1 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

2 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

3 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

4 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

5 Pelc II

6 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

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8 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 to December 1992

9 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

10 PRAMA

11 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

12 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

13 Primary Objective –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

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15 Protocol specified primary efficacy endpoints –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

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17 Medium dose acamprosate 2g/d failed to show a superior effect on pre-specified endpoints 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

18 New primary efficacy endpoint –Cumulative Abstinence Duration (CAD) (post-hoc definition) Endpoint considered: CCAD (=PDA) Endpoint actually used: ALCCAD (PDA adjusted for treatment discontinuation) US 96.1 Trial

19 Chosen by the sponsor 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

20 - 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

21 Modified CCAD: No Statistically significant findings on Model #1 or Model #2 or unadjusted analysis ALCCAD: endpoint actually used (CCAD adjusted for treatment discontinuation) Versions of Primary Efficacy Outcome

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24 Why post-hoc ANCOVA model #1? Seven covariates + Trt Why post-hoc ANCOVA model #2? Excluding ‘treatment exposure’ US 96.1 Trial

25 Reviewer’s exploratory analyses - 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

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29 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

30 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!!)

31 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

32 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)

33 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’

34 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

35 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

36 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