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Efficacy Results from Three Pivotal Efficacy Trials

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.

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Efficacy Results from Three Pivotal Efficacy Trials

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  1. Efficacy Results from Three Pivotal Efficacy Trials Karl F. Mann, M.D.Professor and ChairmanDirector, Department of Addictive Behavior and Addiction MedicineCentral Institute of Mental Health of MannheimUniversity of Heidelberg

  2. 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

  3. Pivotal European Efficacy Studies Number of:Study Name Centers Subjects* Country Dates of Study Pelc II 12 188 Belgium/ 1990-1992 France PRAMA 12 272 Germany 1990-1992 Paille 31 538 France 1989-1992 TOTAL 55 998 * ITT population Source: ISE Section 8.7.2.2

  4. Pivotal European Efficacy Studies:Study Design Features - General Criterion Pelc II PRAMA Paille Double-blind, randomized,   placebo-controlled Multicenter    Acamprosate Dose-Levels, 1332, 1998 1332,mg/day 1998 1998 Treatment/Follow-up 3/-- 12/12 12/6Duration, months Site-specific psychosocial therapy    Source: ISE Section 8.7.2.2

  5. Pivotal European Study Design Features Entrance Criteria Criterion Pelc II PRAMA Paille 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 7-30at Baseline, days Source: ISE Section 8.7.2.2

  6. Methods for Collecting Drinking Data in Pivotal European Efficacy Studies Derived from an abstinence-orientedtreatment 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.

  7. Patient DispositionPivotal European Efficacy Studies 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%) Source: ISE Section 8.7.2.3

  8. Reasons for Discontinuation Pivotal European Efficacy Studies ACAMP (all doses) Placebo Total 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%) Source: ISE Section 8.7.2.3

  9. Pivotal European Efficacy Studies: Demographic and Baseline Characteristics 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 alcoholdep/abuse, years 9 - 10 10 % >10 std. drinks*/day 77% 69% 79% 73% % Detox. 100% 100% 100% 100% % Abstinent (Baseline) 99% 100% 100% >99% *Standard drink = 12 g pure alcoholSource: ISE Section 8.7.2.4

  10. Pivotal European Efficacy StudiesMean (S.E.) Study Drug Exposure in Weeks ACAMP ACAMP 1332 1998 Placebo 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) Source: ISE Section 8.7.2.6

  11. Pivotal European Efficacy StudiesMean 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

  12. Pivotal European Efficacy StudiesDefinitions of Common Outcome Parameters • 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 Source: ISE Section 8.7.1.2.5

  13. Survival Estimate of Time to First Drink* - Pelc II Median time to 1st drink3X longer in acamp 1998 vs placebo, p<0.001 0 * Dropout = failure Source: ISE Section 8.7.2.7.2

  14. Survival Estimate of Time to First Drink* - PRAMA Median time to 1st drink3X longer in acamp vs placebo, p<0.001 0 * Dropout = failureSource: ISE Section 8.7.2.7.2

  15. Survival Estimate of Time to First Drink* - Paille Median time to 1st drink2X longer in acamp 1998 mg vs placebo, p=0.005 0 * Dropout = failureSource: ISE Section 8.7.2.7.2

  16. European Pivotal Efficacy StudiesRate of Complete Abstinence ** ** ** * 3 mos 1 yr 1 yr * P  .050; **P  .010 Source: ISE Section 8.7.2.7.3

  17. European Pivotal Efficacy StudiesMedian Percentage of Abstinent Days on Study (CAD%) ** ** ** ** * P  .050; **P  .010 Source: ISE Section 8.7.2.7.1

  18. 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

  19. ISBRA15th–18th September 2004Heidelberg, Germany Prof. Karl F. Mann, M.D.Chair in Addiction ResearchUniversity of Heidelberg

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