Analysis of U.S.A. Multicenter Trial Results

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

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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

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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
• gt65 years of age

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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.

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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 gt75 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)

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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 gt65 Years of Age Yes No
• Detox Required Yes No
• Abstinent at Baseline Yes No
• Standardized Behavioral Therapy No Yes

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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
aidsTimeline follow back calendar
Yes Standard drinks Yes Yes Yes
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One Standard Drink Equals12 Grams of Pure Alcohol
Beer ? 8 oz. Wine ? 4 oz. Hard Liquor (80
proof) ? 1 oz.
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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
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Drinking Data Obtained in Pivotal European and
U.S.A. Trials
Pelc II PRAMA Paille U.S.A. Abstinent/Non-abstin
ent 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 --
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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
  subjects 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

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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
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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

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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
Miami, FL
Houston, TX
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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
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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

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

• Placebo ACAMP 2g
• Treatment Goal of Total Abstinence 45 40
• Medicated Detox 10 12

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Acamprosate U.S.A. Multicenter Trial Lifetime
Baseline Substance Use
Placebo ACAMP 2g Marijuana 79 72 Cocaine 47 5
1 Psychedelics 37 39 Stimulants 36 34 Sedativ
es 23 26 Opiates 12 17 Heroin 7 10
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Acamprosate U.S.A. Multicenter Trial Baseline
Consumption of Cigarettes and Marijuana
Placebo ACAMP 2g Cigarette Smoker 45 47 Positi
ve Urine forCannabinoids 6 8
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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
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U.S.A. Primary Efficacy Results(ITT Population)
for Originally Planned Analyses
Placebo ACAMP 2g (n 257) (n
253) Abstinent at Baseline 49 52Weeks 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
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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

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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 OMalley et
  al, 1992 Rohsenow et al, 2000
• Treatment compliance
• Mattson et al, 1998 Volpicelli et al, 1997

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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)

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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

?
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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 11
5 100 26 241 MEFF 86 71 15 172
ITT
EFF
MEFF MITT
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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 lt 0.05 for 2g vs placebo
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Cumulative Abstinence Duration ()with
Covariates Treatment Follow-up Phase
Placebo ACAMP 2g ITT 50.8 55.9 EFF 53.7 60.2 MIT
T 56.5 67.2 MEFF 58.4 73.3
p lt 0.05 for 2g vs placebo
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Odds Ratios with Covariates of Good Response (CAD
? 90) andPoor Response (CAD ? 10)
ACAMP 2g vs
Placebo Good Response Poor Response ITT 1.34 0.4
5 EFF 1.80 0.44 MITT 1.36 0.31 MEFF 2.72 0.18

p lt 0.05 for 2g vs placebo
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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 1.6
7 MEFF 2.15
p lt 0.05 for 2g vs placebo
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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 MIT
T 60.7 78.1 MEFF 63.0 83.8
p lt 0.05 for 2g vs placebo
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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
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Acamprosate U.S.A. Multicenter Trial Overall
Summary

• Acamprosate U.S. study results support
• External validity 81 of screened patientswere
  randomized
• Safety
• Acceptability gt88 medication compliance

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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

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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.

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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.

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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