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Analysis of U.S.A. Multicenter Trial Results

Analysis of U.S.A. Multicenter Trial Results. Barbara J. Mason, Ph.D. Professor, Department of Psychiatry and Behavioral Sciences Director, Division of Substance Abuse University of Miami School of Medicine. Overview of Presentation. Acamprosate U.S.A. Multicenter Trial Objectives

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Analysis of U.S.A. Multicenter Trial Results

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  1. Analysis of U.S.A. Multicenter Trial Results Barbara J. Mason, Ph.D. Professor, Department of Psychiatry and Behavioral Sciences Director, Division of Substance Abuse University of Miami School of Medicine

  2. Overview of Presentation Acamprosate U.S.A. Multicenter Trial • Objectives • Study Design • Behavioral Therapy • Subjects • Study Results • Summary Acamprosate U.S.A and European Pivotal Trials Conclusions

  3. Objectives of the U.S.A. Multicenter Trial 1. Safety The FDA requested safety experience with acamprosate in the “typical” U.S.A. Outpatient with alcohol dependence, including those with: • Polysubstance abuse • No detoxification • No upper limit for liver function tests or serum creatinine • >65 years of age

  4. Objectives of the U.S.A. Multicenter Trial (continued) 2. Efficacy The sponsor sought to evaluate the efficacy of the standard 2 gram daily dose of acamprosate: • In a new 500 mg tablet strength • According to a new twice a day dosing schedule (two 500 mg tablets b.i.d.) Inclusion of an exploratory higher daily dose group in a smaller number of subjects: • 3 gram daily dose, given as three 500 mg tablets b.i.d.

  5. Approach to Understanding Efficacy in the U.S.A. Trial An efficacy evaluable (EFF) population was pre-specified and included those subjects who: • Took medication for 7 days to reach steady state • Were >75% compliant with medication • Did not have a positive urine test for illicit drugs at any study visit Standardized baseline measures of factors generally associated with alcoholism treatment outcome were collected (as potential covariates)

  6. Pivotal European and U.S.A. Study Methods European U.S.A. Double-blind Yes Yes Placebo-controlled Yes Yes Random Assignment Yes Yes DSM Criteria for Alcohol Dependence Yes Yes Excluded Current Substance Abusers Yes No Excluded >65 Years of Age Yes No Detox Required Yes No Abstinent at Baseline Yes No Standardized Behavioral Therapy No Yes

  7. Drinking Data Collection Methods in Pivotal European and U.S.A. Trials Pelc II PRAMA Paille U.S.A. Self-report elicited Yes Yes Yes Yes by alcoholism expert Written assurance Yes Yes Yes Yes of confidentiality Setting encouraged Yes Yes Yes Yes honest reporting (e.g., no legal ramifications) Diary Yes – Yes Yes Recall aids:Timeline follow back calendar – – – Yes Standard drinks – Yes Yes Yes

  8. One Standard Drink Equals12 Grams of Pure Alcohol Beer 8 oz. Wine 4 oz. Hard Liquor (80 proof) 1 oz.

  9. Drinking Data Collection Methods in Pivotal European and U.S.A. Trials (continued) Pelc II PRAMA Paille U.S.A. Biochemical confirmation Yes Yes Yes Yes GGT Yes Yes Yes Yes Transaminases Yes -- Yes -- MCV Yes Yes Yes -- Breathalyzer -- Yes -- Yes Alcohol in urine Yes -- -- Yes Collateral Informant -- Yes Yes Yes Time intervals assessed 2 wks 1-3 mo 1-2 mo 1 mo

  10. Drinking Data Obtained in Pivotal European and U.S.A. Trials Pelc II PRAMA Paille U.S.A. Abstinent/Non-abstinent Yes Yes Yes Yes Time to first drink Yes Yes Yes Yes No. of drinking days -- Yes Yes Yes Graduated frequency Yes Yes -- -- No. of grams per Yes -- Yes Yes drinking day Graduated quantity Yes Yes Yes --

  11. Timeline Follow Back Method The U.S.A. trial used the Timeline Follow Back Method to obtain drinking data • Developed as a continuous variable to assess controlled drinking rather than abstinence • Provides variables that describe pattern of subject’s drinking beyond simpler quantity/frequency methods • Limitation is more time to administer and increased burden on subject • Can cause increased attrition • Its self-monitoring nature can causereduced drinking

  12. U.S.A. Multicenter Study Schema 741 Patients Screened 140 Not Randomized 98 Not Eligible 42 Declined Participation 601 Randomized 260 Received Placebo 258 Received Acamprosate 2g/d 83 Received Acamprosate 3g/d 2 Month Post-Treatment Follow-Up

  13. Manual-Guided Brief Intervention and Medication Compliance Procedures Goals: Abstinence and medication compliance Procedures: • Motivation enhancement strategies • Patient handouts about alcohol, tips for quitting, and self assessment of drinking • Treatment Goals Worksheet: Changes desired, reasons, steps, obstacles • Acamprosate Information Sheet • Treatment Progress Summary

  14. Acamprosate U.S.A. Multicenter Trial21 Investigational Sites South Burlington, VT Minneapolis, MN Buffalo, NY Boston, MA Milwaukee, WI Pittsburgh, PA Providence, RI Cleveland, OH Cincinnati, OH New Haven, CT Farmington, CT New York, NY Oakland, CA Philadelphia, PA Menlo Park, CA Baltimore, MD Los Angeles, CA Charleston, SC Albuquerque, NM Houston, TX Miami, FL

  15. Acamprosate U.S.A. Multicenter Trial Patient Characteristics Placebo ACAMP 2g Age, years 44.4 44.9Range 22 – 69 23 – 72 Males 65% 70% White 86% 86% Lives alone 17% 21% Employed F/T 59% 53% Psychiatric history 13% 15%

  16. Acamprosate U.S.A. Multicenter Trial Baseline Clinical Characteristics • Placebo ACAMP 2g Clinical Global Impression (1-7) 4.4 4.6 • Alcohol Dependence Scale  22 18% 23% • Parental Alcoholism 40% 42% • Drinking Days/Week 5.3 5.4 • Drinks/Drinking Day 10.8 11.2 • Heavy Drinking Years 12.6 13.0 • 2 Prior Detoxes 28% 32%

  17. Acamprosate U.S.A. Multicenter Trial Baseline Abstinence Parameters Placebo ACAMP 2g Treatment Goal of Total Abstinence 45% 40% Medicated Detox 10% 12%

  18. Acamprosate U.S.A. Multicenter Trial Lifetime Baseline Substance Use Placebo ACAMP 2g Marijuana79% 72% Cocaine 47% 51% Psychedelics 37% 39% Stimulants 36% 34% Sedatives 23% 26% Opiates 12% 17% Heroin 7% 10%

  19. Acamprosate U.S.A. Multicenter Trial Baseline Consumption of Cigarettes and Marijuana Placebo ACAMP 2g Cigarette Smoker 45% 47% Positive Urine forCannabinoids 6% 8%

  20. Acamprosate U.S.A. Multicenter Trial Patient Disposition and Treatment Participation - Safety Population Placebo ACAMP 2g(n = 260) (n = 258) Medication Compliance 93% 89% Weeks on Study 18.0 16.0 % Completed 55% 41% Premature Termination 45% 59% Due to alcohol 52% 39% Due to adverse events 5% 4%

  21. U.S.A. Primary Efficacy Results(ITT Population) for Originally Planned Analyses Placebo ACAMP 2g (n = 257) (n = 253) Abstinent at Baseline 49% 52%Weeks on Study 19.0 17.4 Time to Relapse Any Drinking, days 4 4 Heavy Drinking, days 12 15 Complete Abstinence, % 11 8 Cumulative Abstinence Duration Days 83.7 72.9 % 51.2 45.8

  22. Baseline Factors Reliably Associated with Alcoholism Treatment Outcome • Psychiatric history • McLellan et al, 1983; Woody et al, 1984; Rounsaville et al, 1987; Project MATCH Research Group, 1997; Greenfield et al, 1998 • Substance use • Hersh et al, 1998; Miller and Bennett, 1996; Caetano and Weisner, 1995; Grant and Pickering, 1996 • Severity of alcohol dependence • Institute of Medicine, 1989

  23. Baseline Factors Reliably Associated with Alcoholism Treatment Outcome (continued) • Psychosocial support (e.g., full-time employment, marital status) • McLellan et al, 1983; Institute of Medicine, 1989 • Readiness to Change • DiClemente and Hughes, 1990; Project MATCH Research Group, 1997 • Treatment goal of complete abstinence • Polich et al, 1980; Hall et al, 1990; O’Malley et al, 1992; Rohsenow et al, 2000 • Treatment compliance • Mattson et al, 1998; Volpicelli et al, 1997

  24. Acamprosate U.S.A. Multicenter Trial Covariates Applied Uniformly Across Outcome Measures • Baseline CGI severity (1-7) • Treatment goal (total abstinence versus not) • Readiness to Change (precontemplation, contemplation, and action) • Psychiatric history (present or not) • Addiction index (Fagerström Score x Illicit Drug Use Index) • Treatment exposure(Study drug duration [wks] x Compliance [%]) / 100 • Baseline values (analyses of change from baseline)

  25. Acamprosate U.S.A. Multicenter Trial Case Report Form Question for Treatment Goal What is your treatment goal? • Total abstinence • Total abstinence but I realize a slip is possible • Occasional use • Temporary abstinence • Regular use but quantity controlled • No goal 

  26. U.S.A. Trial Patient Subgroups Placebo ACAMP 2g ACAMP 3g Total Safety 260 258 83 601 ITT 257 253 82 592 EFF 198 177 56 431 MITT 115 100 26 241 MEFF 86 71 15 172 ITT EFF MEFF MITT

  27. Cumulative Abstinence Duration (%) with Covariates Placebo ACAMP 2g ITT 52.3 58.2* EFF 54.8 62.3* MITT 58.1 70.0* MEFF 59.4 75.5* * p < 0.05 for 2g vs placebo

  28. Cumulative Abstinence Duration (%)with Covariates Treatment + Follow-up Phase Placebo ACAMP 2g ITT 50.8 55.9 EFF 53.7 60.2 MITT 56.5 67.2* MEFF 58.4 73.3* * p < 0.05 for 2g vs placebo

  29. Odds Ratios with Covariates of Good Response (CAD  90%) andPoor Response (CAD  10%) ACAMP 2g vs Placebo Good Response Poor Response ITT 1.34 0.45* EFF 1.80* 0.44* MITT 1.36 0.31* MEFF 2.72* 0.18* * p < 0.05 for 2g vs placebo

  30. Odds Ratios with Covariates of Complete Abstinence During the Last Visit (Treatment Phase) Interval [LOCF] ACAMP 2g vs Placebo ITT 1.43 EFF 1.64 MITT 1.67 MEFF 2.15* * p < 0.05 for 2g vs placebo

  31. Percent Reduction(Relative to Baseline) in Drinks per Week on Study with Covariates Placebo ACAMP 2g ITT 59.7 64.8 EFF 61.2 68.3 MITT 60.7 78.1* MEFF 63.0 83.8* * p < 0.05 for 2g vs placebo

  32. Change from Baseline GGT at Treatment Phase Endpoint Placebo ACAMP 2g Baseline Mean (IU/L) 89.7 99.3 Endpoint Mean (IU/L) 62.4 62.2 Mean Change fromBaseline (IU/L) -28.6 -35.1 Normal Range: Females 5 – 49 IU/L; Males 7 – 64 IU/L

  33. Acamprosate U.S.A. Multicenter Trial Overall Summary Acamprosate U.S. study results support: External validity: 81% of screened patientswere randomized Safety Acceptability: >88% medication compliance

  34. Acamprosate U.S.A. Multicenter Trial Overall Summary Acamprosate U.S. study results support: Efficacy, controlling for baseline variables and treatment exposure, and especially in patients with a goal of abstinence: • Increased cumulative abstinence duration • Increased likelihood of good response • Decreased likelihood of poor response • Increased likelihood of abstinence at termination • Other changes relative to pre-treatment status: • less alcohol consumption • normalization of GGT

  35. Conclusions from Acamprosate U.S.A. and European Pivotal Trials 1. Acamprosate, 2 grams per day, showed beneficial and clinically relevant effects on abstinence outcomes in almost 2000 alcohol-dependent outpatients who participated in double-blind, placebo-controlled trials of up to 1 year in duration. 2. Acamprosate, 2 grams per day, showed sustained efficacy, for post-treatment periods of up to 1 year, relative to placebo.

  36. Conclusions from Acamprosate U.S.A. and European Pivotal Trials 3.To optimize acamprosate treatment outcome, patients should be motivated to have abstinence as their treatment goal. • US data suggest that acamprosate does not induce abstinence in unmotivated drinkers. • The US data suggest that it may not be necessary to undergo formal detoxification in order to obtain therapeutic benefit from acamprosate, provided patients are motivated to have abstinence as their treatment goal.

  37. Conclusions from Acamprosate U.S.A. and European Pivotal Trials 4. High rates of compliance support the acceptability of acamprosate and the b.i.d. and t.i.d. dosing schedules 5. Long term beneficial effects of acamprosate are evident across a range of countries, clinical settings, and behavioral therapies

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