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Statistical Perspective Acamprosate Experience

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

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Statistical Perspective Acamprosate Experience

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  1. Statistical PerspectiveAcamprosate 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. 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

  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

  7. Paille

  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. 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. US 96.1 Trial • 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

  14. US 96.1 Trial

  15. US 96.1 Trial • 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

  16. US 96.1 Trial • 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

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

  18. Post-hoc ANCOVA Model #1 • 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

  19. Post-hoc ANCOVA Model #2 - use 6 covariates (excluding treatment exposure) from model #1 Treatment Exposure: defined astreatment compliance*treatment duration/100 -potentially treatment related -due to differential time to discontinuation -and differential dropout

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

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

  22. Post-Hoc Model #1:Why 7-covariates 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’

  23. 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

  24. 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!!)

  25. 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

  26. 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)

  27. 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’

  28. 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

  29. 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

  30. 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

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