Statistical Perspective Acamprosate Experience

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Statistical PerspectiveAcamprosate Experience
Sue-Jane Wang, Ph.D. Statistics
Leader Alcoholism Treatment Clinical Trials May
10, 2002 Drug Abuse Advisory Committee Meeting
DACCADP/DB2/OB/CDER/FDA
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OUTLINE

• The Three European Pivotal Trials
• Pelc II, Paille, PRAMA
• Differential treatment discontinuation
• The US 96.1 Trial
• Acamprosate effect (2000 mg/day) observed in only
  the sponsor defined Post-Hoc Analysis but not
  supported by many other analyses
• Difference between European and US Trials
• Analytic Issues

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Dosages of Treatment

• Placebo (pbo)
• Acamprosate 1332 mg/day (low dose)
• European two 333 mg tablets bid
• Acamprosate 1998 mg/day (medium dose)
• European two 333 mg tablets tid
• US two 500 mg tablets bid
• Acamprosate 3000 mg/day (high dose)
• US three 500 mg tablets bid

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Pelc II

• Study Design A multicenter, double blind,
  randomized, placebo-controlled 3-arm study
• Study Objective Effectiveness and
• tolerance of acamprosate in helping to
  maintain abstinence in weaned alcoholic
• Main criterion of judgement
• The consumption of alcohol
• Trial duration 3 months
• Trial period June 1990 to April 1992

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Pelc II
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Paille

• Study Design A multicenter, double blind,
  randomized, placebo-controlled 3-arm study
• Main Objective
• maintenance of abstinence with acamprosate 1332
  mg/day (low dose) in alcoholic patients who were
  followed as outpatients after withdrawal
• Trial duration 360 days
• Trial Period April 1989 to November 1992

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Paille
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PRAMA

• Study Design A multicenter, double blind,
  randomized, placebo-controlled 2-arm study
• PBO vs. Acamprosate
• Study Objective
• Effectiveness and tolerance of acamprosate, which
  helps to maintain abstinence after detoxification
  in the alcoholic patients
• Trial Duration 48 weeks
• Trial Period Oct. 1990 to December 1992

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PRAMA

• Primary efficacy time to 1st relapse
• Definition of relapse
• short-term relapse alcohol consumption for
• up to 24 hours
• long-term relapse alcohol consumption for more
  than 24 hours with/without the need for
  hospitalization
• continuous relapse constant alcohol consumption

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PRAMA
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The European Pivotal Trials

• Drinking Data was retrospectively collected
• Dropout rate higher in pbo than in acamprosate
• Effect of acamprosate 1998 mg/d (r.t. pbo) was
  shown in complete abstinence
• Effect of acamprosate 1332 mg/day (low dose) was
  not shown in Paille Trial
• Trials were conducted in late 1980s to early 1990s

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US 96.1 Trial

• Patient Population Alcohol dependence who had
  been withdrawn from alcohol or who had completed
  medicated detoxification within ?2 to ?10 days of
  study entry
• Study Design a multicenter (21 centers),
  double-blind, randomized, placebo controlled
• Randomization well-balanced among 3-arms PBO,
  M-dose (2 g/d), H-dose (3 g/d)
• Data rigorous TLFB drinking measurement

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US 96.1 Trial

• Primary Objective
• to confirm efficacy safety of medium dose (2000
  mg/day) acamprosate in association with
  standardized but minimal psychosocial support,
  guided by a protocol-specific manual
• Secondary Objective
• explore high dose (3000 mg/day) acamprosate
  efficacy safety
• Trial Duration 24 weeks
• Trial Period May 1997 to January 1999

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US 96.1 Trial
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US 96.1 Trial

• Protocol specified primary efficacy endpoints
• Time to 1st day of any drinking
• Time to 1st day of heavy drinking
• (?6 drinks for men, ?4 drinks for women)
• Cumulative abstinence duration (CAD)
• CCAD (percent days abstinence PDA)
• Rate of complete abstinence

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US 96.1 Trial

• Medium dose acamprosate 2g/d failed to show a
  superior effect on pre-specified endpoints
• Exploratory analysis pre-specified
• CAD or CCAD adjusted for T, C, Detoxification
• Supportive analysis pre-specified
• adjusted for T,C, amount of psychosocial therapy
• adjusted for T,C, illicit drug use

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US 96.1 Trial

• New primary efficacy endpoint
• Cumulative Abstinence Duration (CAD)
• (post-hoc definition)
• Endpoint considered CCAD (PDA)
• Endpoint actually used ALCCAD (PDA adjusted for
  treatment discontinuation)

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Post-hoc ANCOVA Model 1

• Chosen by the sponsor
• Use the following covariates for adjustments
• treatment exposure
• pooled site (?)
• baseline CGI-severity
• stage of readiness to change
• psychological antecedent
• addiction index
• goal of abstinence

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Post-hoc ANCOVA Model 2
- use 6 covariates (excluding treatment
exposure) from model 1 Treatment Exposure
defined astreatment compliancetreatment
duration/100 -potentially treatment related
-due to differential time to discontinuation
-and differential dropout
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Versions of Primary Efficacy Outcome

• Modified CCAD No Statistically significant
  findings on Model 1 or Model 2 or unadjusted
  analysis
• ALCCAD endpoint actually used
• (CCAD adjusted for treatment discontinuation)

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US 96.1 Trial
Why post-hoc ANCOVA model 1? Seven covariates
Trt Why post-hoc ANCOVA model 2? Excluding
treatment exposure
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Post-Hoc Model 1Why 7-covariates
Reviewers exploratory analyses - to
examine how the results of the sponsors post-hoc
ANCOVA depend on which covariate(s) to include
- center always included - each covariate
included one at a time - other combinations of
covariates included with or without the
abstinence goal
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Medium dose (2 g/d) effective?
US trial was sufficiently powered for efficacy
evaluation of this dose gt No evidence of
effect, after adjusting for any one
covariate alone gt Excluding treatment exposure
from ANCOVA, No evidence of the effect gt
Numerically worse than placebo in mean
heavy drinking days
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Medium dose (2 g/d) effective?
Whether this dose appears to show efficacy
depends on post-hoc selection of covariates for
adjustment e.g., including abstinence
goal trt exposure or all 7
covariates (multiplicity!!)
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Exploration for High Dose???
Not sufficiently powered (1/3 sample
size) Insufficient safety data in the US
trial Numerically superior to placebo in mean
heavy drinking days The abstinence goal
seemed prognostic of high dose (3 g/d) effect,
but only if using the ALCCAD Effect was not seen
if adjustments did not include abstinence
goal
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Summary - US 96.1 Trial

• Dropout rate was significantly higher and
  treatment exposure was shorter in medium 2g/d
  dose acamprosate than in high dose or placebo
• Effect of 2 g/day (r.t. pbo) not established on
  protocol specified primary efficacy outcome or
  post-hoc defined primary endpoint (CCAD percent
  days abstinence)

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Summary - US 96.1 Trial

• Post-hoc chosen model 1 or 2 on ALCCAD can be
  problematic
• - The significant results for 2 g/d acamprosate
  depend on which post-hoc independent covariate(s)
  to include for adjustments no effect after
  multiplicity adjustments
• - Analysis for 3 g/d acamprosate was exploratory
  
• time to 1st heavy drinking, mean heavy
  drinking over
• time but, small n

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Difference between European vs. US

• Acamprosate in Europe 3-mon, 360d, 48-wk
• less dropouts
• longer treatment exposure
• Acamprosate 2g/d in US 24-wk
• more dropouts
• shorter treatment exposure
• Analytic Issues
• need of well-thought pre-specified algorithm for
  handling dropout patterns

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Differences between European vs. US

• Drinking data
• European retrospective collection from
  clinician
• US TLFB diary
• Criteria of total abstinence at study entry
• Europe explicitly required
• US not explicitly required
• Medicated detoxification
• European 100 US10
• Patients baseline characteristics
• European 18 to 65 years of age
• US no upper age limit

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Differences between European vs. US

• Psychosocial support
• European non-structured psychosocial
  therapy
• US standardized, manual-guided psychosocial
• support
• Dosage form
• European 333 mg tablets
• US 500 mg tablets
• Other design features of the US study were not
  typical in the European studies
• e.g., mandatory follow-up algorithms for missed
• visits or missed phone contacts