1

Efficacy of Acamprosate: Clinical Issues

Celia Jaffe Winchell, M.D.Medical Team Leader

Addiction Drug Products

2

Questions• How can the discrepant results between

the older, European studies and the more recently conducted American study be reconciled?

• Do the data support any conclusions regarding subgroups of patients more likely to benefit from acamprosate?

• Given the conflicting results, is there sufficient evidence of the efficacy of acamprosate in the treatment of alcoholism to warrant approval?

3

Overview• Why CAD is not persuasive in

European trials• Conclusions supported by

European trials• Exploratory analysis of

American trial

4

What is the Problem with CAD In These Studies?

• No systematic capture of drinking data day-by-day

• Retrospective reconstruction of large periods of time

• Mathematical imputation based on extensive assumptions

5Pelc-II• 7 visits over 90-day treatment period

– Intervisit interval NMT 15 days• Outcome measure: Fields calling for

“Avg daily consumption” and “Avg frequency of alcohol consumption”– subjects with “zero” = abstinent

• Conservative imputation of non-abstinence for all days in inter-visit interval

• Obscures differences between one drinking day and many

6

Paille• 9 visits over 1 year of treatment

– Intervisit interval•30 days for on-treatment visits 1-6•60 days for on treatment visits 7-9

• Outcome measure: physician estimate • CAD calculated by subtracting

physician’s estimate of non-abstinent days and summing remaining days

• Relies on nonsystematic reconstruction of as much as 60 days of drinking data

7PRAMA• 6 visits over 48 weeks of treatment

– Inter-visit interval• 4 weeks for OT visits 1, 2, and 3• 12 weeks for OT visits 4, 5, and 6

• Outcome measure “physician’s global assessment” of abstinence

• Complex mathematical reconstruction of number of days drinking/abstinent

• Strains credibility of calculated CAD

8

Calculation of CAD: PRAMAIf the physician’s global assessment indicated success, then all days since the previous visit

were considered abstinent. When failure was indicated, then the number of abstinent days was determined using the patient’s and relative’s report on drinking, where the higher category was used if there was a difference between the two and the patient’s report if the categories reported were the same. When there was no reported category of relapse, then half of the days between visits were considered abstinent. When the relapse was considered to have started as a continuous relapse between visits, all days between visits were considered non-abstinent. The number of brief relapses plus three times the number of longer relapses were subtracted from the number of days since the previous visit if either type of relapse was indicated; if either type of relapse was indicated and no numbers were provided, it was assumed that the patient was abstinent for half of the days.

Several methods of determining the number of abstinent days were used when there was no physician global assessment provided. In cases where there were two consecutive post-baseline visits with the assessment missing but there was a nonmissing assessment later, then both time visit intervals were considered abstinent if either the prior or next visit was indicated as a success by the physician’s global assessment; both visit intervals were considered non-abstinent if both visits were indicated as failures by the physician’s global assessment. When no assessment was made for Visit 1, the patient was assumed to have been abstinent half of the days. For all other cases, a missing global assessment following a successful one was considered to indicate abstinence for half the period, while a missing global assessment following a successful one was considered to indicate abstinence for half the period, while a missing global assessment following a missing or failure was considered to indicate non-abstinence for the period.”

9

What CAN we make out of the European studies?

• Continuous Abstinence Throughout Treatment

• Non-Continuous Abstinence: number of visits at which subject was assessed as abstinent

10Results: Continuous Abstinence

TreatmentSTUDY Duration of

Treatment Placebo Acamprosate1332 mg/ day

Acamprosate1998 mg/ day

Pelc-I I 90 days 15% 41% 41%

Paille 360 days 11% 18% 19%

PRAMA 48 weeks(336 days)

12% N/ A 29%

11Results: Non-Continuous Abstinence Pelc-II

Acamprosate1332 mg

N=63

Acamprosate1998 mg

N=63

PlaceboN=62

#Abstinent

VisitsN % N % N %

0 0 0 0 0 2 31 8 13 7 11 16 262 8 13 2 3 9 153 8 13 7 11 5 84 2 3 4 6 3 55 5 8 9 14 8 136 3 5 5 8 5 87 3 5 3 5 5 88 26 41 26 41 9 15

12Results: Non-Continuous Abstinence Paille

Acamprosate1332 mgN=188

Acamprosate1998 mgN=173

PlaceboN=177

#Abstinent

VisitsN % N % N %

0 50 27 29 17 56 321 24 13 23 13 24 142 15 8 17 10 16 93 11 6 15 9 15 84 14 7 10 6 10 65 12 6 11 6 9 56 10 5 10 6 7 47 8 4 14 8 18 108 11 6 11 6 3 29 33 18 33 19 19 11

A t-test shows a statistically significant difference between acamprosate 1998 mg and placebo.

13Results: Non-Continuous Abstinence PRAMA

AcamprosateN=136

PlaceboN=136# Abstinent

Visits N % N %0 26 19 37 271 13 10 26 192 13 10 16 123 16 12 13 104 10 7 11 85 18 13 16 126 40 29 17 13

A t-test of this data shows that the groups are different at a level of p < 0.0003

14

Evidence of Efficacy from European Studies

• Continuous Abstinence• Non-Continuous Abstinence

– Number of visits where subjects were assessed as abstinent

15Study US 96.1• 500 mg tablet• 6 months of treatment• 8 on-treatment visits, 4 weeks apart• TLFB reconstruction of drinking data at

each visit– patient diaries – collateral informant interviews– BAC, – “Worst case” chosen

• Standardized, manual-guided social tx

16Corrected Cumulative Abstinence Duration (% Days Abstinent) Calculation

• Timeline Follow Back (TLFB)• Missing data on the TLFB (prior to discontinuations or

loss to follow-up) was assigned the average of the previous 7 days of non-missing data as follows: the number of days with missing data was multiplied by the percent of the previous 7 days that were non-abstinent

• Denominator for % Days Abstinent:– Completers: total treatment duration– Premature d/c associated with EtOH per blinded

rating panel: anticipated duration of the treatment phase (the “uncensored” duration)

– Premature d/c not associated with EtOH: actual time the patient participated in the treatment phase (the “censored” duration)

17Results: Intent-to-Treat Population

Acamprosate2000 mg/ day

N=253

Acamprosate3000 mg/ day

N=82

PlaceboN=256

Mean (SE)Median

46% (2.2)39%

50% (4.1)47%

51% (2.2)53%

Percent Days Abstinent

Table prepared by reviewer from datasets US_CAD and US_POP using CCADTX

18

Potential Explanations• European studies required

abstinence at baseline

• European subjects assumed to have a high level of motivation (required for entry in some studies)

• European populations have a low prevalence of polysubstance abuse

19Sponsor-Defined Population “Motivated Efficacy Evaluable”

• All randomized patients who:– took double-blind study medication for at least 7

days,– returned for at least one post-baseline visit,– did not have a positive urine test for a drug of

abuse at any time after randomization,– were at least 75% compliant for the duration of

the treatment phase,– a had a treatment goal of “complete abstinence”

• Includes <30% of randomized population• % days abstinent: 70% acamprosate vs.

63% placebo

20Reviewer-Defined Populations:Based on pre-randomized variables

• Abstinent at baseline• Motivated: identified goal of “total

abstinence” or “total abstinence but I realize a slip is possible”

• Non-polysubstance abusing– Several definitions possible– No drug use past year/no drug use past year

other than marijuana most useful for analysis

Subjects meeting all three criteria comprise less than 20% of randomized population

21Results: % Days Abstinent No Explanation Based on Pre-Randomization

VariablesPopulation Acamprosate

2000 mgPlacebo

Motivated NMean ± SEMedian

17451% ± 2.749%

17951% ± 2.752%

Abstinent > 5days beforerandomization

NMean ± SEMedian

8160% ± 3.867%

6770% ± 4.284%

No history ofillicit drugs(I DUS=0)

NMean ± SEMedian

5453% ± 4.751%

4755% ± 5.159%

No illicit drugspast year

NMean ± SEMedian

8748% ± 3.849%

11553% ± 3.359%

Only marijuanapast year

NMean ± SEMedian

18948% ± 2.646%

21751% ± 2.456%

22Results: No Explanation in Motivated/Abstinent Subsets

Population Acamprosate2000 mg

Placebo

Abstinent at baseline ANDGoal of abstinence orabstinence + slip

NMean ± SEMedian

17451% ± 2.749%

17951% ± 2.852%

Abstinent at baseline ANDGoal of abstinence orabstinence + slip ANDno illicit drugs other thanmarijuana in past year

NMean ± SEMedian

8160% ± 3.867%

6770% ± 4.284%

23

Other Measures • Complete Abstinence• Categorical Analysis of “Good

Response”

24Abstinence From Sustained Heavy Drinking

Total Acamprosate2000 mgN=253

Placebo

N=257ITT No relapse

No data339121

152/253 (60%)20/253 (20%)

141/257 (55%)54/257 (21%)

Abstinent SubsetNo relapse 137 61/81 (75%) 60/68 (88%)

Motivated SubsetNo relapse 310 131/182 (72%) 137/189 (72%)

No drugs (exceptmarijuana) past year No relapse 358 140/191 (73%) 165/221 (75%)Abstinent, motivated, nodrugs (except marijuana)past year

No relapse 95 39/56 (70%) 43/49 (88%)Sponsor’s MotivatedEfficacy Evaluable No relapse 135 58/71 (82%) 66/86 (77%)

Table prepared by reviewer from datasets US_RELAP, US_POP

25

Other Explorations• Drinking History: Very Heavy

Drinkers• Drinking History +

– motivation– baseline abstinence– no past year illicit drug use

26

Summary• European studies indicate effect of

acamprosate on continuous or non-continuous abstinence

• U.S. study data does not demonstrate efficacy of acamprosate in any subset defined by pre-randomization variables meaningful for patient selection

27

Questions• Can the discrepant results between the

older, European studies and the more recently conducted American study be reconciled?

• Do the data support any conclusions regarding subgroups of patients more likely to benefit from acamprosate?

• Given the conflicting results, is there sufficient evidence of the efficacy of acamprosate in the treatment of alcoholism to warrant approval?