Efficacy Results from Three Pivotal Efficacy Trials

1
Efficacy 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

2
Pivotal 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
3
Pivotal 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
4
Pivotal 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
5
Pivotal 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
6
Methods 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.

7
Patient 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
8
Reasons 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
9
Pivotal 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
10
Pivotal 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
11
Pivotal 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
12
Pivotal 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
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Survival 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
14
Survival 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
15
Survival 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
16
European Pivotal Efficacy StudiesRate of
Complete Abstinence




3 mos
1 yr
1 yr
P ? .050 P ? .010 Source ISE Section
8.7.2.7.3
17
European Pivotal Efficacy StudiesMedian
Percentage of Abstinent Days on Study (CAD)




P ? .050 P ? .010 Source ISE Section
8.7.2.7.1
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European 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
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ISBRA15th18th September 2004Heidelberg, Germany
Prof. Karl F. Mann, M.D.Chair in Addiction
ResearchUniversity of Heidelberg