Title: Efficacy Results from Three Pivotal Efficacy Trials
1Efficacy Results from Three Pivotal Efficacy
Trials
- Karl F. Mann, M.D.Professor and
ChairmanDirector, Department of Addictive
Behavior and Addiction MedicineCentral
Institute of Mental Health of MannheimUniversity
of Heidelberg
2Pivotal European Efficacy Studies - Objective
- Compare the safety and efficacy of acamprosate
versus placebo in maintaining long-term
abstinence in alcohol-dependent outpatients
following alcohol withdrawal.
Source ISE Section 8.7.2.2
3Pivotal European Efficacy Studies
Number ofStudy
Name Centers Subjects Country Dates of
Study Pelc II 12 188 Belgium/ 1990-1992 France
PRAMA 12 272 Germany 1990-1992 Paille 31 538 Fra
nce 1989-1992 TOTAL 55 998
ITT population Source ISE Section 8.7.2.2
4Pivotal European Efficacy StudiesStudy Design
Features - General
Criterion Pelc II PRAMA Paille Double-blind,
randomized, ? ? ?placebo-controlled Multicenter
? ? ? Acamprosate Dose-Levels, 1332, 1998 1332,mg
/day 1998 1998 Treatment/Follow-up
3/-- 12/12 12/6Duration, months Site-specific
psychosocial therapy ? ? ?
Source ISE Section 8.7.2.2
5Pivotal European Study Design Features Entrance
Criteria
Criterion Pelc II PRAMA Paille Males and
females ? ? ? Age, years 18-65 18-65 18-65 DSM
III/III-R for alcohol ? ? ?dependence In-patient
detoxification ? ? ? Required abstinent
period gt5 gt14-lt28 7-30at Baseline, days
Source ISE Section 8.7.2.2
6Methods for Collecting Drinking Data in Pivotal
European Efficacy Studies
- Derived from an abstinence-orientedtreatment
tradition - Self-report of any alcohol consumption at each
visit - Biochemical confirmation using at least one of
the following GGT, LFTs, MCV, CDT, breath/urine
alcohol levels - Investigators Clinical Global Impression
- Family member or other caretaker report (PRAMA
and Paille) - In case of discrepancies among data sources, the
most negative outcome was assumed accurate.
7Patient DispositionPivotal European Efficacy
Studies
ACAMP (all doses) Placebo Total Randomized 624 3
77 1001 ITT (Treated) 623 (gt99) 375 (gt99) 998
(gt99) Completed Study 335 (54) 147 (39) 482
(48) Discontinued Study 288 (46) 228 (60)
516 (52)
Source ISE Section 8.7.2.3
8Reasons for Discontinuation Pivotal European
Efficacy Studies
ACAMP (all doses) Placebo Total Discontinued
Study 288 (46) 228 (60) 516 (52) Lost to
Follow-up 87 (14) 69 (18) 156
(16) Treatment Failure 93 (15) 50 (13)
143 (14) Other 64 (10) 81 (21) 145
(14)Patient Refusal 51 (8) 74 (20) 125
(12)Improvement 8 (lt1) 5 (1) 13
(1)Other 5 (lt1) 2 (lt1) 7 (lt1) Adverse
Event 37 (6) 22 (6) 59 (6) Death 6 (1)
3 (1) 9 (1) Protocol Violation 1 (lt1) 3
(1) 4 (lt1)
Source ISE Section 8.7.2.3
9Pivotal European Efficacy Studies Demographic
and Baseline Characteristics
Characteristic Pelc II Paille PRAMA Overall
Male 85 80 78 80 Mean age, years 42 43 41 42 M
ean weight, kg 73 69 73 71 Mean duration of
alcoholdep/abuse, years 9 - 10 10 gt10 std.
drinks/day 77 69 79 73 Detox. 100 100 100
100 Abstinent (Baseline) 99 100 100 gt99
Standard drink 12 g pure alcoholSource ISE
Section 8.7.2.4
10Pivotal European Efficacy StudiesMean (S.E.)
Study Drug Exposure in Weeks
ACAMP ACAMP 1332 1998 Placebo Pelc II n 63 n
63 n 62(13 weeks) 10.6 (0.5) 11.2 (0.5) 9.4
(0.6) PRAMA -- n 136 n 136(48 weeks) 32.2
(1.7) 26.1 (1.8) Paille n 188 n 173 n
177(52 weeks) 35.3 (1.4) 37.7 (1.4) 31.6 (1.5)
Source ISE Section 8.7.2.6
11Pivotal European Efficacy StudiesMean Percent
Medication Compliance
ACAMP ACAMP 1332 1998 Placebo Pelc II n 55 n
53 n 49(13 weeks) 97 97 100 PRAMA -- n
118 n 109(48 weeks) 81 81 Paille n 157 n
154 n 158(52 weeks) 82 88 83
Source ISE Section 8.7.2.6
12Pivotal European Efficacy StudiesDefinitions of
Common Outcome Parameters
- Time to first drink
- The number of days from the start of double-blind
study medication to the estimated day of first
consumption of any alcohol. - Rate of complete abstinence
- Percent of patients completing the study without
consuming any alcohol (relative to number of
patients treated). - Cumulative Abstinence Duration,
- Estimated percent of abstinent time on study
Source ISE Section 8.7.1.2.5
13Survival Estimate of Time to First Drink - Pelc
II
Median time to 1st drink3X longer in acamp 1998
vs placebo, plt0.001
0
Dropout failure Source ISE Section 8.7.2.7.2
14Survival Estimate of Time to First Drink - PRAMA
Median time to 1st drink3X longer in acamp vs
placebo, plt0.001
0
Dropout failureSource ISE Section 8.7.2.7.2
15Survival Estimate of Time to First Drink - Paille
Median time to 1st drink2X longer in acamp 1998
mg vs placebo, p0.005
0
Dropout failureSource ISE Section 8.7.2.7.2
16European Pivotal Efficacy StudiesRate of
Complete Abstinence
3 mos
1 yr
1 yr
P ? .050 P ? .010 Source ISE Section
8.7.2.7.3
17European Pivotal Efficacy StudiesMedian
Percentage of Abstinent Days on Study (CAD)
P ? .050 P ? .010 Source ISE Section
8.7.2.7.1
18European Pivotal Efficacy Studies Primary
Efficacy Variables - Summary
- Time to First Drink, days
- With acamprosate, median values 2 to 3 times
longer than with placebo (P ? .005 for all 3
studies) - Complete Abstinence Rate,
- With acamprosate, 1.7-2.7 times greater than with
placebo (P ? .028 for all 3 studies) - Estimated Percentage of Abstinent Days (CAD)
- With acamprosate, greater percentage of study
time in abstinent state (P ? .001 for all 3
studies)
Source ISE Sections 8.7.2.7.1-3
19ISBRA15th18th September 2004Heidelberg, Germany
Prof. Karl F. Mann, M.D.Chair in Addiction
ResearchUniversity of Heidelberg