# Presentation: 046599

## 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**

**Acamprosate U.S.A. Multicenter Trial**
**Objectives**
**Study Design**
**Behavioral Therapy**
**Subjects**
**Study Results**
**Summary**
**Acamprosate U.S.A and European Pivotal Trials Conclusions**

**Overview of Presentation**

## 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**

## 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.**

## 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)**

## 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**

## 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 **

## One Standard Drink Equals12 Grams of Pure Alcohol

**Beer****	**** ********	****8 oz.**
**Wine****	**** ******** ****	****4 oz.**
**Hard Liquor (80 proof)****	********	****1 oz.**

## Drinking Data Collection Methods in Pivotal European and U.S.A. Trials (continued)

**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**

**Drinking Data Collection Methods ****in Pivotal European and U.S.A. Trials (continued)**

## 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 ****	**** --**

## 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 cause****reduced drinking**

## U.S.A. Multicenter Study Schema

**140 Not Randomized**

**601 Randomized**

**260 Received **
** ****Placebo**

**258 Received **
**Acamprosate 2g/d**

**83 Received **
**Acamprosate 3g/d**

**U.S.A. Multicenter Study Schema**

**741 Patients Screened**

**2 Month Post-Treatment Follow-Up**

**98 Not Eligible**

**42 Declined Participation**

## 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**

## Acamprosate U.S.A. Multicenter Trial21 Investigational Sites 

**Milwaukee, WI**

**Cincinnati, OH**

**Cleveland, OH**

**South Burlington, VT**

**Boston, MA**

**Providence, RI**

**New Haven, CT**

**Farmington, CT**

**New York, NY**

**Buffalo, NY**

**Pittsburgh, PA**

**Charleston, SC**

**Miami, FL**

**Baltimore, MD**

**Albuquerque, NM**

**Los Angeles, CA**

**Menlo Park, CA**

**Oakland, CA**

**Philadelphia, PA**

**Houston, TX**

**Acamprosate U.S.A. Multicenter Trial****21 Investigational Sites **

## Acamprosate U.S.A. Multicenter Trial Patient Characteristics

**Age, years ****	****44.4****	****44.9****Range****	****22 – 69****	****23 – 72**
**Males****	****65%****	****70%**
**White****	****86%****	****86%**
**Lives alone****	****17%****	****21%**
**Employed F/T****	****59%****	****53%**
**Psychiatric history****	****13%****	****15%**

**Acamprosate U.S.A. Multicenter Trial Patient Characteristics**

## Acamprosate U.S.A. Multicenter Trial Baseline Clinical Characteristics

**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%**

**Acamprosate U.S.A. Multicenter Trial Baseline Clinical Characteristics**

## Acamprosate U.S.A. Multicenter Trial Baseline Abstinence Parameters

**Treatment Goal of ****   Total Abstinence****	****45%****	****40%**
**Medicated Detox****	****10%****	****12%**

**Acamprosate U.S.A. Multicenter Trial Baseline Abstinence Parameters**

## Acamprosate U.S.A. Multicenter Trial Lifetime Baseline Substance Use

**Marijuana**	**79%****	****72%**
**Cocaine****	****47%****	****51%**
**Psychedelics****	****37%****	****39%**
- S**timulants****	****36%****	****34%**
**Sedatives****	****23%****	****26%**
**Opiates****	****12%****	****17%**
**Heroin****	****7%****	****10%**

**Acamprosate U.S.A. Multicenter Trial Lifetime Baseline Substance Use**

## Acamprosate U.S.A. Multicenter Trial Baseline Consumption of Cigarettes and Marijuana

**Cigarette Smoker****	****45%****	****47%**
**Positive Urine for****Cannabinoids****	****6%****	****8%**

**Acamprosate U.S.A. Multicenter Trial Baseline Consumption of Cigarettes and Marijuana**

## Acamprosate U.S.A. Multicenter Trial Patient Disposition and Treatment Participation - Safety Population

**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%**

**Acamprosate U.S.A. Multicenter Trial Patient Disposition and Treatment Participation - Safety Population**

## 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**

## 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

## 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** **

## 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)**

## 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**

****

## U.S.A. Trial Patient Subgroups

**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 **

**EFF**

**MEFF**
**           ****MITT**

**ITT**

**U.S.A. Trial Patient Subgroups**

## Cumulative Abstinence Duration (%) with Covariates

**ITT****	****52.3****	****58.2*****	**
**EFF****	****54.8****	****62.3***
**MITT****	****58.1****	****70.0***
**MEFF****	****59.4****	****75.5***

**Cumulative Abstinence Duration (%) with Covariates**

*** p < 0.05 for 2g vs placebo**

## Cumulative Abstinence Duration (%)with Covariates Treatment + Follow-up Phase

**ITT****	****50.8****	****55.9**
**EFF****	****53.7****	****60.2**
**MITT****	****56.5****	****67.2***
**MEFF****	****58.4****	****73.3***

**Cumulative Abstinence Duration (%)****with Covariates ****Treatment + Follow-up Phase**

*** p < 0.05 for 2g vs placebo**

## Odds Ratios with Covariates of Good Response (CAD  90%) andPoor Response (CAD  10%) 

**	****	****Good Response****	****Poor Response**
**ITT****	****1.34****	****0.45***
**EFF****	****1.80*****	****0.44***
**MITT****	****1.36****	****0.31***
**MEFF****	****2.72*****	****0.18***

**Odds Ratios with Covariates of Good Response (CAD ******** 90%) and****Poor Response (CAD ******** 10%) **

*** p < 0.05 for 2g vs placebo**

## Odds Ratios with Covariates of Complete Abstinence During the Last Visit (Treatment Phase) Interval [LOCF] 

**ITT****	****1.43****	**
**EFF****	****1.64****	**
**MITT****	****1.67****	**
**MEFF****	****2.15***

**Odds Ratios with Covariates of Complete Abstinence During the Last Visit (Treatment Phase) Interval [LOCF] **

*** p < 0.05 for 2g vs placebo**

## Percent Reduction(Relative to Baseline) in Drinks per Week on Study with Covariates

**ITT****	****59.7****	****64.8**
**EFF****	****61.2****	****68.3**
**MITT****	****60.7****	****78.1***
**MEFF****	****63.0****	****83.8***

**Percent Reduction****(Relative to Baseline) in Drinks per Week on Study with Covariates**

*** p < 0.05 for 2g vs placebo**

## Change from Baseline GGT at Treatment Phase Endpoint

**Baseline Mean (IU/L)****	****89.7****	****99.3****	**
**Endpoint Mean (IU/L)****	****62.4****	****62.2****	**
**Mean Change from****Baseline (IU/L)****	****-28.6****	****-35.1**

**Normal Range:  Females 5 – 49 IU/L; Males 7 – 64 IU/L**

**Change from Baseline GGT at Treatment Phase Endpoint**

## Acamprosate U.S.A. Multicenter Trial Overall Summary

**Acamprosate U.S. study results support:**
**External validity: 81% of screened patients****were randomized**
**Safety ****	**
**Acceptability: >88% medication compliance**

## 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**

## 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.**

## 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.**

## 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**