# Presentation: 672186

## Statistical PerspectiveAcamprosate Experience

**Sue-Jane Wang, Ph.D.**
**Statistics Leader**
**Alcoholism Treatment Clinical Trials**
**May 10, 2002**
**Drug Abuse Advisory Committee Meeting **
**DACCADP/DB2/OB/CDER/FDA**

## OUTLINE

**The Three European Pivotal Trials**
**Pelc II, Paille, PRAMA**
**Differential treatment discontinuation**
**The US 96.1 Trial**
**Acamprosate effect (2000 mg/day) observed in *****only***** the sponsor defined *****Post-Hoc Analysis***** but not supported by many other analyses**
**Difference between European and US Trials**
**Analytic Issues**

## Dosages of Treatment

**Placebo (****pbo****)**
**Acamprosate 1332 mg/day (****low dose****)**
**European: two 333 mg tablets bid**
**Acamprosate 1998 mg/day (****medium dose****)**
**European: two 333 mg tablets tid**
**US: two 500 mg tablets bid**
**Acamprosate 3000 mg/day (****high dose****)**
**US: three 500 mg tablets bid**

**Dosages of Treatment**

## Pelc II

_**Study Design:**_ **A multicenter, double blind, randomized, placebo-controlled 3-arm study**
_**Study Objective:**_** Effectiveness and **
**   ****tolerance of acamprosate in helping to**** maintain abstinence**** in weaned alcoholic**
**Main criterion of judgement:**** **
**   ****The consumption of alcohol**
**Trial duration: ****3 months**
**Trial period: June 1990 to April 1992**

## Pelc II

**Pelc II**

## Paille

_**Study Design:**_ **A multicenter, double blind, randomized, placebo-controlled 3-arm study**
_**Main Objective:**_
**maintenance of abstinence**** with acamprosate 1332 mg/day ****(low dose)**** in alcoholic patients who were followed as outpatients after withdrawal**
**Trial duration: ****360 days**
**Trial Period: April 1989 to November 1992**

## Paille

## PRAMA

_**Study Design:**_ **A multicenter, double blind, randomized, placebo-controlled 2-arm study**
**PBO vs. Acamprosate**
_**Study Objective:**_
**Effectiveness and tolerance of acamprosate, which ****helps to maintain abstinence**** after detoxification in the alcoholic patients**
**Trial Duration: ****48 weeks**
**Trial Period: Oct. 1990 to December 1992**

## PRAMA

**Primary efficacy: time to 1st relapse**** **
_**Definition of relapse**_
**short-term relapse****: alcohol consumption for **
**    ****up to 24 hours **
**long-term relapse****: alcohol consumption for more than 24 hours with/without the need for hospitalization **
**continuous relapse****: constant alcohol  consumption**

## PRAMA

**PRAMA**

## The European Pivotal Trials

**Drinking Data was retrospectively collected**
**Dropout rate higher in pbo than in acamprosate **
**Effect of acamprosate 1998 mg/d (r.t. pbo) was shown in “% complete abstinence”**
**Effect of acamprosate 1332 mg/day (low dose) was not shown in Paille Trial**
**Trials were conducted in late 1980s to early 1990s**

## US 96.1 Trial

_**Patient Population**_**: Alcohol dependence who had been withdrawn from alcohol or who had completed medicated detoxification within ********2 to ********10 days of study entry**
_**Study Design**_**: a multicenter (21 centers), double-blind, randomized, placebo controlled**
**Randomization: well-balanced among 3-arms: PBO, M-dose (2 g/d), H-dose (3 g/d)**
**Data: rigorous TLFB drinking measurement**

## US 96.1 Trial

**to confirm efficacy & safety of ****medium dose (2000 mg/day)**** acamprosate in association with standardized but minimal psychosocial support, guided by a protocol-specific manual**
**Secondary Objective**
**explore ****high dose (3000 mg/day) acamprosate**** efficacy & safety**
**Trial Duration: ****24 weeks**
**Trial Period: May 1997 to January 1999**

**US 96.1 Trial**

## US 96.1 Trial

## US 96.1 Trial

**Time to 1st day of any drinking**
**Time to 1st day of heavy drinking **
**   ****(********6 drinks for men, ********4 drinks for women) **
**Cumulative abstinence duration (CAD)**
**CCAD (=percent days abstinence PDA)**
**Rate of complete abstinence**

**US 96.1 Trial**

## Slide 16

## US 96.1 Trial

**Exploratory analysis pre-specified**
**CAD or CCAD adjusted for T, C, Detoxification**
**Supportive analysis pre-specified**
**adjusted for T,C, amount of psychosocial therapy**
**adjusted for T,C, illicit drug use**

**US 96.1 Trial**

## US 96.1 Trial

**Cumulative Abstinence Duration (CAD)**
**   ****(post-hoc definition)**
**Endpoint considered: CCAD (=PDA)**
**Endpoint actually used: ALCCAD (PDA adjusted for treatment discontinuation)**

**US 96.1 Trial**

## Post-hoc ANCOVA Model #1

**Use the following covariates for adjustments:**
**treatment exposure**
**pooled site (********)**
**baseline CGI-severity  **
**stage of readiness to change  **
**psychological antecedent  **
**addiction index **
**goal of abstinence****  **

**Post-hoc ANCOVA ****Model #1**

## - use 6 covariates   (excluding treatment exposure) from model #1 Treatment Exposure: defined astreatment compliance*treatment duration/100	-potentially treatment related 	-due to differential time to discontinuation 	-and differential dropout 

**Post-hoc ANCOVA Model #2**

## Versions of Primary Efficacy Outcome

**ALCCAD:**** ****endpoint actually used**
**    ****(CCAD adjusted for treatment discontinuation)**

**Versions of Primary Efficacy Outcome**

## Slide 22

## Slide 23

## US 96.1 Trial

**US 96.1 Trial**

## Post-Hoc Model #1:Why 7-covariates

**    ****to examine how the results of the sponsor’s post-hoc ANCOVA depend on which covariate(s) to include**
**    ****- center always included**
**    ****- ****each covariate included one at a time**
**	****- ****other combinations of covariates included with or**
**      ****without the ‘abstinence goal’**

**Post-Hoc Model #1:Why 7-covariates**

## Slide 26

## Slide 27

## Slide 28

## Medium dose (2 g/d) effective?

**US trial was sufficiently powered for efficacy evaluation of this dose**
**=> ****No evidence**** of effect, after adjusting for any**
**      ****one covariate alone**
**=> Excluding treatment exposure from ANCOVA,**
**     ****No evidence**** of the effect**
**=> ****Numerically worse than placebo in mean**
**      ****heavy drinking days**

## Medium dose (2 g/d) effective?

**Whether this dose appears to show efficacy depends on post-hoc selection of covariates for adjustment  **
** ****e.g.,  including ****“abstinence goal” + “trt exposure”**
**       ****   ****or ****all 7 covariates****  (multiplicity!!)**

## Exploration for High Dose???

**Not sufficiently powered (1/3 sample size)**
**Insufficient safety data in the US trial**
**Numerically superior to placebo ****in**** mean heavy**
**       ****drinking days**
**The abstinence goal seemed prognostic of high dose**
**(3 g/d) effect, but only if using the ALCCAD**
**Effect was not seen if adjustments did not include**
**      ****abstinence goal**

## Summary - US 96.1 Trial

**Dropout rate was significantly higher and treatment exposure was shorter in medium 2g/d dose acamprosate than in high dose or placebo**
**Effect of 2 g/day (r.t. pbo) not established on protocol specified primary efficacy outcome or post-hoc defined primary endpoint (CCAD = percent days abstinence)**

## Summary - US 96.1 Trial

**Post-hoc chosen model #1 or #2 on ALCCAD can be problematic: **** **
**-  The significant results for 2 g/d acamprosate depend on which post-hoc independent covariate(s) to include for adjustments; no effect after multiplicity adjustments **
**- Analysis for 3 g/d acamprosate was exploratory: **
**   ****time to 1st heavy drinking, mean heavy drinking over**
**   ****time; but, small ‘n’**

## Difference between European vs. US

**Acamprosate in Europe: 3-mon, 360d, 48-wk**
**less dropouts **
**longer treatment exposure**
**Acamprosate 2g/d in US: 24-wk**
**more dropouts **
**shorter treatment exposure**
**Analytic Issues**
**need of well-thought pre-specified algorithm for handling dropout patterns**

## Differences between European vs. US

**Drinking data:**
**   ****European: retrospective collection from clinician**
**   ****US: TLFB diary**
**Criteria of total abstinence at study entry**
**   ****Europe: explicitly required **
**   ****US: not explicitly required**
**Medicated detoxification**
**   ****European: 100%         US:10%**
**Patients’ baseline characteristics**
**   ****European: 18 to 65 years of age **
**   ****US: no upper age limit**

## Differences between European vs. US

**Psychosocial support**
**      ****European: non-structured psychosocial therapy**
**  ****US: standardized, manual-guided psychosocial**
**          ****support**
**Dosage form**
**      ****European: 333 mg tablets**
**  ****US: 500 mg tablets**
**Other design features of the US study were not typical in the European studies**
**  ****e.g., mandatory follow-up algorithms for missed**
**          ****visits or missed phone contacts**