# Presentation: 693156

## 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

**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

**Pelc II****	****12****	****188****	****Belgium/****	****1990-1992****	****	****	****France**
**PRAMA ****	****12****	****272****	****Germany****	****1990-1992**
**Paille****	****31****	****538****	****France****	****1989-1992**
**TOTAL****	****55****	****998**

**Pivotal European Efficacy Studies**

*** ITT population**
**Source: ISE Section 8.7.2.2**

## Pivotal European Efficacy Studies:Study Design Features - General

**Double-blind, randomized,****	********	******** ****	********placebo-controlled**
**Multicenter****	********	********	******
**Acamprosate Dose-Levels,****	****1332,****	****1998****	****1332,****mg/day****	****1998****	****	****1998**
**Treatment/Follow-up ****	****3/--****	****12/12****	****12/6****Duration, months**
**Site-specific psychosocial therapy****	********	********	******

**Pivotal European Efficacy Studies:****Study Design Features - General**

**Source: ISE Section 8.7.2.2**

## Pivotal European Study Design Features  Entrance Criteria

**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****	****7-30****at Baseline, days**

**Pivotal European Study Design Features  Entrance Criteria**

**Source: ISE Section 8.7.2.2**

## Methods for Collecting Drinking Data in Pivotal European Efficacy Studies

**Derived from an *****abstinence-oriented*****treatment 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

**Source: ISE Section 8.7.2.3**

**	****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%)**

## Reasons for Discontinuation Pivotal European Efficacy Studies

**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%)**

**Reasons for Discontinuation ****Pivotal European Efficacy Studies**

**Source: ISE Section 8.7.2.3**

## Pivotal European Efficacy Studies: Demographic and Baseline Characteristics

***Standard drink = 12 g pure alcohol****Source: ISE Section 8.7.2.4**

**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 alcohol****dep/abuse, years****	****9****	****-****	****10****	****10**
**% >10 std. drinks*/day****	****77%****	****69%****	****79%****	****73%**
**% Detox.****	****100%****	****100%****	****100%****	****100%**
**% Abstinent (Baseline)****	****99%****	****100%****	****100%****	****>99%**

## Pivotal European Efficacy StudiesMean (S.E.) Study Drug Exposure in Weeks

**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)**

**Pivotal European Efficacy Studies****Mean (S.E.) Study Drug Exposure in Weeks**

**Source: ISE Section 8.7.2.6**

## Pivotal European Efficacy StudiesMean 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**

## 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 

**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 **

**Pivotal European Efficacy Studies****Definitions of Common Outcome Parameters**

**Source: ISE Section 8.7.1.2.5**

## Survival Estimate of Time to First Drink* - Pelc II

**Median time to 1st drink****3X longer in acamp 1998 vs placebo, p<0.001**

*** Dropout = failure**
**Source: ISE Section 8.7.2.7.2**

**0**

## Survival Estimate of Time to First Drink* - PRAMA

*** Dropout = failure****Source: ISE Section 8.7.2.7.2**

**Median time to 1st drink****3X longer in acamp vs placebo, p<0.001**

**0**

## Survival Estimate of Time to First Drink* - Paille

**Median time to 1st drink****2X longer in acamp 1998 mg ****vs placebo, p=0.005**

*** Dropout = failure****Source: ISE Section 8.7.2.7.2**

**0**

## European Pivotal Efficacy StudiesRate 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%)

******

******

******

*** P ******** .050; **P ******** .010**
**Source: ISE Section 8.7.2.7.1**

******

## 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15th–18th September 2004Heidelberg, Germany

**Prof. Karl F. Mann, M.D.****Chair in Addiction Research****University of Heidelberg**