1. 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. 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. 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. 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. 5 Pelc II

6. 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

7. 7 Paille

8. 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. 1990 to December 1992

9. 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. 10 PRAMA

11. 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. 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. 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

14. 14 US 96.1 Trial

15. 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. 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. 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. 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. 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. 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. 24 Why post-hoc ANCOVA model #1? Seven covariates + Trt Why post-hoc ANCOVA model #2? Excluding ‘treatment exposure’ US 96.1 Trial

25. 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. 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. 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. 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. 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. 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. 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. 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. 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