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Efficacy Results from Three Pivotal Efficacy Trials. Karl F. Mann, M.D. Professor and Chairman Director, Department of Addictive Behavior and Addiction Medicine Central Institute of Mental Health of Mannheim University of Heidelberg. Pivotal European Efficacy Studies - Objective.

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Efficacy results from three pivotal efficacy trials

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


Pivotal european efficacy studies objective
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


Pivotal european efficacy studies
Pivotal European Efficacy Studies

Number of:Study Name Centers Subjects* Country Dates of Study

Pelc II 12 188 Belgium/ 1990-1992 France

PRAMA 12 272 Germany 1990-1992

Paille 31 538 France 1989-1992

TOTAL 55 998

* ITT population

Source: ISE Section 8.7.2.2


Pivotal european efficacy studies study design features general
Pivotal European Efficacy Studies:Study 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


Pivotal european study design features entrance criteria
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 >5 >14-<28 7-30at Baseline, days

Source: ISE Section 8.7.2.2


Methods for collecting drinking data in pivotal european efficacy studies
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

  • Investigator’s 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.


Patient disposition pivotal european efficacy studies
Patient Disposition Efficacy StudiesPivotal European Efficacy Studies

ACAMP (all doses) Placebo Total

Randomized 624 377 1001

ITT (Treated) 623 (>99%) 375 (>99%) 998 (>99%)

Completed Study 335 (54%) 147 (39%) 482 (48%)

Discontinued Study 288 (46%) 228 (60%) 516 (52%)

Source: ISE Section 8.7.2.3


Reasons for discontinuation pivotal european efficacy studies
Reasons for Discontinuation Efficacy StudiesPivotal 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 (<1%) 5 (1%) 13 (1%)“Other” 5 (<1%) 2 (<1%) 7 (<1%)

Adverse Event 37 (6%) 22 (6%) 59 (6%)

Death 6 (1%) 3 (1%) 9 (1%)

Protocol Violation 1 (<1%) 3 (1%) 4 (<1%)

Source: ISE Section 8.7.2.3


Pivotal european efficacy studies demographic and baseline characteristics
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

Mean weight, kg 73 69 73 71

Mean duration of alcoholdep/abuse, years 9 - 10 10

% >10 std. drinks*/day 77% 69% 79% 73%

% Detox. 100% 100% 100% 100%

% Abstinent (Baseline) 99% 100% 100% >99%

*Standard drink = 12 g pure alcoholSource: ISE Section 8.7.2.4


Pivotal european efficacy studies mean s e study drug exposure in weeks
Pivotal European Efficacy Studies CharacteristicsMean (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


Pivotal european efficacy studies mean percent medication compliance
Pivotal European Efficacy Studies CharacteristicsMean 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


Pivotal european efficacy studies definitions of common outcome parameters
Pivotal European Efficacy Studies CharacteristicsDefinitions 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


Survival estimate of time to first drink pelc ii
Survival Estimate of Time to First Drink* - Pelc II Characteristics

Median time to 1st drink3X longer in acamp 1998 vs placebo, p<0.001

0

* Dropout = failure

Source: ISE Section 8.7.2.7.2


Survival estimate of time to first drink prama
Survival Estimate of Time to First Drink* - PRAMA Characteristics

Median time to 1st drink3X longer in acamp vs placebo, p<0.001

0

* Dropout = failureSource: ISE Section 8.7.2.7.2


Survival estimate of time to first drink paille
Survival Estimate of Time to First Drink* - Paille Characteristics

Median time to 1st drink2X longer in acamp 1998 mg vs placebo, p=0.005

0

* Dropout = failureSource: ISE Section 8.7.2.7.2


European pivotal efficacy studies rate of complete abstinence
European Pivotal Efficacy Studies CharacteristicsRate of Complete Abstinence

**

**

**

*

3 mos

1 yr

1 yr

* P  .050; **P  .010

Source: ISE Section 8.7.2.7.3


European pivotal efficacy studies median percentage of abstinent days on study cad
European Pivotal Efficacy Studies CharacteristicsMedian Percentage of Abstinent Days on Study (CAD%)

**

**

**

**

* P  .050; **P  .010

Source: ISE Section 8.7.2.7.1


European pivotal efficacy studies primary efficacy variables summary
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


Isbra 15 th 18 th september 2004 heidelberg germany
ISBRA - Summary15th–18th September 2004Heidelberg, Germany

Prof. Karl F. Mann, M.D.Chair in Addiction ResearchUniversity of Heidelberg


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