presentation
Phase II Phase III– Design and endpoints– Results
Summary
EF 5
24 mg/d; n = 110
12 mg/d; n = 110
4 mg/d; n = 108
1 mg/d; n = 107
Placebo; n = 113
Baseline
Week –4
Randomization
Week 4 Week 8 Week 12Week 0
Phase II Study Design (B251)1
EF 6
Phase II Subject’s Global Assessment (SGA) of Overall GI Symptoms (B251)
0
10
20
30
40
50
Endpoint
Res
pons
e, %
Placebo 1 mg 4 mg 12 mg 24 mg
1
EF 71
Phase III Design ConsiderationsOutcome Measures in IBS Trials (1)
No consensus No consensus on primary outcome measure Assessment variable– Overall measure that integrates
IBS symptoms– Specific symptom measure:
abdominal discomfort/pain Measurement– Ordinal and visual analog scales (VAS)
EF 81
Outcome Measures in IBS Trials (2)
General consensus Responder approach for primary efficacy
variable Frequency: at least weekly Self-administered by patient
EF 9
Phase III Study Designs1
B351
4 mg/d
12 mg/d
Placebo
12 weeks4 weeks
Baseline
4 mg/d
12 mg/d
Placebo
12 weeks4 weeks
B301
Baseline
B3074 mg/d
12 mg/d
Placebo
12 weeks4 weeks
4 mg/d4 mg/dBaseline
EF 101
Inclusion Criteria
Males and females 18 years of age (B351: 12 years) Colon evaluated within last 5 years Rome criteria
Continuous or recurrent discomfort/pain in lower abdomen in last 3 monthsDiscomfort/pain • Relieved by BM(1 of 3) • Associated with change in frequency of BMs
• Associated with change in consistency of stool
25% of the time • < 3 BMs/week(2 of 3) • Hard or lumpy stool
• Straining
EF 111
Exclusion Criteria
Diarrhea associated with IBS 25% of the time
Other relevant GI conditions Concurrent use of
– Narcotics, motility agents
– Laxative use except as rescue
EF 121
Randomization Criteria
Abdominal discomfort/pain – Mean baseline score 35 mm on 100-mm VAS– No upper limit cutoff for pain severity
Stool consistency– No specific mean score
Eligibility based on clinical history• Abdominal discomfort/pain• Constipation
VAS = Visual analogue scale.
EF 13
Primary Efficacy VariableSGA of Relief (B351)
Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain, and altered bowel habit.Compared to the way you usually felt before entering the study, how would you rate your relief symptoms during the past week: Completely relieved Considerably relieved Somewhat relieved Unchanged Worse
Response: 50% complete/considerable relief at study endpoint
1
EF 14
Response: 40% reduction and at least 20-mm absolute reduction from baseline at study endpoint
“How much of a problem was your abdominal discomfort/pain over the last week?”
Absent Very Mild Moderate Severe Verymild severe
100 mm
Primary Efficacy VariableSGA of Abdominal Discomfort/Pain (B351)
1
EF 151
Statistical Methodology for Primary Efficacy Variables
Study endpoint: last 4 available weekly scores
Treatment comparisons by Mantel-Haenszel test stratified by center
A multiple comparison procedure was used to ensure the overall 2-sided type I error rate of < .05
EF 16
Adjustment Rules
Applied to primary efficacy variables at endpoint: Patient defined as nonresponder if
– No postrandomization SGA assessment
– < 28 days treatment
– Laxative intake > 5 days overall or any use in last 4 weeks of study
1
EF 17
Secondary Efficacy Assessments
Weekly: • SGA of bowel habit (VAS)Daily: • Intensity of abdominal
discomfort/pain (6-point scale)• Intensity of bloating (6-point scale)• Number of bowel movements• Stool consistency (7-point scale)
Intensity scale0 = none1 = very mild2 = mild3 = moderate4 = severe5 = very severe
Stool consistency scale1 = watery2 = loose3 = somewhat loose4 = neither loose nor hard5 = somewhat hard6 = hard7 = very hard
EF 18
Patient Disposition
B351 B301 B307
Enrolled 1,093 1,122 1,163
Discontinued 292 (27) 240 (21) 313 (27)during baseline
Randomized 799 881 845
Completed 633 (79) 751 (85) 680 (80)
Discontinued during 166 (21) 130 (15) 165 (20)double-blind period
1
Patients, n (%)
EF 19
Demographics
Variable (mean) B351 B301 B307
Age, years 43 46 45Gender, % female 87 83 84Race, % Caucasian 88 98 91Weight, kg 71 68 70Smoking, % 21 26 22Duration of IBS, years 14 13 14Use of bulking agents, % 18 11 17Fiber score, g 9 11 9
1
EF 20
Baseline Characteristics
Variable (mean) B351 B301 B307
Abdominal discomfort/pain 63 60 61VAS score, mmBowel habit VAS score, mm 64 60 62Days with significant 87 84 86abdominal discomfort/pain, %Days with significant bloating, % 88 83 86Number of bowel movements/week 5.7 5.4 6.2Days without bowel movements, % 46 44 41Days with hard stools, % 31 28 29Stool consistency score 4.7 4.7 4.6
1
EF 21
Efficacy ResultsPresentation Overview
Efficacy results of study B351 Modification of primary efficacy variable
for studies B301 and B307 Efficacy results of study B301 Efficacy results of study B307 Summary
EF 22
SGA Data Presentation
1 2 3 4 5 6 7 8 9 10 11 12
Res
pons
e, %
Weekly responseWeekly response
Monthly responseMonthly response
Endpoint:Endpoint:Last 4 available SGA valuesLast 4 available SGA valuesAdjustment rules*Adjustment rules*
1
Week
*No SGAs, < 28 d treatment, laxative use.
EF 23
Primary Efficacy Variables at Endpoint (B351)
22.118.7
29.4
23.426.2 25.1
0
10
20
30
40
SGA of relief SGA of abdominaldiscomfort/pain
Res
pons
e, %
Placebo 4 mg/d 12 mg/d
P = .05 .27 P = .19 .08
1
EF 24
Complete or Considerable Relief by Week (B351)
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11 12Week
Res
pons
e, %
1
†
*
* **
*
*P < .05 versus placebo.†P < .01 versus placebo.
Placebo 4 mg/d 12 mg/d
†
†
EF 25
SGA of Abdominal Discomfort/Pain by Week (B351)
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11 12
Week
Res
pons
e, %
9
*
Placebo 4 mg/d 12 mg/d
*P < .05 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.
EF 26
SGA of Bowel Habit (B351)
20.2
26.424.7
0
10
20
30
Endpoint
Resp
onse
, %
*P < .05 versus placebo.†P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11 12
Week
Resp
onse
, %
*
Placebo 4 mg/d 12 mg/d
Weekly
*†
*
EF 27
Daily Diary: Abdominal Discomfort/Pain (B351)
-3.9
15.216.9
-5
0
5
10
15
20Significant days at endpoint
Mea
n re
duct
ion
from
bas
elin
e, %
Impr
ovem
ent
Impr
ovem
ent
*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).Significant: at least mild; 2 on a 6-point scale.
*
2.0
2.2
2.4
2.6
2.8
3.0
3.2
3.4
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12
Week
Mea
n pa
in s
core
*
* * * *
*
Placebo 4 mg/d 12 mg/d
† †
†
Pain score
EF 28
Daily Diary: Bloating (B351)
5.6
14.9 15.1
-5
0
5
10
15
20Significant days at endpoint
Mea
n re
duct
ion
from
bas
elin
e, %
Impr
ovem
ent
Impr
ovem
ent
*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).Significant: at least mild; 2 on a 6-point scale.
†
2.0
2.2
2.4
2.6
2.8
3.0
3.2
3.4
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12
Week
Mea
n bl
oatin
g sc
ore
**
* * * **
* *
† †
Bloating score
Placebo 4 mg/d 12 mg/d
EF 29
Number of Bowel Movements and Stool Consistency by Week (B351)
3
4
5
6
7
8
9
10
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12Week
Mea
n nu
mbe
r of b
owel
mov
emen
ts/w
eek
1
Placebo 4 mg/d 12 mg/d
*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).
3.0
3.5
4.0
4.5
5.0
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12Week
Mea
n st
ool c
onsi
sten
cy/w
eek
*†
†
****†††
†
*** †††
†
††
***† † ††
††
††††
††
†
† †* †
† †
† †††
††
Bowel movements Stool consistency
EF 301
Summary (B351)
No statistically significant differences in primary efficacy variables– Low placebo response rates:• SGA of relief 22%• SGA of abdominal discomfort/pain 19%
Significant treatment differences observed in daily diary variables
Consistent pattern of improvement for tegaserod across primary and secondary variables
EF 31
B351
Original SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint
B301/B307
SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint
ORAt least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint
1
Modification of Primary Efficacy Variables
EF 32
Associations Between SGA of Relief and Other Efficacy Variables (B351)
Efficacy variable % change from baseline Responder Nonresponder
VAS score: SGA abd discomfort/pain –48 –6 Days with significant pain –35 9 Daily pain score –40 –0.2 Days with significant bloating –32 3Daily bloating score –38 –2VAS score: SGA bowel habit –47 –6Days with no bowel movement –44 –15 Days with hard or very hard stool –66 –23
1
All comparisons significant (P < .001)
Response: 50% complete/considerable or 100% at least somewhat relief.
EF 33
Associations Between SGA of Relief and Other Efficacy Variables (B351)
Efficacy variable Complete Considerable Somewhat Unchanged Worse% change from baseline (n = 48) (n = 164) (n = 222) (n = 256) (n = 61)VAS score: SGA abd –79 –50 –23 –5 8discomfort/pain Days with significant pain –73 –40 –7 18 3Daily pain score –72 –44 –16 4 8Days with significant –61 –37 –7 6 3 bloating
Daily bloating score –64 –41 –16 1 7VAS score: SGA bowel –75 –50 –23 –3 6 habitDays with no bowel –62 –46 –28 –10 –16 movement
Days with hard or –71 –70 –50 –19 3 very hard stool
1
Last study week
EF 34
B351
Original SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint
B301/B307
SGA of reliefComplete or considerable relief at least 50% of the time at study endpoint
ORAt least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint
1
Modification of Primary Efficacy Variables for Studies B301/B307
SGA of abdominal discomfort/pain 40% reduction and at least 20-mm absolute reduction from baseline Secondary efficacy variable
EF 35
Efficacy Results SGA of Relief (B351)
22.1
33.329.4
38.9
26.2
45.7
0
10
20
30
40
50
60
Res
pons
e, %
Placebo 4 mg 12 mg
P = .05 .27 P = .16 .004
1
SGA of relief(retrospective analysis)
Original SGA of relief
EF 36
Study B301Efficacy Results
EF 37
4 mg/d
12 mg/d
Placebo
Baseline
Week –4
Randomization
Week 4 Week 8 Week 12Week 0
1
Study Design (B351 and B301)
EF 38
SGA of Relief at Endpoint (B301)
30.2
38.8 38.4
0
10
20
30
40
50
60
70R
espo
nse,
%Placebo 4 mg/d 12 mg/d
*Statistically significant.Response: 50% complete/considerable or 100% at least somewhat relief.
1
P = .018* .033*
EF 39
SGA of Relief at Endpoint
3033
3943
38
45
0
10
20
30
40
50
60
70
Adjusted Not laxativeadjusted
Resp
onse
, %
B301
*Statistically significant.Response: 50% complete/considerable or 100% at least somewhat relief.
1
P = .018* .033* P = .007* .003*
B351 (retrospective analysis)
333739
4246
49
0
10
20
30
40
50
60
70
Adjusted Not laxativeadjusted
Resp
onse
, %
P = .157 .004* P = .251 .006*
Placebo 4 mg/d 12 mg/d
EF 40
Monthly SGA of Relief
21
3237
26
44 46
34
42
50
0
10
20
30
40
50
60
70
Month 1 Month 2 Month 3
Resp
onse
, %
B301
*P < .05 versus placebo; †P < 0.01 versus placebo.Response: 50% complete/considerable or 100% at least somewhat relief.
1
31
44 4239
424545
50
57
0
10
20
30
40
50
60
70
Month 1 Month 2 Month 3
Resp
onse
, %
B351 (retrospective analysis)
†
†
†
† ††
*
Placebo 4 mg/d 12 mg/d
EF 41
At Least Somewhat Relief by Week1
Placebo 4 mg/d 12 mg/d
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 11 12Week
At le
ast s
omew
hat r
elie
f, %
B301
*
** **
††
† ††
† †† †
†† † † † †
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 11 12Week
B351
* **††
† † †
*P < .05 versus placebo.†P < .01 versus placebo.
EF 42
SGA of Abdominal Discomfort/Pain (B301)
22.6
29.8 29.9
0
10
20
30
40
Endpoint
Resp
onse
, %
*P < .05 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.
*
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
Resp
onse
, % **
**
*
Placebo 4 mg/d 12 mg/d
Weekly
EF 43
SGA of Bowel Habit (B301)
22.6
28.826.2
0
10
20
30
40
Endpoint
Resp
onse
, %
*P < .05 versus placebo.†P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
Res
pons
e, %
Placebo 4 mg/d 12 mg/d
**
* * *
**
*
** *
*†
Weekly
EF 44
Daily Diary: Abdominal Discomfort/Pain (B301)
10.4
18.9 18.6
0
5
10
15
20Significant days at endpoint
Mea
n re
duct
ion
from
bas
elin
e, %
Impr
ovem
ent
Impr
ovem
ent
*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).Significant: at least mild; 2 on a 6-point scale.
1.8
2.0
2.2
2.4
2.6
2.8
3.0
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12
Week
Mea
n pa
in s
core
* * **
*
* *
†
††
† †
†
†
† †† †
†
†
Placebo 4 mg/d 12 mg/d
Pain score
EF 45
Daily Diary: Bloating (B301)
-4.0
10.7
8.3
-5
0
5
10
15Significant days at endpoint
Mea
n re
duct
ion
from
bas
elin
e, %
Impr
ovem
ent
Impr
ovem
ent
*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).Significant: at least mild; 2 on a 6-point scale.
1.8
2.0
2.2
2.4
2.6
2.8
3.0
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12
Week
Mea
n bl
oatin
g sc
ore
*
*
**
**
**
*
†
†
††
††
†
Bloating score
Placebo 4 mg/d 12 mg/d
EF 46
Number of Bowel Movements and Stool Consistency by Week (B301)
3
4
5
6
7
8
9
10
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12Week
Mea
n nu
mbe
r of b
owel
mov
emen
ts/w
eek
1
Placebo 4 mg/d 12 mg/d
†
†
***
*†† † † † † †
††
††
*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).
3.0
3.5
4.0
4.5
5.0
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12Week
Mea
n st
ool c
onsi
sten
cy/w
eek
†
† † † †† † † † †
†† † † † † † † ††
†† †
† † †
† †
*†
Bowel movements Stool consistency
EF 47
Summary Study B301
Clear evidence of efficacy– Significant treatment differences for SGA
of relief – Consistent positive findings on secondary
efficacy variables
EF 48
Study B307Efficacy Results
EF 49
Nonresponder: 12 mg/d (65%)
4 mg/d
Placebo
Baseline
Week –4
Randomization
Week 4 Week 8 Week 12Week 0
1
Study Design (B307)
4 mg/dResponder: 4 mg/d (35%)
EF 50
SGA of Relief (B307)
37 39
25
38
46
3842
32
39
50
4246
40
47 49
0
10
20
30
40
50
60
70
Adjusted Not laxativeadjusted
Month 1 Month 2 Month 3
Resp
onse
, %
Placebo 4 mg/d 4-12 mg/d
1
Endpoint Monthly
†*
*P < .05 versus placebo; †P < .01 versus placebo.Response: 50% complete/considerable or 100% at least somewhat relief.
EF 51
At Least Somewhat Relief by Week (B307)
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 11 12Week
At l
east
som
ewha
t rel
ief,
%
Placebo 4 mg/d 4-12 mg/d
1
*P < .05 versus placebo.†P < .01 versus placebo.
*†
*†
†
*
EF 52
SGA of Abdominal Discomfort/Pain (B307)
30.6
25.527.6
0
10
20
30
40
Endpoint
Resp
onse
, %
*P < .05 versus placebo; †P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
Resp
onse
, %
*
* †
Placebo 4 mg/d 4-12 mg/d
Weekly
EF 53
SGA of Bowel Habit (B307)
2527
24
0
10
20
30
40
Endpoint
Resp
onse
, %
*P < .05 versus placebo; †P < .01 versus placebo.Response: 40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
Resp
onse
, %
*†
*
Placebo 4 mg/d 4-12 mg/d
Weekly
EF 54
Number of Bowel Movements and Stool Consistency by Week (B307)
3
4
5
6
7
8
9
10
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12Week
Mea
n nu
mbe
r of b
owel
mov
emen
ts
3.0
3.5
4.0
4.5
5.0
-4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12Week
Mea
n st
ool c
onsi
sten
cy
1
*†
†
†
*† † †
*P < .05 versus placebo; †P < .01 versus placebo (change from baseline).
*
†
*†*
†
† † *
† †
† †
Placebo 4 mg/d 4-12 mg/d
† ††††
† ††
† † † †
Bowel movements Stool consistency
EF 55
Summary Study B307
Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint
Not statistically significant for primary efficacy variable
EF 56
Comparative EfficacySummary
EF 57
Phase III StudiesAt Least Somewhat Relief
01020304050607080
0 2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8 10 12
Week
At l
east
som
ewha
t rel
ief,
%
Placebo 12 mg/d 4-12 mg/d
B351 B301 B307
*P < .05 versus placebo.†P < .01 versus placebo.
** * * † † †
** * * * * †
† * * †
*†
**
EF 58
Phase III StudiesComplete/Considerable Relief
0
10
20
30
40
0 2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8 10 12
Week
Com
plet
e/co
nsid
erab
le re
lief,
%
Placebo 12 mg/d 4-12 mg/d
B351 B301 B307
*P < .05 versus placebo.†P < .01 versus placebo.
*
†
***
*
†
** †
†
†† †
†† †
EF 59
Efficacy Variables at Endpoint B351 B301 B307
Efficacy variable 4 mg/d 12 mg/d 4 mg/d 12 mg/d 4 mg/d 4-12 mg/d
SGA efficacy variables SGA of relief + < .01 < .05 < .05 + + Original SGA of relief < .05 + < .05 + - - SGA of abdominal + + + < .05 - - discomfort/pain SGA of bowel habits + + + + + -Daily diary variables Days with significant: Abdominal pain + < .05 + + + + Abdominal bloating + < .01 + + - - Number of: Bowel movements < .01 < .001 < .001 < .01 < .05 < .001 Days without BMs + < .01 < .05 < .05 + < .05 % days with hard stools + < .01 + + + +
12
+ = Positive direction for tegaserod, P > .05 versus placebo.- = Negative direction for tegaserod, P > .05 versus placebo.
EF 60
Additional Analyses
EF 61
Pooled Analysis
Prespecified primary efficacy variables B351: Original SGA of relief and SGA of abdominal discomfort/pain
B301/B307: SGA of relief
Endpoint analysis Longitudinal analysis
P value versus placebo P value versus placebo
12 mg/d 12 mg/d 4 mg/d (4-12 mg/d) 4 mg/d (4-12 mg/d)
.0141 .0028 .0085 < .0001
EF 62
Number of Months With Positive Response for SGA of Relief§
P value versus placebo
12 mg/d Study 4 mg/d (4-12 mg/d)
B351 Original SGA of relief .107 .047
B351 SGA of relief .353 .013*
B301 SGA of relief .008* < .001*
B307 SGA of relief .479 .008*
1
* Statistically significant with adjustment for multiple comparisons.
§ Primary analysis of alosetron data. Gastrointestinal Drug Advisory Committee meeting, November 16, 1999.
EF 63
% Weeks With At Least Somewhat Relief
5346
5160
55 53
6556 60
0102030405060708090
B351 B301 B307
At l
east
som
ewha
t rel
ief,
%
Placebo 4 mg/d 12 mg/d 4-12 mg/d
4
P = .021 < .001 P = .005 < .001 P = .278 .003
EF 64
SGA of Relief by GenderPooled Results: B351/B301/B307
2633
24
3834
3933
384043
3236
0
10
20
30
40
50
Month 1 AdjustedEndpoint
Month 1 AdjustedEndpoint
Res
pons
e, %
Placebo 4 mg/d 12 or 4-12 mg/d
1
(n = 2,025) (n = 2,037) (n = 373) (n = 373)
MaleFemale
*P < .05 versus placebo; †P < .01 versus placebo. 4-12 mg/d group pooled with 4 mg/d group at Month 1 and with 12 mg/d group at endpoint.
*†
††
EF 65
SGA of Relief at EndpointPlacebo-Subtracted Values by Gender
-2
6.7
0.4
10.2
0.8 1.4
-1.1
14.2
-7.8
11.4
4.15.3
-10
-5
0
5
10
15
20
Male Female Male Female Male Female
Res
pons
e, %
4 mg/d 12 mg/d 4-12 mg/d
B351 B301 B307
*†
†
*P < .05 versus placebo.†P < .01 versus placebo.
(n = 102) (n = 697) (n = 150) (n = 731) (n = 138) (n = 703)
EF 66
Summary of Efficacy (1)
Study B301: clear evidence of efficacy– Significant treatment differences for SGA of relief – Consistent positive findings on secondary
efficacy variables Study B351: although not statistically significant on
prespecified primary efficacy endpoints, overall results strongly supportive of efficacy– Daily diary variables statistically significant in
favor of tegaserod– Positive trends for all SGA assessments
EF 67
Summary of Efficacy (2)
Studies B301 and B351– B351 results largely replicated in study B301– Consistent results between weekly SGA and daily diary
variables – Tegaserod 12 mg/d group had most consistent effect
across efficacy variables and over time Study B307
– Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint
– Not statistically significant for primary efficacy variable
EF 68
Summary of Efficacy (3)
Additional analyses (pooled analyses, number of months with positive response, % weeks with relief) reinforce findings of a positive treatment effect
Positive treatment effect primarily due to efficacy in women
Totality of data across multiple efficacy variables provides convincing evidence that tegaserod is effective in treatment of constipation-predominant IBS
EF 69
Safety
2
EF 70
Safety Overview
Exposure Adverse events Laboratory evaluations ECG Summary
EF 71
Overall Exposure
3,510 healthy subjects or patients
– Maximum daily dose up to 200 mg in healthy subjects
1,874 IBS patients for 85 days 302 IBS patients for 335 days
EF 72
Serious Adverse Events
Database Placebo Tegaserod
Pooled phase II studies 5/151 3.3% 10/519 1.9%Pooled phase III studies 13/837 1.6% 30/1,679 1.8%Pooled phase II/III studies 18/988 1.8% 40/2,198 1.8%Long-term studies 28/675 4.1%
2
EF 73
Reasons for Discontinuations (Phase III)
0
5
10
15
20
25
Total Adverseevent
Consentwithdrawal
Lost tofollow up
Lack ofefficacy
Protocolviolation
Other
Patie
nts,
%
Placebo (n = 837)4 mg/d (n = 844)4-12 mg/d (n = 275)12 mg/d (n = 560)
2
EF 74
Overall Adverse Events (Phase III)
0
20
40
60
80
100
Any AE Any severe AE Serious AE Discontinuationdue to AE
Patie
nts,
%
Placebo (n = 837)4 mg/d (n = 844)4-12 mg/d (n = 275)12 mg/d (n = 560)
2
EF 75
Adverse Events > 5% (Phase III)
%
Placebo 4 mg/d 4-12 mg/d 12 mg/d(n = 837) (n = 844) (n = 275) (n = 560)
Headache 21 21 17 23Abdominal pain 18 20 22 19Diarrhea 5 11 12 12Nausea 9 9 8 10Flatulence 7 8 8 7Back pain 5 6 6 8Influenza-like symptoms 6 7 4 8Upper respiratory tract infections 8 6 10 5Dyspepsia 6 6 7 6Dizziness 6 6 3 6Pharyngitis 3 3 5 4
2
EF 76
Time to First Episode of Diarrhea (Phase III)
0.0
1.0
2.0
3.0
4.0
5.0
Day 1 Days 2 - 7 Days 8 - 29 Days 30 - 59 Days > 60
Patie
nts,
%
Placebo 4 mg/d 12 mg/d
- Majority (75%) single episode - Median duration, 2 days; mean duration, 7 days
2
EF 77
Adverse Events ( 1%) Leading to Discontinuation (Phase III)
%
Placebo 4 mg/d 4-12 mg/d 12 mg/d Events (n = 837) (n = 844) (n = 275) (n = 560)
Total 5.7 7.7 7.6 6.6
Abdominal pain 1.9 1.5 2.5 1.3 Diarrhea 0.4 1.7 1.5 1.6 Flatulence 0.7 1.1 1.1 0.4 Headache 0.8 0.7 2.2 0.4 Dizziness 1.0 1.3 0.4 0.2
2
EF 78
Long-Term Safety Study (B209)
12-month, open label 4-12 mg/d dose titration
– 80% titrated to 12 mg/d Enrolled: 579 Completed: 304
EF 79
Adverse Events > 5% (Long-term Study: 12 Months)
Event
Headache 30%Abdominal pain 17%Upper respiratory 16%tract infection Diarrhea 15%Back pain 9%Sinusitis 8%Nausea 8%Flatulence 8%
2
Total patients, N = 567 (4-12 mg/d)
EF 80
Adverse Events (> 1%) Leading to Discontinuation (Long-term Study)
Events
Total 11% Diarrhea 4% Abdominal pain 3% Flatulence 3% Headache 1%
2
Total patients, N = 567 (4-12 mg/d)
EF 81
Laboratory Evaluations (Phase III)
Clinically relevant laboratory abnormalities in hematology and biochemistry values were rare and with similar frequency for tegaserod- and placebo-treated groups
Liver chemistries (LFTs)– ALT > 3-fold normal: tegaserod 0.4% versus placebo 0.2%– AST > 3-fold normal: tegaserod 0.1% versus placebo 0.1%– No simultaneous elevations in ALT/AST and bilirubin– No serious adverse event of hepatitis or elevated LFTs No evidence of tegaserod-induced hepatotoxicity was noted
EF 822
ECG Recording and Analysis
12-lead electrocardiograms (> 10,000 tracings) Timepoint recording – Phase III: baseline, first dose (2 h),
Months 1 and 3 (2 h) – Long-term: baseline; Months 2, 6, and 12
Analysis:– Central analysis by independent cardiologist– Intervals evaluated by SigmaScan technique
No effects on ECG (QTc intervals or arrhythmias)
EF 832
Safety Summary
Tegaserod 4 and 12 mg/d – Well tolerated– Similar safety profile
Diarrhea: – Only adverse event with higher frequency
than placebo– Low discontinuation rate (~ 2%)
No effects on ECG (QTc intervals or arrhythmias) or laboratory parameters
EF 84
Conclusions
Totality of data demonstrates that tegaserod is effective in the treatment of IBS in patients who identify abdominal pain/discomfort and constipation as their predominant symptoms
Tegaserod 12 mg/d improves:– Abdominal discomfort/pain– Bloating– Constipation (stool frequency and stool consistency)
Favorable safety profile Favorable benefit-to-risk profile