ACAMPROSATE Analysis of U.S.A. Multicenter Trial Results Barbara J. Mason, Ph.D. Professor, Department of Psychiatry and Behavioral Sciences Director,

ACAMPROSATEACAMPROSATE

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

Barbara J. Mason, Ph.D.

Professor, Department of Psychiatry and Behavioral Sciences

Director, Division of Substance Abuse

University of Miami School of Medicine


MAS-2


Acamprosate U.S.A. Multicenter Trial

Objectives

Study Design

Behavioral Therapy

Subjects

Study Results

Summary

Acamprosate U.S.A and European Pivotal Trials Conclusions

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 PresentationOverview of Presentation


MAS-3


Objectives of the U.S.A. Multicenter Trial

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

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


MAS-4


Objectives of the U.S.A. Multicenter Trial (continued)

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.

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.


MAS-5


Approach to Understanding Efficacy in the U.S.A. Trial

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)

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)


MAS-6


Pivotal European and U.S.A. Study Methods

Pivotal European and U.S.A. Study Methods

EuropeanEuropean U.S.A.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

EuropeanEuropean U.S.A.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


MAS-7


Drinking Data Collection Methods in Pivotal European and U.S.A. Trials


Pelc II PRAMA PailleU.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

Pelc II PRAMA PailleU.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


MAS-8


One Standard Drink Equals12 Grams of Pure Alcohol

One Standard Drink Equals12 Grams of Pure Alcohol

Beer 8 oz.

Wine 4 oz.

Hard Liquor (80 proof) 1 oz.

Beer 8 oz.

Wine 4 oz.

Hard Liquor (80 proof) 1 oz.


MAS-9


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


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


(continued)


(continued)


MAS-10


Drinking Data Obtained in Pivotal European and U.S.A. Trials

Drinking Data Obtained in Pivotal European and U.S.A. Trials


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 --


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 --


MAS-11


Timeline Follow Back MethodTimeline Follow Back MethodThe U.S.A. trial used the Timeline Follow Back Method to obtain drinking data

1 Developed as a continuous variable to assess controlled drinking rather than abstinence

2 Provides variables that describe pattern of subject’s drinking beyond simpler quantity/frequency methods

3 Limitation is more time to administer and increased burden on subject

a Can cause increased attrition

b Its self-monitoring nature can causereduced drinking

The U.S.A. trial used the Timeline Follow Back Method to obtain drinking data

1 Developed as a continuous variable to assess controlled drinking rather than abstinence

2 Provides variables that describe pattern of subject’s drinking beyond simpler quantity/frequency methods

3 Limitation is more time to administer and increased burden on subject

a Can cause increased attrition

b Its self-monitoring nature can causereduced drinking


MAS-12


140 Not Randomized140 Not Randomized

601 Randomized601 Randomized

260 Received 260 Received PlaceboPlacebo

258 Received 258 Received Acamprosate 2g/dAcamprosate 2g/d

83 Received 83 Received Acamprosate 3g/dAcamprosate 3g/d

U.S.A. Multicenter Study Schema

U.S.A. Multicenter Study Schema

741 Patients Screened741 Patients Screened

2 Month Post-Treatment Follow-Up2 Month Post-Treatment Follow-Up

98 Not Eligible98 Not Eligible 42 Declined Participation42 Declined Participation


MAS-13


Manual-Guided Brief Intervention and Medication Compliance Procedures

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

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


MAS-14


Minneapolis, MN

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 Trial21 Investigational Sites

Acamprosate U.S.A. Multicenter Trial21 Investigational Sites


MAS-15


PlaceboPlacebo ACAMP 2gACAMP 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%


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%

Acamprosate U.S.A. Multicenter Trial Patient Characteristics

Acamprosate U.S.A. Multicenter Trial Patient Characteristics


MAS-16



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%


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 Clinical Characteristics


MAS-17



Treatment Goal of Total Abstinence 45% 40%

Medicated Detox 10% 12%


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 Baseline Abstinence Parameters


MAS-18



Marijuana 79% 72%

Cocaine 47% 51%

Psychedelics 37% 39%

Stimulants 36% 34%

Sedatives 23% 26%

Opiates 12% 17%

Heroin 7% 10%


Marijuana 79% 72%

Cocaine 47% 51%

Psychedelics 37% 39%

Stimulants 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 Lifetime Baseline Substance Use


MAS-19



Cigarette Smoker 45% 47%

Positive Urine forCannabinoids 6% 8%


Cigarette Smoker 45% 47%

Positive Urine forCannabinoids 6% 8%

Acamprosate U.S.A. Multicenter Trial Baseline Consumption of Cigarettes

and Marijuana

Acamprosate U.S.A. Multicenter Trial Baseline Consumption of Cigarettes

and Marijuana


MAS-20


PlaceboPlacebo ACAMP 2gACAMP 2g(n = 260)(n = 260) (n = 258)(n = 258)

Medication ComplianceMedication Compliance 93%93% 89%89%

Weeks on StudyWeeks on Study 18.018.0 16.016.0

% Completed% Completed 55%55% 41%41%

Premature TerminationPremature Termination 45%45% 59%59%

Due to alcoholDue to alcohol 52%52% 39%39%

Due to adverse eventsDue to adverse events 5%5% 4%4%


Medication ComplianceMedication Compliance 93%93% 89%89%

Weeks on StudyWeeks on Study 18.018.0 16.016.0

% Completed% Completed 55%55% 41%41%

Premature TerminationPremature Termination 45%45% 59%59%

Due to alcoholDue to alcohol 52%52% 39%39%

Due to adverse eventsDue to adverse events 5%5% 4%4%

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

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


MAS-21


U.S.A. Primary Efficacy Results(ITT Population) for Originally Planned

Analyses

U.S.A. Primary Efficacy Results(ITT Population) for Originally Planned

Analyses


Abstinent at Baseline 49% 52%Weeks on Study 19.0 17.4

Time to RelapseAny Drinking, days 4 4Heavy Drinking, days 12 15

Complete Abstinence, % 11 8

Cumulative Abstinence DurationDays 83.7 72.9% 51.2 45.8


Abstinent at Baseline 49% 52%Weeks on Study 19.0 17.4

Time to RelapseAny Drinking, days 4 4Heavy Drinking, days 12 15

Complete Abstinence, % 11 8

Cumulative Abstinence DurationDays 83.7 72.9% 51.2 45.8


MAS-22


Baseline Factors Reliably Associated with Alcoholism Treatment OutcomeBaseline 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

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


MAS-23


Baseline Factors Reliably Associated with Alcoholism Treatment Outcome (continued)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

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


MAS-24


Acamprosate U.S.A. Multicenter Trial Covariates Applied Uniformly Across

Outcome Measures

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)

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)


MAS-25


Acamprosate U.S.A. Multicenter Trial Case Report Form Question for Treatment GoalAcamprosate 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

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


MAS-26


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

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

EFFEFF

MEFFMEFF MITTMITT

ITTITT

U.S.A. Trial Patient SubgroupsU.S.A. Trial Patient Subgroups


MAS-27



ITTITT 52.352.3 58.2*58.2*

EFFEFF 54.854.8 62.3*62.3*

MITTMITT 58.158.1 70.0*70.0*

MEFFMEFF 59.459.4 75.5*75.5*


ITTITT 52.352.3 58.2*58.2*

EFFEFF 54.854.8 62.3*62.3*

MITTMITT 58.158.1 70.0*70.0*

MEFFMEFF 59.459.4 75.5*75.5*

Cumulative Abstinence Duration (%) with Covariates

Cumulative Abstinence Duration (%) with Covariates

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


MAS-28



ITTITT 50.850.8 55.955.9

EFFEFF 53.753.7 60.260.2

MITTMITT 56.556.5 67.2*67.2*

MEFFMEFF 58.458.4 73.3*73.3*


ITTITT 50.850.8 55.955.9

EFFEFF 53.753.7 60.260.2

MITTMITT 56.556.5 67.2*67.2*

MEFFMEFF 58.458.4 73.3*73.3*

Cumulative Abstinence Duration (%)with Covariates

Treatment + Follow-up Phase

Cumulative Abstinence Duration (%)with Covariates

Treatment + Follow-up Phase



MAS-29


ACAMP 2g vs PlaceboACAMP 2g vs Placebo

Good ResponseGood Response Poor ResponsePoor Response

ITTITT 1.341.34 0.45*0.45*

EFFEFF 1.80*1.80* 0.44*0.44*

MITTMITT 1.361.36 0.31*0.31*

MEFFMEFF 2.72*2.72* 0.18*0.18*

ACAMP 2g vs PlaceboACAMP 2g vs Placebo

Good ResponseGood Response Poor ResponsePoor Response

ITTITT 1.341.34 0.45*0.45*

EFFEFF 1.80*1.80* 0.44*0.44*

MITTMITT 1.361.36 0.31*0.31*

MEFFMEFF 2.72*2.72* 0.18*0.18*

Odds Ratios with Covariates of Good Response (CAD 90%) and

Poor Response (CAD 10%)

Odds Ratios with Covariates of Good Response (CAD 90%) and

Poor Response (CAD 10%)



MAS-30


ACAMP 2g vs ACAMP 2g vs PlaceboPlacebo

ITTITT 1.431.43

EFFEFF 1.641.64

MITTMITT 1.671.67

MEFFMEFF 2.15*2.15*

ACAMP 2g vs ACAMP 2g vs PlaceboPlacebo

ITTITT 1.431.43

EFFEFF 1.641.64

MITTMITT 1.671.67

MEFFMEFF 2.15*2.15*

Odds Ratios with Covariates of Complete Abstinence During the Last Visit

(Treatment Phase) Interval [LOCF]

Odds Ratios with Covariates of Complete Abstinence During the Last Visit

(Treatment Phase) Interval [LOCF]



MAS-31



ITTITT 59.759.7 64.864.8

EFFEFF 61.261.2 68.368.3

MITTMITT 60.760.7 78.1*78.1*

MEFFMEFF 63.063.0 83.8*83.8*


ITTITT 59.759.7 64.864.8

EFFEFF 61.261.2 68.368.3

MITTMITT 60.760.7 78.1*78.1*

MEFFMEFF 63.063.0 83.8*83.8*

Percent Reduction(Relative to Baseline) in Drinks per Week

on Study with Covariates

Percent Reduction(Relative to Baseline) in Drinks per Week

on Study with Covariates



MAS-32



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


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

Change from Baseline GGT at Treatment Phase Endpoint

Change from Baseline GGT at Treatment Phase Endpoint


MAS-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


External validity: 81% of screened patientswere randomized

Safety

Acceptability: >88% medication compliance


MAS-34





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


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


MAS-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.

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.


MAS-36




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.

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.


MAS-37




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

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

Documents

ACAMPROSATE Analysis of U.S.A. Multicenter Trial Results Barbara J. Mason, Ph.D. Professor, Department of Psychiatry and Behavioral Sciences Director,