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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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• 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

Dosages of Treatment

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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(3-mons)

Pbo Acamp1332 mg/d

L-dose

Acamp1998 mg/d

M-dose

Nominalp-value

N 62 63 63

% dropouts1 48% 30% 32% 0.065

Time on treatmentDiscontinuation

84 d 85 d 85 d 0.146

% no relapse-Dropout as is-as relapse

21%15%

51%41%

44%41%

0.0010.002

Time to 1st relapse 17 d 53 d 53 d <0.0011Dropout rates differ, primarily in ‘lost-to-follow-up’, No death

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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PaillePaille

(360 days)Placebo Acamp

1332 mg/dL-dose

Acamp1998 mg/d

M-dose

Nominalp-value

N 177 188 173

% dropouts1 65% 55% 48% 0.006

median time ontreatment period

8-mon 10.5 11.8 0.051

% abstinence-Dropout as is-use 340d cutoff-as relapse

23%11%7%

27%18%14%

30%19%15%

0.2850.0960.044

Time to 1st relapse 1-mon ~1 mon 2-mon .01-.071Dropout rates differ, primarily in ‘relapse’, ‘refusal’; 2-deaths per arm

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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(48 weeks)

Placebo Acamp1332 mg/d&1998 mg/d

L- & M-dose

Nominalp-value

N 136 136

% dropouts 60% 42% <0.001median time ontreatment period

169 days 337 days 0.005

% abstinence-Dropout as is-as relapse

40%12%

51%29%

0.052<0.001

Time to 1st relapse 3-mon 8.4-mon 0.005Time to 1st relapse 1.5-mon 4.5-mon <0.001

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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• 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

US 96.1 Trial

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US 96.1 Trial

US 96.1(24 weeks)

Placebo Acamp2000 mg/d

M-dose

Acamp3000 mg/d

H-dose

Nominalp-value

N 260 258 84

% dropouts 45% 59% 48% 0.005

Time to treatmentdiscontinuation

168d 136d 164d 0.110

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• 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

US 96.1 Trial

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Originally Planned Efficacy Analyses(ITT popn)

Parameter Statistic PlaceboACAMP2 g/day

ACAMP3 g/day

% Patients whorelapsed to drinking

% 89% 92% 90%

Time to 1st drink (d) Median 4 4 4Time to heavy drink Median 12 14 17CAD (d) N

Mean (SE)Median

25683.3 (3.9)

78

25372.3 (3.7)

56

8281.5 (7.1)

75 CCAD (%) N

Mean (SE)Median

25651.2 (2.2)

53

25345.5 (2.2)

38

8249.9 (4.1)

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• 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

US 96.1 Trial

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• New primary efficacy endpoint

– Cumulative Abstinence Duration (CAD)

(post-hoc definition)

• Endpoint considered: CCAD (=PDA)

• Endpoint actually used: ALCCAD (PDA adjusted for treatment discontinuation)

US 96.1 Trial

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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

Post-hoc ANCOVA Model #1

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- use 6 covariates (excluding treatment exposure) from model #1

Treatment Exposure: defined astreatment compliance*treatment duration/100

-potentially treatment related -due to differential time to discontinuation

-and differential dropout

Post-hoc ANCOVA Model #2

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• Modified CCAD: No Statistically significant findings on Model #1 or Model #2 or unadjusted analysis

• ALCCAD: endpoint actually used (CCAD adjusted for treatment discontinuation)

Versions of Primary Efficacy Outcome

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ALCCAD: Treatment Group Comparisons and Adjusted (Least-Square) Means ITTPopulation

Plbo Aca 2 g/d(M-dose)

Aca 3 g/d(H-dose)

p-valM-dose: P

p-valH-dose:P

N 256 253 82

Unadjustedmean

54.3 56.1 60.7

Unadjustedmedian

59 59 63 0.703 0.205LS Means #1 52.3 58.2 62.7 0.044 0.009LS Means #2 53.4 56.8 63.1 0.296 0.021

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ALCCAD: Treatment Group Comparisons and Adjusted (Least-Square) Means

Population StatisticACAMP2 g/day Placebo P-Val

Intent-to-Treat nLSMean (1)LSMean (2)

25358.256.8

25652.353.4

0.044*0.296

Efficacy Evaluable nLSMean (1)LSMean (2)

17762.360.6

19854.855.8

0.023*0.157

Motivated Intent-to-Treat

nLSMean (1)LSMean (2)

10070.068.3

11558.159.0

0.021*0.100

Motivated EfficacyEvaluable

nLSMean (1)LSMean (2)

7175.573.0

8659.461.3

0.008**0.068

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Why post-hoc ANCOVA model #1?Seven covariates + Trt

Why post-hoc ANCOVA model #2?Excluding ‘treatment exposure’

US 96.1 Trial

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Reviewer’s exploratory analyses -

to examine how the results of the sponsor’s 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’

Post-Hoc Model #1:Why 7-covariates

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US 96.1 Trial (ITT Pops)Covariates

Placebo(n=256)

Aca 2 g/d(n=253)

(M-dose)

Aca 3 g/d(n=82)

(H-dose)

Treatment ExposureMean (T related?)Median;p=.0172

16.521

14.215

15.720

Abstinence Goal(p=0.033 trend) 45% 40% 32%Slip is Possible(p=0.072 trend) 28% 31% 39%Abstinence Goal + Slipis Possible 73% 71% 71%

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Figure 2. Observed Mean Heavy Drinking Days at Each VisitUS 96.1 Trial

0

1

2

3

4

5

6

Weeks on Study

Hea

vy D

rinki

ng D

ays

pbo

medium(2g/d) dose

high (3g/d) dose

Time% n_pbo%n_2000%n_3000

wk24wk20wk16wk12wk8wk4wk2wk10.570.610.670.720.800.890.940.99

0.560.590.630.660.760.880.991.000.420.470.560.660.770.890.941.00

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Figure 3. Observed Mean Any Drinking Days at Each VisitUS 96.1 Trial

0

5

10

15

20

25

Weeks on Study

Any

Dri

nkin

g D

ays

Pbo Aca 2g/d Aca 3 g/d

wk1 wk24wk20wk16wk12wk8wk4wk20.99 0.94 0.89 0.80 0.72 0.67 0.61 0.57

%n_3000%n_2000% n_pbo

Time

0.420.470.560.660.770.890.941.001.00 0.99 0.88 0.76 0.66 0.63 0.59 0.56

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Medium dose (2 g/d) effective?

US trial was sufficiently powered for efficacy evaluation of this dose

=> No evidence of effect, after adjusting for any

one covariate alone

=> Excluding treatment exposure from ANCOVA,

No evidence of the effect

=> 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% US:10%• 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