STATISTICAL REVIEW AND EVALUATION

\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~

NDA#: 21-431

Applicant: Lipha Pharmaceuticals

Name of Drug: Acamprosate Tablets

Indication: Maintenance of abstinence from alcohol in patients with
alcohol dependence who

have been withdrawn from alcohol and want to maintain their abstinence

Documents Reviewed: Electronic submission dated December 21, 2001, SAS
data sets and its related submissions dated January 31, 2002, March 20,
2002

Medical Officer: Celia Winchell, M.D. (HFD-170) Efficacy Reviewer and
Team Leader

Michael Sevka, M.D. (HFD-170) Safety Reviewer

\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~

This review has been discussed with the review team.

# EXECUTIVE SUMMARY {#executive-summary .unnumbered}

**Pelc II** (European Trial)

A total of 188 eligible patients with 21 to 71 years of age were
randomized to receive Acamprosate 1332 mg/day (n=63), Acamprosate 1998
mg/day (n=63) or placebo (n=62) for 3-months treatment of
gastro-resistant Acamprosate tablets. The trial was completed in April
1992. The dropout rates appeared to be marginally different among the
three treatment groups (48% in placebo, 30% in Acamprosate 1332 mg/d,
32% in Acamprosate 1998 mg/d). From either the sponsor's post-hoc
defined primary efficacy endpoints (relapse rate and Cumulative
Abstinence Duration (CAD)) or this reviewer's assessment of maintenance
of abstinence based on no-relapse rate during the entire 3-months
treatment period months and time to first relapse, the effects of low
dose and median dose Acamprosate as compared to placebo were consistent
and the pairwise comparisons (placebo vs. low-dose and placebo vs.
median-dose) yielded statistically significant p-values. The
statistically significantly higher complete abstinence rates in the
Acamprosate groups were consistently observed using the last value
carried forward type analysis (dropout without drinking was defined as
abstinence) and the conservative analysis (dropout without drinking was
defined as non-abstinence).

**Paille** (European Trial)

Five hundred and thirty-eight (538) eligible patients were randomized to
receive Acamprosate 1332 mg/day (n=188), Acamprosate 1998 mg/day
(n=173), or placebo (n=177) for 1-year (360 days) treatment. The trial
was completed in November 1992. Study completion rates differed among
the three treatment groups, nominal p=0.0055. It appeared that only
about ½ of the patients treated with Acamprosate (52% with 1998 mg/day
regimen and 45% with 1332 mg/day regimen) completed the study and a
little over 1/3 of the patients treated with placebo completed the study
(35%). The conservative type analyses are attractive because it might be
reliably used to be sure that a patient was completely abstinent during
the treatment phase. Although these methods yielded a higher complete
abstinence rates with Acamprosate 1332 mg/day treatment (14% or 18%)
compared to placebo (7% or 11%), the median time to first drink was
essentially the same between these two groups (about 30 days) using the
conservative method or the LOCF (last observation carried forward)
method. In contrast, the higher complete abstinence rates with
Acamprosate 1998 mg/day treatment (14% or 19%) were further supported by
the time to first drink analyses using both approaches and yielded twice
longer median time (about 60 days) as compared to placebo or Acamprosate
1332 mg/day treatment. The primary comparison in this study was
Acamprosate 1332 mg/d and placebo. The sponsor's conclusion that
"Acamprosate 1332 mg/day failed to reach significantly better results
than placebo for most main efficacy criteria" was consistent with this
reviewer's conclusion. It is noted that the second objective of a
superior complete abstinence rate with Acamprosate 1332 mg/day was not
shown through the observation phase.

**PRAMA** (European Trial)

A total of 272 patients received study medication were randomized to
receive Acamprosate (n=136) or placebo (n=136) for 48 weeks treatment.
The trial was completed in December 1992. The percentage of patients who
completed the study between placebo (40%) and Acamprosate (58%) was
shown to be different, nominal p=0.0004. The Acamprosate treated
patients appeared to stay on study twice longer (48 weeks vs. 24 weeks)
than the placebo treated patients. Acamprosate was shown to have longer
time to first relapse, higher percentage of continuous abstinence and
higher percentage of cumulative abstinence rate during the treatment
phase as compared to placebo. Further investigation suggested that a
higher percentage of patients completed the study without relapsed to
drinking with Acamprosate (31%) compared to placebo (15%), and that
among those who discontinued the study early, a lower percentage of
Acamprosate treated patients (21%) relapsed compared to placebo treated
patients (35%).

US 96.1 (US Trial)

The NDA report was dated November 19, 2001. A total of 601 patients were
randomized to receive placebo (n=260), Acamprosate 2000 mg/day (n=258)
(median dose), or Acamprosate 3000 mg/day (n=83) (high dose) for
24-weeks (6-months) treatment. The intent-to-treat population or the all
efficacy population was based on 592 patients (256, 253 and 83,
respectively). The main interest was the comparison between Acamprosate
2000 mg/day vs. placebo and Acamprosate 3000 mg/day group was a dosage
exploratory arm.

The placebo arm and Acamprosate 3000 mg/day arm had one month longer
exposure to the treatment than Acamprosate 2000 mg/day arm during the
treatment phase and a total of two months longer exposure including the
follow-up phase. In addition, the dropout rates were significantly
higher with Acamprosate 2000 mg/day (59%) than with placebo (45%),
nominal p=0.0015. It appeared that data indicated an informative
censoring and differential dropout pattern. The median dose Acamprosate
(2000 mg/day) failed to show a superior treatment effect on all the
protocol specified efficacy endpoints.

The sponsor argued the need to restructure the intended statistical
analysis plan because European outcome parameters that were contingent
on a population abstinent at baseline (e.g., time to first drink and
rate of complete abstinence) were not relevant in the largely
non-abstinent US sample. In the US population, 50% of the patients had
not discontinued drinking at randomization (100% in European trials) and
only 10% of patients underwent medicated detoxification (primarily
outpatient) (100% in European trials). Details of the differences
between the three European pivotal trials (Paille, Pelc II and PRAMA)
and the US 96.1 Trial can be found in the Appendix -- US96.1 of this
review.

The post-hoc defined primary efficacy endpoint, viz., the CCAD
(corrected CAD) adjusted for the discontinuation of alcohol and the
post-hoc defined covariates (baseline CGI-severity (clinical global
impression-severity), stage of readiness to change, psychological
antecedent, addiction index, and goal of complete abstinence) or outcome
related treatment exposure, was carefully assessed. It appeared that
partial inclusion of the post-hoc covariates may or may not reach a
statistically significant effect with Acamprosate 2000 mg/day compared
to placebo. This study did not show an effect of Acamprosate 2000 mg/day
treatment without any adjustment on the covariates. Adjustment of
treatment goal alone (a subjective covariate) or treatment exposure
alone (a potential treatment related variable) still failed to
demonstrate a significant Acamprosate 2000 mg/day effect, the primary
comparison arm of interest.

From the repeated measure analysis, the GEE (generalized estimating
equation) analysis and the cross sectional analysis of the total heavy
drinking days and the total any drinking days, no statistically
significant Acamprosate 2000 mg/day effect was observed. Acamprosate
2000 mg/day appeared to have numerically similar or more heavy drinking
days than the placebo. The details were provided under the Section on
US96.1 Trial.

Although Acamprosate 3000 mg/day treatment was only an exploratory arm
and had only 1/3 of the patient size, it has comparable dropout rate and
treatment exposure compared to the placebo. It appeared that this high
dose arm might have a favorable (often statistically significant) higher
percent of cumulative abstinence duration, lower number of heavy
drinking days over time.

#   {#section .unnumbered}

EXECUTIVE SUMMARY [1](#executive-summary)

1 BACKGROUND [7](#background)

2 PIVOTAL EFFICACY CLINICAL TRIALS
[7](#pivotal-efficacy-clinical-trials)

Pelc II [8](#pelc-ii)

   •   SYNOPSIS [8](#synopsis)

   •   ΟVERVIEW OF THE STUDY RESULTS AND REVIEWER'S EVALUATION AND
COMMENTS
[8](#overview-of-the-study-results-and-reviewers-evaluation-and-comments)

\- PATIENT ACCOUNTABILITY [8](#patient-accountability)

Figure 1. Distribution of available patients over time -- Pelc II Trial
[9](#figure-1.-distribution-of-available-patients-over-time-pelc-ii-trial)

Table 1. Patients accountability -- Pelc II Study (3 months trial
period) ^§^
[9](#table-1.-patients-accountability-pelc-ii-study-3-months-trial-period)

\- TIME TO DISCONTINUATION [9](#time-to-discontinuation)

Table 2. Distribution of time to discontinuation from the study -- Pelc
II^§^
[9](#table-2.-distribution-of-time-to-discontinuation-from-the-study-pelc-ii)

\- EFFICACY IN HELPING TO MAINTAIN ABSTINENCE
[10](#efficacy-in-helping-to-maintain-abstinence)

CAD (Cumulative Abstinence Duration)
[10](#cad-cumulative-abstinence-duration)

Table 3. Distribution of cumulative abstinence duration (CAD) -- Pelc II
Trial
[10](#table-3.-distribution-of-cumulative-abstinence-duration-cad-pelc-ii-trial)

RELAPSE RATE (assessed by the score for alcohol consumed determined at
each visit)
[10](#relapse-rate-assessed-by-the-score-for-alcohol-consumed-determined-at-each-visit)

Figure 2. % of patients abstinent at each visit -- Pelc II Trial
[11](#figure-2.-of-patients-abstinent-at-each-visit-pelc-ii-trial)

ABSTINENCE RATE [11](#abstinence-rate)

Table 4. No-relapse rates -- Pelc II Trial
[11](#table-4.-no-relapse-rates-pelc-ii-trial)

TIME TO FIRST RELAPSE [12](#time-to-first-relapse)

Figure 8.7.2.7.2:1 Time to First relapse -- Pelc II Trial
[12](#figure-8.7.2.7.21-time-to-first-relapse-pelc-ii-trial)

• REVIEWER'S SUMMARY [12](#reviewers-summary)

Paille (Acamprosate gastro-resistant tablets)
[13](#paille-acamprosate-gastro-resistant-tablets)

   •   PROTOCOL SYNOPSIS [13](#protocol-synopsis)

\- REVIEWER'S COMMENTS [13](#reviewers-comments)

• OVERVIEW OF THE SPONSOR RESULTS AND REVIEWER'S EVALUATION & COMMENTS
[14](#overview-of-the-sponsor-results-and-reviewers-evaluation-comments)

\- PATIENT ACCOUNTABILITY [14](#patient-accountability-1)

Table 1. Patient Accountability -- Paille^§^
[14](#table-1.-patient-accountability-paille)

Table 2. Patient Accountability categorized into four categories^§^
[14](#table-2.-patient-accountability-categorized-into-four-categories)

\- TREATMENT EXPOSURE [15](#treatment-exposure)

Table 3. Distribution of time to discontinuation from the study --
Paille Trial
[15](#table-3.-distribution-of-time-to-discontinuation-from-the-study-paille-trial)

Figure 1. % of patients available over treatment period -- Paille Trial
[15](#figure-1.-of-patients-available-over-treatment-period-paille-trial)

\- EFFICACY ON MAINTENANCE OF ABSTINENCE
[15](#efficacy-on-maintenance-of-abstinence)

PERCENTAGE OF COMPLETE ABSTINENCE
[16](#percentage-of-complete-abstinence)

Table 4. Complete abstinence rates - Paille^§^
[16](#table-4.-complete-abstinence-rates---paille)

TIME TO FIRST DRINK [16](#time-to-first-drink)

Figure 8.7.2.7.2:3 Kaplan-Meier Estimate of Time to First Drink During
Treatment Phase --
[17](#intext-figure-8.7.2.7.23-kaplan-meier-estimate-of-time-to-first-drink-during-treatment-phase)

Pivotal Efficacy Study Paille [17](#pivotal-efficacy-study-paille)

Table 5. Estimated median time and its 95%CI (days) - distribution of
time to 1^st^ relapse

(Paille) 17

CUMULATIVE ABSTINENCE DURATION (CAD)
[17](#cumulative-abstinence-duration-cad)

Table 6. Distribution of cumulative abstinence duration (CAD) -
Paille^§^
[18](#table-6.-distribution-of-cumulative-abstinence-duration-cad---paille)

PERCENTAGE OF SUCCESS [18](#percentage-of-success)

INCIDENCE OF COMPLETE ABSTINENCE THROUGH OBSERVATION PHASE (1.5

years)
[18](#incidence-of-complete-abstinence-through-observation-phase-1.5-years)

Table 7. Complete abstinence rates over the observation phase - Paille
[18](#table-7.-complete-abstinence-rates-over-the-observation-phase---paille)

• SPONSOR'S CONCLUSION [18](#sponsors-conclusion)

• REVIEWER'S SUMMARY [19](#reviewers-summary-1)

PRAMA [20](#prama)

   •   PROTOCOL SYNOPSIS [20](#protocol-synopsis-1)

• OVERVIEW OF THE STUDY RESULTS AND REVIEWER'S EVALUATION AND COMMENTS
[21](#overview-of-the-study-results-and-reviewers-evaluation-and-comments-1)

\- PATIENT ACCOUNTABILITY [21](#patient-accountability-2)

Table 1. Patient Accountability - PRAMA^§^
[21](#table-1.-patient-accountability---prama)

Figure 1 % of patients completed the study visit -- PRAMA Trial
[22](#figure-1-of-patients-completed-the-study-visit-prama-trial)

\- TIME TO DISCONTINUATION [22](#time-to-discontinuation-1)

Table 2. Time to discontinuation -- PRAMA Trial
[22](#table-2.-time-to-discontinuation-prama-trial)

\- EFFICACY IN HELPING TO MAINTAIN ABSTINENCE (treatment period)
[22](#efficacy-in-helping-to-maintain-abstinence-treatment-period)

TIME TO FIRST RELAPSE [22](#time-to-first-relapse-1)

Table 3. The primary efficacy endpoint: time to first relapse (PRAMA
Trial)
[23](#table-3.-the-primary-efficacy-endpoint-time-to-first-relapse-prama-trial)

COMPLETE ABSTINENCE RATE (or CONTINUOUS ABSTINENCE RATE)
[23](#complete-abstinence-rate-or-continuous-abstinence-rate)

Table 4. Distribution of no relapse during the treatment phase -- PRAMA
Trial^§^
[23](#table-4.-distribution-of-no-relapse-during-the-treatment-phase-prama-trial)

Table 5. Summary of patients based on their status completing the trial
and their status

'abstinence' during the entire 48 weeks treatment period
[24](#table-5.-summary-of-patients-based-on-their-status-completing-the-trial-and-their-status-abstinence-during-the-entire-48-weeks-treatment-period)

CUMULATIVE DURATION OF ABSTINENCE
[24](#cumulative-duration-of-abstinence)

Table 6. Cumulative abstinence duration in days
[24](#table-6.-cumulative-abstinence-duration-in-days)

• REVIEWER'S SUMMARY [25](#reviewers-summary-2)

US96.1 [25](#us96.1)

• STUDY SYNPOSIS [25](#study-synposis)

• OVERVIEW OF THE STUDY RESULTS AND REVIEWER'S EVALUATION AND COMMENTS
[26](#overview-of-the-study-results-and-reviewers-evaluation-and-comments-2)

\- PATIENT ACCOUNTABILITY [27](#patient-accountability-3)

Table 1. Patient Accountability of early discontinued patients during
treatment phase -- US 96.1

Trial
[27](#table-1.-patient-accountability-of-early-discontinued-patients-during-treatment-phase-us-96.1-trial)

Figure 1. % of patients available over time -- US 96.1 Trial
[27](#figure-1.-of-patients-available-over-time-us-96.1-trial)

\- TIME TO DISCONTINUATION [28](#time-to-discontinuation-2)

Table 2. Time to discontinuation in days -- US96.1 Trial^§^
[28](#table-2.-time-to-discontinuation-in-days-us96.1-trial)

\- PRIMARY EFFICACY ENDPOINTS [28](#primary-efficacy-endpoints)

Table 8.7.4.1:1 Summary of Originally Planned Efficacy Analyses -- ITT
Population --

US Short -Term Supportive Efficacy Study
[29](#intext-table-8.7.4.11-summary-of-originally-planned-efficacy-analyses-itt-population-us-short-term-supportive-efficacy-study)

\- CHANGE OF PRIMARY EFFICACY ENDPOINT
[29](#change-of-primary-efficacy-endpoint)

\- NEW PRIMARY EFFICACY ENDPOINT [29](#new-primary-efficacy-endpoint)

CCAD (Corrected Cumulative Abstinence Duration)
[30](#ccad-corrected-cumulative-abstinence-duration)

Table 8.7.4.7:2 Corrected Cumulative Abstinence Duration (CCAD) (%):
Treatment Group

Comparisons and Adjusted Means -- US Short-Term Supportive Efficacy
Study 

-- All Efficacy Popns
[30](#in-text-table-8.7.4.72-corrected-cumulative-abstinence-duration-ccad-treatment-group-comparisons-and-adjusted-means-us-short-term-supportive-efficacy-study-all-efficacy-popns)

   •   REVIEWER'S EVALUATION AND COMMENTS
[30](#reviewers-evaluation-and-comments)

Table 3. Corrected Cumulative Abstinence Duration (CCAD) (%): Treatment
Group

Comparisons and Adjusted Means -- US Short-Term Supportive Efficacy
Study 

-- All Efficacy Populations (ITT)
[31](#table-3.-corrected-cumulative-abstinence-duration-ccad-treatment-group-comparisons-and-adjusted-means-us-short-term-supportive-efficacy-study-all-efficacy-populations-itt)

Figure 2. Observed mean and median on heavy drinking days --US 96.1
Trial
[32](#figure-2.-observed-mean-on-heavy-drinking-days-at-each-study-visit-us-96.1-trial)

Figure 3. Observed mean and median on any drinking days -- US 96.1 Trial
[33](#figure-3.-observed-mean-on-any-drinking-days-at-each-study-visit-us-96.1-trial)

• SAFETY [33](#section-5)

• REVIEWER'S SUMMARY [33](#reviewers-summary-3)

3 CONCLUSION [34](#conclusion)

4 APPENDIX [36](#appendix)

Table 8.7.4.4:1 Demographic Characteristics at Baseline -- US Short-Term
Supportive Efficacy Study ITT Pop.
[36](#table-8.7.4.41-demographic-characteristics-at-baseline-us-short-term-supportive-efficacy-study-itt-pop.)

DIFFERENCE BETWEEN THE US AND EUROPEAN (PAILLE, PRAMA, PELC II) STUDIES

37

#   {#section-1 .unnumbered}

# 1 BACKGROUND {#background .unnumbered}

Acamprosate (calcium acetylaminopropanesulfonate) is a synthetic
centrally acting drug with a molecular structure related to that of
taurine and the neuromediator gamma-amino butyric acid (GABA). Animal
and human studies of Acamprosate indicate a specific action on symptoms
of alcohol dependence, which may result from antagonism of excitatory
amino acids as well as some GABA-agonist action of Acamprosate.
According to the submitted document, Acamprosate has been approved over
the past decade in more than 30 countries worldwide, including most of
Europe and Scandinavia, much of Latin America, Australia, South Africa
and Hong Kong, as a therapy to maintain abstinence following alcohol
withdrawal in the chronic alcohol-dependent patient.

In this priority NDA, the sponsor submitted 13 placebo-controlled
clinical trials related to claims of effectiveness. Among these, the
sponsor categorized them into three controlled pivotal efficacy studies
(Pelc II, PRAMA and Paille), six European controlled short-term
supportive studies (Poldrugo, Tempesta, UKMAS, BENELUX, ADISA, and
Ladewig), one US controlled short-term supportive study (US 96.1), and
three European controlled long-term supportive studies (Lesch, Barrias,
Besson).

After the review team meeting of FDA, it was decided that the three
European studies (Pelc II, PRAMA and Paille) and the US96.1 study were
considered the pivotal efficacy studies in this review. This review
pertains to the efficacy evaluation of these four trials. The medical
reviewer is Dr. Celia Winchell for the efficacy evaluation and is Dr.
Sevka for the safety evaluation.

It is noted that in all the 13 studies listed above, except for US96.1,
Acamprosate was administered as 333 mg tablets, generally at a total
daily dose of 1998 mg/day, given in 3 equal divided doses. In US 96.1,
the identically formulated 500 mg tablet strength of Acamprosate was
employed, at a total daily dose of 2000 mg/day, given in 2 equal divided
doses (a smaller arm explored a daily dose of 3000 mg, given in 2 equal
doses). According to the sponsor, "in general, drinking behavior relied
on self-report of drinking between study visits, often corroborated by a
second party and verified by breath, blood, or urine alcohol
measurements. Drinking diaries were not used in the European studies
(with the exception of UKMAS, which recorded number of abstinent days).
Accordingly, in the individual study report analyses, if there was any
reported drinking within an inter-visit interval, the entire interval
was considered non-abstinent. In addition to a UKMAS, the other
exception to this general rule was for US96.1, where patients maintained
a daily drinking diary, using standard drinks, so that more precise
feedback on number of drinking days and quantity of drinking was
obtained."

# 2 PIVOTAL EFFICACY CLINICAL TRIALS {#pivotal-efficacy-clinical-trials .unnumbered}

The four pivotal trials were summarized in the order of its completion.

Pelc II -- a 3-month study. The trial was initiated in June 1990 and
completed in April 1992.

Paille -- a 360-days study. The trial was initiated in April 1989 and
completed in November 1992.

PRAMA -- a 48-week study. The trial was initiated in Oct. 1990 and
completed in December 1992.

US 96.1 -- a 24-week study. The trial was initiated in May 1997 and
completed in January 1999.

Keywords: NDA review, Clinical Trials, abstinence rate, cumulative
abstinence duration

## Pelc II {#pelc-ii .unnumbered}

Study of the activity and tolerance of calcium acetyl Homotaurinate
(AOTA-Ca) in helping to maintain abstinence in the weaned alcoholic
double-blind versus placebo

#### SYNOPSIS

This was a multicenter (11 hospitals or clinics with 1 hospital from
France and the others from Belgium), double blind, randomized
placebo-controlled study. The study was initiated in June 1990 and
completed in April 1992. Eligible patients weighing over 60 kgs at the
start of the trial were randomized to receive Acamprosate (AOTA-Ca) 1333
mg/day (low dose), Acamprosate 1999 mg/day (median dose), or placebo.
The study objective was to evaluate the effectiveness and tolerance of
Acamprosate at 1333 mg/day and 1999 mg/day in helping to **maintain
abstinence** in the weaned alcoholic (after the acute weaning phase)
during a 3-month treatment period. There were eight visits for this
three months study. Self-assessment of alcohol dependency was carried
out with the aid of a booklet entitled "monitoring booklet" given to
each patient. The booklet allowed for daily recording and quantification
by the patient of nervousness, sleeping disorders, shaking of the hands,
and desire for alcohol. The booklet was used to monitor the patient.

Note that the dosages of the Acamprosate treatment stated in the
protocol were 1333 mg/day and 1999 mg/day whereas these dosages were
1332 mg/day (low dose) and 1998/2000 mg/day (median dose) in the study
reports. In this review, the median dose Acamprosate group is
abbreviated as 1998 mg/day group.

Statistical analysis plan stated 'quantitative parameters (variance
analysis) and qualitative parameters (at minimum test of the χ^2^), the
progress within the group and comparison between the groups of the
quantitative parameters will be analyzed according to the example of
repeated measurements.' The protocol called for 'the main criterion of
judgement will be the **consumption of alcohol**' and 'the other
criteria will be: clinical signs linked to alcoholism = physical signs,
MAST (Michigan Alcoholism Screening Test), alcohol dependency;
biological signs: GT gamma, alcoholuria, transaminases; tolerance to the
treatment.'

#### OVERVIEW OF THE STUDY RESULTS AND REVIEWER'S EVALUATION AND COMMENTS

A total of 188 eligible patients with 21 to 71 years of age were
randomized to receive Acamprosate 1332 mg/day (n=63), Acamprosate 1998
mg/day (n=63) or placebo (n=62). Eighty-five percent of them were males.
Patients' demographics at baseline are summarized in the sponsor Table 5
(p.24 of vol.1.076). The three treatment groups appeared to be
comparable at baseline.

##### - PATIENT ACCOUNTABILITY {#patient-accountability .unnumbered}

Distribution of available patients over time is shown in Figure 1 and
patients accountability is summarized in Table 1, confirmed by this
reviewer. Dropout rates among the three treatment groups were 48% with
placebo, 30% with low dose and 32% with median dose Acamprosate, nominal
p=0.065.

The final study report amendments reclassified the discontinuation
reasons in 5 placebo, 5 low dose, 2 median dose treated patients. Ten of
these 12 patients were in the electronic effpt.sd2 file (patid=24 and
patid=113 were not found). The completion status of these 10 patients
was not changed, i.e., incompleters.

####### ![](media/image1.wmf)Figure 1. Distribution of available patients over time -- Pelc II Trial {#figure-1.-distribution-of-available-patients-over-time-pelc-ii-trial .unnumbered}

####### Table 1. Patients accountability -- Pelc II Study (3 months trial period) ^§^ {#table-1.-patients-accountability-pelc-ii-study-3-months-trial-period .unnumbered}

+--------------------------+------------+--------------+--------------+
| Patients accountability  | Treatment  |              |              |
+--------------------------+------------+--------------+--------------+
|                          | Placebo    | Acamprosate  | Acamprosate  |
|                          |            |              |              |
|                          | (n=62)     | 1332 mg/day  | 1998 mg/day  |
|                          |            | (n=63)       | (n=63)       |
+--------------------------+------------+--------------+--------------+
| Patients completing the  | 32 (51.6%) | 44 (69.8%)   | 43 (68.3%)   |
| study                    |            |              |              |
|                          | 30 (48.4%) | 19 (30.2%)   | 20 (31.7%)   |
| Patients early           |            |              |              |
| discontinued             |            |              |              |
+--------------------------+------------+--------------+--------------+
| Severe adverse event     | 1 (1.6%)   | 2 (3.2%)     | 1 (1.6%)     |
|                          |            |              |              |
| Concurrent illness       | 3 (4.8%)   | 2 (3.2%)     | 1 (1.6%)     |
|                          |            |              |              |
| Death                    | 0          | 0            | 0            |
|                          |            |              |              |
| Relapse                  | 10 (16.1%) | 6 (9.5%)     | 9 (14.3%)    |
|                          |            |              |              |
| Lost to follow-up        | 15 (24.2%) | 6 (9.5%)     | 8 (12.7%)    |
|                          |            |              |              |
| Protocol violation       | 0          | 1 (1.6%)     | 0            |
|                          |            |              |              |
| Patient refused to       | 1 (1.6%)   | 1 (1.6%)     | 1 (1.6%)     |
| continue                 |            |              |              |
|                          | 0          | 1 (1.6%)     | 0            |
| Non-compliance           |            |              |              |
|                          | 0          | 0            | 0            |
| Prohibited concomitant   |            |              |              |
| medication               |            |              |              |
+--------------------------+------------+--------------+--------------+

^§^ Extracted from the sponsor Table 2 of vol.1.076.

##### - TIME TO DISCONTINUATION {#time-to-discontinuation .unnumbered}

The dropout rates appeared to be different among the three groups. This
reviewer further evaluated the patients' treatment exposure times, i.e.,
the time to discontinuation. As shown in Table 2, the estimated median
time to discontinuation were quite comparable among the three treatment
groups (about 85 days for all three groups), p=0.1456, non-parametric
Kruskal-Wallis test.

####### Table 2. Distribution of time to discontinuation from the study -- Pelc II^§^ {#table-2.-distribution-of-time-to-discontinuation-from-the-study-pelc-ii .unnumbered}

  ---------------- ------------------ ------------------ -----------------
                   Placebo            Acamp1332 mg/day   Acamp1998 mg/day

  Median (range)   84 days (4, 110)   85 days (1, 110)   85 days (6, 116)
  ---------------- ------------------ ------------------ -----------------

^§^ based on study duration in the electronic database

##### - EFFICACY IN HELPING TO MAINTAIN ABSTINENCE {#efficacy-in-helping-to-maintain-abstinence .unnumbered}

The sponsor considered the cumulative abstinence duration (CAD) and the
relapse rate as the primary efficacy variables. The sponsor also
reported relapsed rate (based on the score for alcohol consumed
determined at each visit). The reviewer's evaluation and comments in
reference to the sponsor's summary of the study and statistical reports
follow.

###### **CAD (Cumulative Abstinence Duration)** {#cad-cumulative-abstinence-duration .unnumbered}

The CAD was defined as the total number of days of abstinence and
calculated as the sum of only those periods of complete abstinence. The
mean cumulative abstinence duration in days were 34.4 (+/- 33.8) with
placebo, 51.9 (+/- 37.2) with Acamprosate 1332 mg/d, and 56.6 (+/- 33.7)
with Acamprosate 1998 mg/d groups, respectively, p=0.001, parametric
1-way ANOVA. This reviewer confirmed these results.

The distribution of CAD in each group was highly skewed. This reviewer
performed a non-parametric analysis. As shown in Table 3, the median CAD
was 60 days with Acamprosate low and median doses and was less than half
(26.5 days) in days with placebo, overall p=0.0006. Both the low and the
median dose Acamprosate treated patients had longer CAD than placebo.

To assess CAD as a fraction of the duration of treatment, the sponsor
also calculated the corrected cumulative abstinence duration (CCAD). The
CCAD analysis reported by the sponsor was consistent with the CAD
analysis. This was probably because the treatment exposure times were
very similar among the three treatment groups.

####### Table 3. Distribution of cumulative abstinence duration (CAD) -- Pelc II Trial {#table-3.-distribution-of-cumulative-abstinence-duration-cad-pelc-ii-trial .unnumbered}

  ---------------- ------------------ ------------------ -----------------
                   Placebo            Acamp1332          Acamp1998

  Median (range)   26.5 days (0, 90)  60.0 days (0, 90)  60.0 days (0, 90)
  ---------------- ------------------ ------------------ -----------------

^§^ based on the variable, CAD, of the electronic submission

###### **RELAPSE RATE (assessed by the score for alcohol consumed determined at each visit)** {#relapse-rate-assessed-by-the-score-for-alcohol-consumed-determined-at-each-visit .unnumbered}

The protocol called for 'the main criterion of judgement will be the
consumption of alcohol' and the summary of study from the NDA submission
reported "As a primary parameter for determining efficacy, the relapse
rate based on the score for alcohol consumed was determined at each
visit. The alcohol consumption was rated as 0 = no alcohol; 1 = \<5
drinks per day; 2 = 5-10 drinks per day; 3= \>10 drinking per day. A
drink was defined as 250 ml of 6^o^ beer, 120 ml of wine, 80 ml of
aperitif (18^o^) or 30 ml of 40^o^ spirit. **Only patients who consumed
no alcohol were rated as abstinent and all others were considered as
relapses**."

This reviewer summarized the sponsor report Table 7 (p.27 of vol.1.076)
using the above criteria and classified patients as non-abstinent if the
status was missing or non-abstinent, see Figure 2. The separation of the
abstinence rates between the Acamprosate groups (both low and median
doses) and the placebo group appeared to become apparent starting day 45
of the treatment and untill the end of the trial. At day 90, the
abstinence rates were 26% with placebo, 44% with low dose Acamprosate
and 51% with median dose Acamprosate, respectively. The three group
comparisons yielded an overall p-value=0.013. The pairwise comparisons
yielded **p-values of 0.029 (placebo vs. low dose),** 0.004 (placebo vs.
median dose).

It is noted that the no-relapse rates, calculated at each visit, do not
reflect the no-relapse rate over the entire treatment period.

####### ![](media/image2.wmf)Figure 2. % of patients abstinent at each visit -- Pelc II Trial  {#figure-2.-of-patients-abstinent-at-each-visit-pelc-ii-trial .unnumbered}

###### **ABSTINENCE RATE** {#abstinence-rate .unnumbered}

For percentage of complete abstinence, the sponsor classified patients
as abstinent if patients completed the study without relapse or patients
discontinued the study early but were known clearly to have no event at
day-90 (Method I). Both Acamprosate low dose and median dose treated
patients appeared to have, on average, higher percentage of complete
abstinence rate (43% with low dose and 41% with median dose) as compared
to placebo 14.5%, p=0.0008. The pairwise comparisons yielded a nominal
p-value\<0.001 for both placebo vs. low-dose and placebo vs. median-dose
comparisons.

Method II classified patients as abstinent only if patients who
completed the study without relapse. That is, all dropouts are
considered as relapsed to drinking, p=0.0011. The pairwise comparisons
yielded nominal p-value \< 0.001 for both low-dose vs. placebo and
median-dose vs. placebo comparisons. This reviewer confirmed these
analyses and the results are summarized in Table 4.

####### Table 4. No-relapse rates -- Pelc II Trial {#table-4.-no-relapse-rates-pelc-ii-trial .unnumbered}

  ------------ ----------------- ---------------- --------------- -----------
  Method       Placebo (n=62)    Acamp1332 (n=63) Acamp1998       χ2 test
                                                  (n=63)          

  I (Sponsor)  9 (14.5%)         27 (42.9%)       26 (41.3%)      0.0008§

  II (Sponsor) 9 (14.5%)         26 (41.3%)       26 (41.3%)      0.0011^+^

  III          13 (21.0%)        32 (50.8%)       28 (44.4%)      0.0015^¦^
  (Reviewer)                                                      
  ------------ ----------------- ---------------- --------------- -----------

§ from electronic database 'RELFLAGC' -- relapsed to drinking flag for
ISE censored analysis

^+^ from electronic database "RELFLAGU" -- relapsed to drinking flag for
ISE uncensored analysis, i.e., include dropouts as 'relapse', see also
In-Text Table 8.7.2.7.3:1, and Table 8, p.28 of vol.1.076

^¦^ this reviewer's analysis based on the patients' all visits data in
the electronic database

The sponsor did not report the usual analysis based on the last
observation carried forward complete abstinence status. That is, if a
patient dropped out the trial early without any drinking, he/she is
defined as 'abstained' while on trial. This reviewer analyzed the
patients' drinking status over all the visits during the entire
treatment period, i.e., a patient would be classified as no-relapse if
all his/her visits had zero drinking frequency up to the time he/she
discontinued the study or completed the study. This analysis is labeled
as 'Method III'. The complete abstinence rates based on the Method III
were 21% with placebo, 51% with Acamprosate 1332 mg/d, and 44% with
Acamprosate 1998 mg/d groups, respectively. The p-value for the
three-group comparison was 0.0015. It appeared that on average patients
treated with Acamprosate low and median doses had higher percentage of
complete abstinence than placebo during the three months treatment
period.

###### **TIME TO FIRST RELAPSE** {#time-to-first-relapse .unnumbered}

In‑Text Figure 8.7.2.7.2:1 Kaplan-Meier Estimate of Time to First Drink
During Treatment Phase -- Pivotal Efficacy Study Pelc II

The sponsor reported the analysis results of time to first relapse
endpoint based on Lee-Desu Test. This reviewer used the usual log-rank
test. The resulting p-values were very similar. The median time to first
drink calculated from the uncensored approach was 52.5 days for the
Acamprosate 1332 mg/day group, 52.5 days for the Acamprosate
1998/2000 mg/day group, and 17.0 days for the placebo group (see also
In‑Text Figure 8.7.2.7.2:1). It appeared that the Acamprosate
1998/2000 mg/day and Acamprosate 1332 mg/day groups had statistically
significantly longer time to first relapse compared to the placebo group
(p\<0.001). The censored analysis approach (Method I) only affected one
patient in the Acamprosate 1998 mg/day group, the results were very
similar to the uncensored results (Method II).

####### Figure 8.7.2.7.2:1 Time to First relapse -- Pelc II Trial {#figure-8.7.2.7.21-time-to-first-relapse-pelc-ii-trial .unnumbered}

![](media/image3.wmf){width="6.207638888888889in"
height="2.9972222222222222in"}

#### • REVIEWER'S SUMMARY {#reviewers-summary .unnumbered}

The dropout rates appeared to be marginally different among the three
treatment groups. The median time to discontinuation was very similar
(around 85 days). It is worth noting that the sponsor's report on
no-relapse rate based on patients' completing the study without relapse
to drinking was conservative. The no-relapse rate based on the score for
alcohol consumption provided the relapse rate at each visit. But, it
does not reflect the complete abstinence rate over the entire three
months treatment period.

From either the sponsor's post-hoc defined primary efficacy endpoints
(CAD and relapse rate) or this reviewer's assessment of maintenance of
abstinence based on no-relapse rate during the entire 3-months treatment
period months and time to first relapse, the effects of low dose and
median dose Acamprosate as compared to placebo were consistent and the
pairwise comparisons (placebo vs. low-dose and placebo vs. median-dose)
yielded statistically significant p-values. The statistically
significantly higher complete abstinence rates in the Acamprosate groups
were consistently observed using the LOCF type analysis (dropout without
drinking was defined as abstinence) and the conservative analysis
(dropout without drinking was defined as non-abstinence) imputation.

## Paille (Acamprosate gastro-resistant tablets)  {#paille-acamprosate-gastro-resistant-tablets .unnumbered}

A multicentre controlled and double-blind comparative study of the
efficacy of AOTA-Ca Studied at two dosages and placebo over a 1-year
period of treatment. Followed by a 6-months post-treatment period of
placebo on alcoholic patients who were followed as outpatients after
withdrawal

#### PROTOCOL SYNOPSIS

This was a multicenter (31 centers in France participated under the
supervision of Professor F. Paille), double-blind, randomized, placebo
controlled three arms study. The study was initiated on April 6, 1989
and completed on Nov. 19, 1992 (\~3.5 years). Eligible patients with
alcohol dependence of the chronic or episodic type as defined by the DSM
III® classification of the American Psychiatric Association were
randomized to receive placebo, Acamprosate 1332 mg/day (low dose) or
Acamprosate 1998 mg/day (median dose), respectively for one year. The
time schedule of the study during the one-year treatment phase followed
by an additional 6 months post-treatment single blinded placebo period
was as follows. The bolded visits were the main visits for the efficacy
evaluation and the other visits included a rapid simplified check-up.

<table>
<colgroup>
<col style="width: 13%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 10%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Visit0</td>
<td>1</td>
<td>2</td>
<td><strong>3</strong></td>
<td>4</td>
<td>5</td>
<td><strong>6</strong></td>
<td>7</td>
<td>8</td>
<td><strong>9</strong></td>
<td>10</td>
<td>11</td>
<td><strong>12</strong></td>
</tr>
<tr class="even">
<td rowspan="2"><p>Assessment of</p>
<p>Withdrawal</p>
<p>1wk - 1month</p></td>
<td>30days</td>
<td>60</td>
<td><strong>90</strong></td>
<td>120</td>
<td>150</td>
<td><strong>180</strong></td>
<td>240</td>
<td>300</td>
<td><strong>360</strong></td>
<td>420</td>
<td>480</td>
<td><strong>540</strong></td>
</tr>
<tr class="odd">
<td colspan="9">Treatment Period (1 year)</td>
<td colspan="3">Follow-up Period (0.5yr)</td>
</tr>
</tbody>
</table>

The main objectives in order of importance were as follows: (1) "to
establish the therapeutic value of the administration of Aota Ca at a
dosage of 1.3 g/day during 1 year in the **maintenance of abstinence**
and to compare this with placebo", (2) "to evaluate the evolution of the
therapeutic result during a 6-month period under placebo after
discontinuation of randomized treatment and before ending the blind
phase of the trial", (3) "to compare dosages by integrating the 2g/day
dosage into the analysis of the French centres; furthermore, the groups
treated with placebo and 2g/day Aota Ca will be included in the analysis
of the European results."

The primary efficacy endpoints stated in the protocol were

A.  "Clinical evaluation: after considering all the elements at his
    disposition, the physician will evaluate **(a) \# of non-abstinent
    days during the month preceding the visit, (b) the average quantity
    of pure alcohol absorbed during these periods of non-abstinence
    during the preceding month."**

B.  "Biological evaluation of the efficacy is based on parameters, which
    ensure the effect of alcohol intoxication on the patient (gamma-GT,
    MCV, and transaminases)."

In this study, the sponsor proposed to study 160 patients per group with
a dropout rate of not exceeding 15%.

##### - REVIEWER'S COMMENTS {#reviewers-comments .unnumbered}

No statistical analysis plan was included in the original protocol. The
sample size proposed was not based on the statistical principle other
than setting what was thought to be a reasonable dropout rate at the
time of planning. There were only four-planned visits for efficacy
assessment for 1-year treatment phase and half year follow up single
blinded placebo phase. They were 3-month, 6-month, 1-year and 1.5 years,
as shown in table above. To evaluate the maintenance of abstinence,
incidence rate of abstinence or time to first relapse may be reasonable
efficacy outcomes for evaluation provided that the drinking data on
abstinence over time was reliable. According to the sponsor's response,
the assessment of the first drinking was based on "the number of days
between actual visits and response to the CRF question which asks the
patient for the estimated number of days of non-abstinence in the last
month or skips a visit, the entire visit interval since the previous
visit is considered non-abstinent and the number of days of continuous
abstinence since baseline is the number of days in study at the previous
visit (equal zero days if the previous visit was the baseline visit)."

#### • OVERVIEW OF THE SPONSOR RESULTS AND REVIEWER'S EVALUATION & COMMENTS {#overview-of-the-sponsor-results-and-reviewers-evaluation-comments .unnumbered}

##### - PATIENT ACCOUNTABILITY {#patient-accountability-1 .unnumbered}

Five hundred and thirty-eight (538) eligible patients were randomized to
receive Acamprosate 1332 mg/day (n=188), Acamprosate 1998 mg/day
(n=173), or placebo (n=177). The mean age at entry was 43 years old and
80% of the patients were males. Patients accountability during the
treatment phase was summarized in Table 1 (submitted when seeking for
approval in Europe) extracted from Table 2 of the Sponsor study report.
A total of six deaths occurred, two patients from each treatment group.
Details of the reason of deaths can be found in the evaluation and
comments of medical review written by Dr. Cellia Winchell and Dr.
Michael Sevka.

####### Table 1. Patient Accountability -- Paille^§^ {#table-1.-patient-accountability-paille .unnumbered}

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 12%" />
<col style="width: 10%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td>Completed Period</td>
<td>Adverse Event/ Illness</td>
<td>Death</td>
<td>Improvement</td>
<td>Loss to Follow-up</td>
<td>Non Permitted medication</td>
<td>Other Reasons</td>
<td><strong>Refusal Non-compliance</strong></td>
<td>Relapse</td>
</tr>
<tr class="even">
<td><p>Placebo</p>
<p>n=177</p></td>
<td><p>62</p>
<p>35%</p></td>
<td><p>13</p>
<p>7%</p></td>
<td><p>2</p>
<p>1%</p></td>
<td><p>6</p>
<p>3%</p></td>
<td><p>28</p>
<p>16%</p></td>
<td><p>3</p>
<p>2%</p></td>
<td><p>2</p>
<p>1%</p></td>
<td><p><strong>25</strong></p>
<p><strong>14%</strong></p></td>
<td><p>36</p>
<p>20%</p></td>
</tr>
<tr class="odd">
<td><p>A1332mg</p>
<p>N=188</p></td>
<td><p>85</p>
<p>45%</p></td>
<td><p>14</p>
<p>7%</p></td>
<td><p>2</p>
<p>1%</p></td>
<td><p>5</p>
<p>3%</p></td>
<td><p>21</p>
<p>11%</p></td>
<td>0</td>
<td><p>2</p>
<p>1%</p></td>
<td><p><strong>16</strong></p>
<p><strong>9%</strong></p></td>
<td><p>43</p>
<p>23%</p></td>
</tr>
<tr class="even">
<td><p>A1998mg</p>
<p>N=173</p></td>
<td><p>90</p>
<p>52%</p></td>
<td><p>10</p>
<p>6%</p></td>
<td><p>2</p>
<p>1%</p></td>
<td><p>3</p>
<p>2%</p></td>
<td><p>26</p>
<p>15%</p></td>
<td>0</td>
<td><p>2</p>
<p>1%</p></td>
<td><p><strong>12</strong></p>
<p><strong>7%</strong></p></td>
<td><p>28</p>
<p>16%</p></td>
</tr>
</tbody>
</table>

^§^ Extracted from Table 2 of the Sponsor study report

Study completion rates differed among the three treatment groups,
nominal p=0.0055. It appeared that only about ½ of the patients treated
with Acamprosate (52% with 1998 mg/day regimen and 45% with 1332 mg/day
regimen) completed the study and a little over 1/3 of the patients
treated with placebo completed the study (35%). The sponsor reevaluated
the reasons of discontinuation after the European approval.
Particularly, three placebo dropout patients had the reason re-coded as
'refusal/non-compliance'. This change made the difference in dropout
rate due to refusal/non-compliance more dramatic between placebo and
acamprosate.

####### Table 2. Patient Accountability categorized into four categories^§^ {#table-2.-patient-accountability-categorized-into-four-categories .unnumbered}

+-------+---------+----------------+----------+----------------------+
|       | Co      | LOE            | AE       | Others (improve, ,   |
|       | mpleted |                |          | loss to-follow-up    |
|       |         | (relapse,      | (AE/     | others,              |
|       |         | death,         | illness) | non-permitted        |
|       |         | refusal)       |          | medication           |
+-------+---------+----------------+----------+----------------------+
| Pl    | 62      | 63 (36%)       | 13 (7%)  | 39 (22%)             |
| acebo | (35%)   |                |          |                      |
|       |         |                |          |                      |
| N=177 |         |                |          |                      |
+-------+---------+----------------+----------+----------------------+
| A1    | 85      | 61 (32%)       | 14 (7%)  | 28 (15%)             |
| 332mg | (45%)   |                |          |                      |
|       |         |                |          |                      |
| N=188 |         |                |          |                      |
+-------+---------+----------------+----------+----------------------+
| A1    | 90      | 42 (24%)       | 10 (6%)  | 31 (18%)             |
| 998mg | (52%)   |                |          |                      |
|       |         |                |          |                      |
| N=173 |         |                |          |                      |
+-------+---------+----------------+----------+----------------------+

^§^ Derived from Table 1 above.

One possible way of evaluating the reasons of dropouts from the original
classification may be to categorize the reasons into lack of efficacy
(LOE), due to adverse events (AE), or others (Others). Table 2 above is
one plausible way. With this classification, it is possible that both
placebo and Acamprosate 1332 mg/day arm appeared to have higher and
similar rates of lack of efficacy compared to Acamprosate 1998 mg/day
arm (nominal p-value 0.061) while AE rates were similar among the three
groups.

##### - TREATMENT EXPOSURE {#treatment-exposure .unnumbered}

The median exposure time was the shortest in placebo (8 months),
followed by Acamprosate 1332 mg/day (10.5 months) and Acamprosate 1998
mg/day (11.8 months), see Table 3 below.

####### Table 3. Distribution of time to discontinuation from the study -- Paille Trial {#table-3.-distribution-of-time-to-discontinuation-from-the-study-paille-trial .unnumbered}

  ----------------- ------------------ ------------------ -----------------
                    Placebo (n=177)    Acamp1332 (n=188)  Acamp1998 (n=173)

  Median (range) in 239 days (0, 420)  320 days (0, 430)  355 days (0,
  days                                                    528^¦^)
  ----------------- ------------------ ------------------ -----------------

^§^ based on study duration data

^¦^ one patient has study duration longer than 430 days (i.e., 528
days). The estimated median time to discontinuation was the same

when the time was set to 430 days.

Figure 1 depicted the percentages of patients completed each study visit
over the treatment period. It appeared that the exposure time to the
treatments varied.

####### Figure 1. % of patients available over treatment period -- Paille Trial {#figure-1.-of-patients-available-over-treatment-period-paille-trial .unnumbered}

![](media/image4.wmf)

##### - EFFICACY ON MAINTENANCE OF ABSTINENCE {#efficacy-on-maintenance-of-abstinence .unnumbered}

The primary objective was "to establish the therapeutic value of the
administration of Aota Ca at a dosage of 1.3 g/day during 1 year in the
**maintenance of abstinence** and to compare this with placebo." Hence,
the primary comparison of interest was Acamprosate 1332 mg/day vs.
placebo on maintenance of abstinence over one year treatment phase.

The sponsor reported results of the following four outcomes: percentage
of complete abstinence during treatment phase, time to first drink,
cumulative abstinence duration (CAD) and percentage of success to
address the maintenance of abstinence. The reviewer's evaluation and
comments follow.

***[TREATMENT PHASE]{.underline}***

###### **PERCENTAGE OF COMPLETE ABSTINENCE**  {#percentage-of-complete-abstinence .unnumbered}

For percentage of complete abstinence, there were three analyses
performed. Method I, as shown in Table 4, classified patients as
abstinence if patients completed the study without relapse and
discontinued the study early without relapse. Method II classified
patients as abstinence only if patients completed the study without
relapse. That is, all dropouts are considered as relapsed to drinking.
Method III classified patients as abstinent if patients' CABST
(continuous abstinence since day 0 categories) is at least 340 days
(including categories 340 days and up).

The complete abstinence rate was consistently lower in placebo using all
three methods. However, depending on how the abstinence status of the
dropouts were imputed, the differences in abstinence rates were shown to
be not statistically significant (p=0.285) using Method I, in which
complete abstinence rates were 23%:27%:30% of placebo, low dose to
median dose, respectively. Such differences became statistically
significant (p=0.044) when the most conservative imputation was applied
(Method II) with rates being 7%:14%:14%. These differences did not reach
statistical significance when a benign imputation method was used, which
only penalized incompleted patients to relapse if these patients had
continuous abstinence less than 340 days from treatment initiation.
These complete abstinence rates, using Method III, were 11%:18%:19% of
placebo, low dose and median dose, p=0.096. This reviewer confirmed
these analyses and the results are summarized in Table 4.

####### Table 4. Complete abstinence rates - Paille^§^ {#table-4.-complete-abstinence-rates---paille .unnumbered}

+--------+---------------+---------------+---------------+-------------+
| Method | Placebo       | Acamp1332     | Acamp1998     | χ2 test     |
|        |               | mg/d          | mg/d          |             |
|        | (n=177)       |               |               | (global)    |
|        |               | (n=188)       | (n=173)       |             |
+--------+---------------+---------------+---------------+-------------+
| I      | 40 (22.6%)    | 50 (26.6%)    | 52 (30.1%)    | .285§       |
+--------+---------------+---------------+---------------+-------------+
| II     | 12 (6.8%)     | 26 (13.8%)    | 25 (14.5%)    | .044^+^     |
+--------+---------------+---------------+---------------+-------------+
| *      | **20          | **34¦         | **33          | **.096¦¦**  |
| *III** | (11.3%)**     | (18.1%)**     | (19.1%)**     |             |
+--------+---------------+---------------+---------------+-------------+

^§^ From electronic database "CABSTYN" - Continuous abstinence through
the treatment period: y/n; or 'RELFLAGC' -- relapsed to

drinking flag for ISE censored analysis, i.e., included dropouts without
drinking as no relapse.

^+^ From electronic database "RELFLAGU" -- relapsed to drinking flag for
ISE uncensored analysis, i.e., included dropouts without

drinking as 'relapse'.

¦ One patient had study duration less than 360 days and was not
considered as completer. When this patient was excluded from being

classified as abstinence (as incompleters were coded as relapsed),
p=0.107.

¦¦ Extracted from Table 1 of the sponsor summary of study (p.5 of
vol.1.083) and Table 6 of the Sponsor study reports (p.29 of

vol.1.083), i.e., CABST (continuous abstinence since day 0 categories)
in the category of 340 days and up.

It is noted that the primary comparison of interest pre-specified in the
protocol is Acamprosate low dose vs. placebo. The p-values for this
pairwise comparison were 0.377 with Method I, 0.028 with Method II, and
0.069 with Method III, respectively. This reviewer further explored the
impact of the dropouts by classifying the patients into
'completer/abstinence', 'incompleter/abstinence', or 'non-abstinence'
categories. It appeared that percentages of patients who were
incompleter/abstinence were similar among the three groups using all
three methods.

###### **TIME TO FIRST DRINK** {#time-to-first-drink .unnumbered}

The sponsor reported time to first drink analysis, the Kaplan-Meier
curves can be found in In-Text Figure 8.7.2.7.2:1.

This reviewer confirmed the sponsor's results and performed the analyses
using three censoring methods described above. In fact, the abstinence
indicators produced with the above three methods are the censoring
indicators for the time to first drink analysis. Given there was a
seemingly differential censoring between the Acamprosate and the placebo
groups, the survival analysis yielded p=0.0695, 0.0148, and 0.0303,
respectively, for Methods I, II and III, log-Rank test. As summarized in
Table 5, consistent median time to first relapse was observed using all
three Methods. The median times to first drink were about two months
with median dose Acamprosate and about one month for low dose
Acamprosate and placebo.

####### In‑Text Figure 8.7.2.7.2:3 Kaplan-Meier Estimate of Time to First Drink During Treatment Phase --  {#intext-figure-8.7.2.7.23-kaplan-meier-estimate-of-time-to-first-drink-during-treatment-phase .unnumbered}

####### Pivotal Efficacy Study Paille {#pivotal-efficacy-study-paille .unnumbered}

![](media/image5.wmf){width="6.14375in" height="2.6909722222222223in"}

####### Table 5. Estimated median time and its 95%CI (days) - distribution of time to 1^st^ relapse (Paille)^§^ {#table-5.-estimated-median-time-and-its-95ci-days---distribution-of-time-to-1st-relapse-paille .unnumbered}

+---------+--------------+--------------+-------------+-------------+
| Method  | Placebo      | Acamp1332    | Acamp1998   | Log-rank    |
|         |              | mg/d         | mg/d        |             |
|         | N=177        |              |             | (global     |
|         |              | N=188        | N=173       | test)       |
+---------+--------------+--------------+-------------+-------------+
| I       | 32 (28, 59)  | 35 (29, 69)  | 63 (55,     | 0.0695      |
|         |              |              | 101)        |             |
+---------+--------------+--------------+-------------+-------------+
| II      | 30 ( 0, 54)  | 33 (29, 63)  | 59 (38, 74) | 0.0148      |
+---------+--------------+--------------+-------------+-------------+
| III     | 30 ( 0, 54)  | 33 (29, 63)  | 59 (38, 74) | 0.0303      |
+---------+--------------+--------------+-------------+-------------+

^§^ Based on the electronic data on time to first drink truncated for
the treatment period.

Note that the significant difference obtained from Method III yielded a
significant difference between median Acamprosate dose (1998 mg/day) vs.
placebo.

###### **CUMULATIVE ABSTINENCE DURATION (CAD)** {#cumulative-abstinence-duration-cad .unnumbered}

The cumulative abstinence duration (CAD) measured the total time the
patient was abstinent by the sum of all periods of complete abstinence.
It takes into account all the non-relapsed days. The sponsor reported a
statistically significant difference in CAD among the three treatment
groups, nominal p=0.002. According to the sponsor, **if a patient did
not attend for a particular visit then the patient was assumed to be
non-abstinent between the visit before the missing data until the visit
after.** The sponsor concluded that the statistical significance was
primarily seen in the comparison between high dose Acamprosate vs.
placebo (p=0.0005), and only borderline significance with low dose
Acamprosate (p=0.055), this report can be found in Table 9 of the
sponsor volume 1.083. This reviewer confirmed the analysis results. The
estimated median days of CAD were \~5.0 months with placebo, \~6.4
months with low dose, and \~8.6 months with median dose Acamprosate, as
shown in Table 6 below.

####### Table 6. Distribution of cumulative abstinence duration (CAD) - Paille^§^ {#table-6.-distribution-of-cumulative-abstinence-duration-cad---paille .unnumbered}

+---------------+--------------+--------------+-------------+--------+
|               | Placebo      | Acamp1332    | Acamp1998   | p      |
|               |              | mg/d         | mg/d        | -value |
+---------------+--------------+--------------+-------------+--------+
| Mean (SD)     | 173.4        | 198.4        | 223.4 (134) | 0.002  |
| days          | (126.1)      | (133.1)      |             |        |
|               |              |              | \~7.4       |        |
| Mean (in      | \~5.8 months | \~6.6 months | months      |        |
| months)       |              |              |             |        |
|               | \~5.0 months | \~6.4 months | \~8.6       |        |
| Median (in    |              |              | months      |        |
| months)^¦^    |              |              |             |        |
+---------------+--------------+--------------+-------------+--------+

^§^ Extracted from Table 9 of the sponsor vol.1.083

^¦^ Provided by this reviewer (note that the distribution of CAD) was
not normally distributed)

###### **PERCENTAGE OF SUCCESS** {#percentage-of-success .unnumbered}

The sponsor also performed an analysis of success with three categories
defined: success (defined as abstinence at day 180 and day 360), partial
success (abstinence at either day 180 or day 360), and failure (not
abstinent on both visits). The success rates (17% with placebo, 26% with
low dose, 30% with median dose) were shown to be statistically
significantly different (nominal p=0.01, can be found in Table 11 of the
sponsor volume 1.083 and was confirmed by this reviewer) among the three
treatment groups. It is noted that one cannot conclude whether a patient
would be completely abstinent if he/she was classified as success in
this analysis.

***[OBSERVATION PHASE]{.underline}* (Treatment Period + Follow-up
Period)**

###### **INCIDENCE OF COMPLETE ABSTINENCE THROUGH OBSERVATION PHASE (1.5 years)**  {#incidence-of-complete-abstinence-through-observation-phase-1.5-years .unnumbered}

To address the second objective "to evaluate the evolution of the
therapeutic result during a 6-month period under placebo after
discontinuation of randomized treatment and before ending the blind
phase of the trial", this reviewer performed an analysis of complete
abstinence through an additional half year observation phase. As shown
in Table 7, there were no statistically significant differences observed
among the three treatment groups in terms of the incidence of complete
abstinence through the observation phase from treatment initiation,
using all three censoring methods applied when analyzing the incidence
rate during the treatment phase. Note that for Method II, a patient was
considered complete abstinent if he/she had study duration at least 360
days and continuous abstinence from day 0 is at least 540 days.

####### Table 7. Complete abstinence rates over the observation phase - Paille {#table-7.-complete-abstinence-rates-over-the-observation-phase---paille .unnumbered}

+-------+---------------+------------------+------------------+-------+
| M     | Placebo       | Acamp1332mg/d    | Acamp1998mg/d    | p-    |
| ethod | (n=177)       | (n=188)          | (n=173)          | value |
|       |               |                  |                  |       |
|       |               |                  |                  | (χ2   |
|       |               |                  |                  | test) |
+-------+---------------+------------------+------------------+-------+
| I     | 35 (20%)      | 40 (21%)         | 46 (27%)         | 0.276 |
+-------+---------------+------------------+------------------+-------+
| II    | 9 (5%)        | 18 (10%)         | 19 (11%)         | 0.118 |
+-------+---------------+------------------+------------------+-------+
| III   | 16 (9%)       | 24 (13%)         | 27 (16%)         | 0.175 |
+-------+---------------+------------------+------------------+-------+

#### • SPONSOR'S CONCLUSION {#sponsors-conclusion .unnumbered}

The sponsor concluded in the summary of study that 'For all principal
and secondary parameters of efficacy the differences were statistically
significant. There was clear evidence of a dose-response. Acamprosate
1998 mg/day was significantly better than placebo. Acamprosate 1332
mg/day failed to reach significantly better results than placebo for
most main efficacy criteria, and fell midway between the results
observed with the higher dose and placebo. However, there were no
statistically significant differences between Acamprosate 1332 mg/day
and placebo or Acamprosate 1998 mg/day. Acamprostae 1998 mg/day is a
safe and effective treatment for maintaining abstinence in patients
weaned off alcohol during the period immediately preceding the
treatment.'

#### • REVIEWER'S SUMMARY {#reviewers-summary-1 .unnumbered}

In this one-year treatment study, the sponsor's main objective is to
compare the Acamprosate 1332 mg/day with placebo. The dropout rates (65%
in placebo, 55% in Acamprosate 1332 mg/day group and 48% in Acamprosate
1998 mg/day group) and the exposure times (ranging from 8 months with
placebo to 11.8 months with 1998 mg/day Acamprosate) appeared to be
differential among the three groups. Under such circumstances, the
CONSERVATIVE TYPE ANALYSIS (by imputing all or most of the dropouts as
failure when the endpoint of interest is success) is likely to be biased
in favor of the less dropped out group(s), viz.-a-viz. Acamprosate
groups. Such an imputation might have given a penalty more than it
should to the group with a higher dropout rate. In contrast, Method I
assigning patients who discontinued early without relapse to complete
abstinence might have given a favor more than it should to the group
with a higher dropout rate. The truth probably lies in between.
Regardless of which imputation method is applied, it can not be
concluded with great confidence that the comparison between Acamprosate
1332 mg/day and placebo in complete abstinence rate was statistically
significant.

The complete abstinence rate was consistently lower in placebo using all
three methods. However, depending on how the abstinence status of the
dropped out patients were imputed, the differences in abstinence rates
were shown to be not statistically significant (p=0.285) using Method I,
in which complete abstinence rates were 23%:27%:30% of placebo, low dose
to median dose, respectively. Such differences became statistically
significant (p=0.044) when the most conservative imputation was applied
(Method II) with rates being 7%:14%:14%. These differences did not reach
statistical significance when a benign imputation method was used, which
only penalized dropped out patients to 'drinking' if these patients had
continuous abstinence less than 340 days from treatment initiation.
These complete abstinence rates, using Method III, were 11%:18%:19% of
placebo, low dose and median dose, p=0.096. The complete abstinence
rates were similar between Acamprosate 1332 mg/day (27%) and placebo
(23%) using Method I (nominal p=0.377). These rates differed
significantly using Method II (14% vs. 7%, nominal p=0.028) and not
significant using the Method III (18% vs. 11%, nominal p=0.069).
Regardless of which imputation method is applied, it could not be
concluded with confidence that the comparison between Acamprosate 1332
mg/day and placebo in complete abstinence rate was statistically
significant. This reviewer further explored the impact of the dropouts
by classifying the patients into 'completer/abstinence',
'incompleter/abstinence', or 'non-abstinence' categories. It appeared
that percentages of patients who were incompleter/abstinence were
similar among the three groups using all three methods. This indicated
that the difference between Acamprosate and placebo is likely to be from
patients who were 'completer/abstinence' or 'non-abstinence irrespective
of completing or incompleting the trial'. However, the data quality for
the latter case is of concern, particularly, drinking diaries was not
used in the study.

For time to first drink, in contrast, consistent median time to first
drink was observed using all three methods whether statistically
significant or not. The median times to first relapse were about two
months with Acamprosate 1998 mg/day group and about one month for
Acamprosate 1332 mg/day and placebo groups. For the comparison between
Acamprosate 1998 mg/day vs. placebo, the Method I did not reach
statistical significance and Methods II and III reached statistical
significance. There was no statistically significant difference between
Acamprosate 1332 mg/day vs. placebo.

The estimated median days of CAD were \~5.0 months with placebo, \~6.4
months with low dose, and \~8.6 months with median dose acamprosate. A
significantly longer CAD with Acamprosate 1998mg/day was observed, but
only borderline significance was observed with Acamprosate 1332mg/day as
compared to placebo.

The conservative type analyses (Methods II and III) are attractive
because it might be reliably used to be sure that a patient was
completely abstinent during the treatment phase. Here, if a patient did
not attend for a particular visit then the patient was assumed to be
non-abstinent between the visit before the missing data until the visit
after. Although these methods yielded a higher complete abstinence rates
with Acamprosate 1332 mg/day treatment (14% or 18%) compared to placebo
(7% or 11%), the median time to first drink was essentially the same
between these two groups (about 30 days) using all three methods. In
contrast, the higher complete abstinence rates with Acamprosate 1998
mg/day treatment (14% or 19%) were further supported by the time to
first drink analyses using all three approaches and yielded twice longer
median time (about 60 days) as compared to placebo or Acamprosate 1332
mg/day treatment.

The sponsor's conclusion that "Acamprosate 1332 mg/day failed to reach
significantly better results than placebo for most main efficacy
criteria" was consistent with this reviewer's conclusion. It is noted
that the second objective of a superior complete abstinence rate with
Acamprosate 1332 mg/day was not shown through the observation phase.

## PRAMA  {#prama .unnumbered}

#  {#section-2 .unnumbered}

Double-blind controlled study versus placebo to assess the effectiveness
and tolerance of AOTA-CA in treatment which helps to maintain abstinence
after detoxification in the alcoholic patient

#### PROTOCOL SYNOPSIS

This was a multicenter (12 psychiatric clinics in Germany under Prof. H.
Sass' supervision), double-blind, randomized, placebo controlled study.
Eligible patients aged 18 to 65 years with a history of at least two
years (females) or three years (males) alcohol dependence, who had
undergone a successful detoxification process of no withdrawal symptoms
and abstinence for at least 14 days, were randomized to receive placebo
or Acamprosate (AOTA-CA) for 48 weeks. Study medication was dosed
stratifying on weight ≥ 60 kg vs. \< 60 kg. That is, patients took 2
tablets t.i.d. containing a total of 1998 mg/day medication if heavier
and 4 tablets daily containing a total of 1332 mg/day medication if
lighter. Note that the distribution of baseline weights between
Acamprosate and placebo was comparable. The time schedule of the study
during the 48 weeks treatment phase, which was followed by an additional
48 weeks without Acamprosate therapy, was as follows.

  --------- ----------- --------- ---------- -------- --------- -----------
  Visit0    1           2         3          4        5         6

  Initial   4wk         8wk       12wk       24wk     36wk      48wk
  exam                                                          
  --------- ----------- --------- ---------- -------- --------- -----------

**The primary objective** was to investigate whether treatment with
Acamprosate increases the proportion of successfully treated, i.e.,
**abstinent patients during the 48-week therapy phase following at least
14 days of abstinence.** The purpose of a follow-on 48 week period
without the study drug was to test whether any primary benefits of the
treatment outlast the therapy period.

**The primary efficacy endpoint was the time when the first relapse
occurs**[^1]. The point in time when a relapse occurs was defined as the
day on which alcohol consumption starts again and was analyzed by
log-rank test in which dropout patients without further information
regarding treatment course would be censored at the last available
information time. Secondary endpoints included (1) frequency of
relapses, (2) craving, (3) transferrin. Other variables included
diagnostic confirmation of alcohol dependence, disease severity, types
of alcoholic drink taken, emotionality of the patient, type and
intensity of accompanying non-drug therapy, patient's psychosocial
situation, laboratory parameters, etc. This review focused on the
drinking related efficacy outcomes.

According to the protocol (p.155 of vol.080), the primary efficacy
variable 'relapse: yes/no' would be established by the investigator,
whose overall assessment takes into consideration information from the
patient and relatives, the result of the Breathalyzer test, the result
of two typical laboratory values, as well as the investigator's own
clinical impression. When discrepancies arise, the decision 'relapse:
yes/no' must be substantiated. The sponsor believed that the procedure
ensured sufficient validation of the investigator's decision about the
occurrence of the relapse.

For sample size estimation, a 20% increase in the rate of abstinence
would be regarded as clinically relevant assuming abstinence rate
without medication is 50% as recognized in the literature. It was
estimated that 200 patients would be needed to detect a 20% difference
in abstinence rate at 1% level of significance and 80% power. In this
study, 136 patients per group were the basis for analysis.

Protocol amendment on March 1991 modified exclusion criteria and
included additional patient contacts in the phase where the individual
examinations have a frequency of 12 weeks.

#### • OVERVIEW OF THE STUDY RESULTS AND REVIEWER'S EVALUATION AND COMMENTS {#overview-of-the-study-results-and-reviewers-evaluation-and-comments-1 .unnumbered}

The study was initiated on October 16, 1990 and completed on December 3,
1992 (\~2 years). A total of 272 patients received study medication were
randomized to receive Acamprosate (n=136) or placebo (n=136). The mean
age at entry was 41 years old and 78% of the patients were males. There
were no significant differences between the treatment groups with regard
to age, sex, weight, height, civil, living or employment status.
According to the sponsor, placebo treated patients appeared to have a
higher percent of family history of alcoholism (14%) than Acamprosate
treated patients (9%).

##### - PATIENT ACCOUNTABILITY {#patient-accountability-2 .unnumbered}

Patients accountability during the treatment phase was summarized in
Table 1 (submitted when seeking for approval in Europe). A total of
three deaths occurred, two of them were from Acamprosate group. Details
of the reason of deaths can be found in the evaluation and comments of
medical review written by Dr. Cellia Winchell.

####### Table 1. Patient Accountability - PRAMA^§^ {#table-1.-patient-accountability---prama .unnumbered}

+---------+-------+---------+-------+-------+-------+---------+-------+
|         | **    | Conc    | Death | Lost  | **Pa  | Serious | S     |
|         | Compl | omitant |       | to    | tient | Aggr    | evere |
|         | ete** | Illness |       | Fol   | Refu  | avation | AE    |
|         |       |         |       | lowup | sal** |         |       |
+---------+-------+---------+-------+-------+-------+---------+-------+
| Placebo | *     | 1       | 1     | 28    | *     | 5       | 1     |
|         | *55** |         |       |       | *45** |         |       |
| (n=136) |       | (1%)    | (1%)  | (20%) |       | (4%)    | (1%)  |
|         | **(4  |         |       |       | **(3  |         |       |
|         | 0%)** |         |       |       | 3%)** |         |       |
+---------+-------+---------+-------+-------+-------+---------+-------+
| Acam    | *     | 0       | 2     | 26    | *     | 7       | 2     |
| prosate | *79** |         |       |       | *20** |         |       |
|         |       | (0%)    | (     | (19%) |       | (5%)    | (     |
| (n=136) | **(5  |         | 1.5%) |       | **(1  |         | 1.5%) |
|         | 8%)** |         |       |       | 5%)** |         |       |
+---------+-------+---------+-------+-------+-------+---------+-------+

^§^ Extracted from the sponsor's Table 2 of vol.1.079 (p.24).

The percentage of patients completed the study between placebo (40%) and
Acamprosate (58%) was shown to be different, nominal p=0.0004. More
patients discontinued the study early with placebo than with
acamprosate. 'Patient refusal' appeared to be the major reason of
discontinuation showing a difference between placebo (33%) and
Acamprosate (15%), nominal p-value=0.0004. The sponsor reclassified the
reasons of early discontinuation on 8 Acamprosate patients and 4 placebo
patients after the European approval. Majority was reclassified to
severe AE. These changes were summarized in the sponsor's final study
report amendments. The amended reasons resulted in 53 (39%) completed
placebo and 73 (54%) completed Acamprosate patients, nominal p=0.015.
The originally observed percents of 'severe AE' had changed to 4% (5
patients) with placebo and 6% (8 patients) with Acamprosate,
respectively.

The percentage of available patients over the treatment period was
summarized in Figure 1.

####### ![](media/image6.wmf)Figure 1 % of patients completed the study visit -- PRAMA Trial {#figure-1-of-patients-completed-the-study-visit-prama-trial .unnumbered}

##### - TIME TO DISCONTINUATION {#time-to-discontinuation-1 .unnumbered}

This reviewer performed an analysis of time to discontinuation using the
electronic data information on last visit date and the baseline date.
Results are summarized in Table 2. The estimated median times were 169
days with placebo and 337 days with Acamprosate, nominal p=0.0054
(Wilcoxon rank sum test). On average, the Acamprosate treated patients
appeared to stay on study twice longer than the placebo treated
patients.

####### Table 2. Time to discontinuation -- PRAMA Trial {#table-2.-time-to-discontinuation-prama-trial .unnumbered}

+-----------------------+------------------------+---------------------+
|                       | Placebo (n=136)        | Acamprosate (n=136) |
+-----------------------+------------------------+---------------------+
| Last visit date --    | 192 days (13 days)     | 245 days (13 days)  |
| baseline date^§^      |                        |                     |
|                       | 169 days (1, 442)      | 337 days (1, 435)   |
| Mean (SE)             |                        |                     |
|                       |                        |                     |
| Median (range)        |                        |                     |
+-----------------------+------------------------+---------------------+

^§^ from electronic data base

##### - EFFICACY IN HELPING TO MAINTAIN ABSTINENCE (treatment period) {#efficacy-in-helping-to-maintain-abstinence-treatment-period .unnumbered}

To evaluate total abstinence from alcohol, the sponsor reported the
following four efficacy endpoints: time to first relapse, continuous
abstinence rate, cumulative duration of abstinence (CAD) and the
investigators global assessment of drinking behavior at each visit. The
reviewer's evaluation and comments in reference to the sponsor's summary
of report follow.

###### **TIME TO FIRST RELAPSE**  {#time-to-first-relapse-1 .unnumbered}

This was the protocol specified primary efficacy endpoint. This reviewer
confirmed the sponsor's report on time to first relapse analysis using
censored approach and the uncensored approach, see Table 3. The median
continuous abstinence duration calculated from the uncensored approach
was almost 3 times longer in the Acamprosate group (134.5 days) compared
to the placebo group (45.0 days). The difference between treatment
groups was statistically significant, p\<0.001.

A total of 69 patients (31 in Acamprosate and 38 in placebo)
discontinued the study early without having any drinking. The inclusion
of these patients as censored observation in the time to first relapse
analysis using the censored approach showed a similar effect on the
median estimates. In both groups the median duration estimates were
essentially halved using the uncensored approach as compared to the
censored approach. Results from the censored analysis showed that the
median time to first drink for the Acamprosate group (253.0 days) was
statistically significantly longer compared to the placebo group
(92.0 days, logrank test p=0.0052), see Table 3.

####### Table 3. The primary efficacy endpoint: time to first relapse (PRAMA Trial) {#table-3.-the-primary-efficacy-endpoint-time-to-first-relapse-prama-trial .unnumbered}

+----------------------+--------------+---------------+---------------+
|                      | Placebo      | Acamprosate   | p-value       |
|                      | (n=136)      | (n=136)       |               |
+----------------------+--------------+---------------+---------------+
| TMRELITT:            | 92 days      | 253 days      | 0.0052        |
| RELFLAGC^1^          | (49-164)     | (128, NA)     | (log-rank)    |
|                      |              |               |               |
| Median (95% CI)      | 40% (54/136) | 51% (70/136)  | 0.052 (χ2)    |
|                      |              |               |               |
| censor%              |              |               |               |
+----------------------+--------------+---------------+---------------+
| TMRELITT:            | 45 days      | 134.5 days    | 0.0005        |
| RELFLAGU^2^          | (36-75)      | (75, 157)     | (log-rank)    |
|                      |              |               |               |
| Median (95% CI)      | 12% (16/136) | 29% (39/136)  | 0.003 (χ2)    |
|                      |              |               |               |
| censor%              |              |               |               |
+----------------------+--------------+---------------+---------------+

^1^: dropout without an event is considered censored (censored approach)

^2^: dropout without an event is considered relapsed (uncensored
approach)

The time to first relapse analysis accounts for censoring distributions
between the two treatment groups. The sponsor concluded "In the survival
analysis, the mean number of days to the first relapse was 165.2 +/-
143.8 days in the Acamprosate group compared with 112.3 +/- 126.5 days
in the placebo group, with 45% of patients recorded as having continuous
abstinence in the Acamprosate group compared with 25% of patients in the
placebo group (Log-Rank test p=0.0052)." The interpretation of the
survival analysis on the time to first relapse may be problematic. The
censoring distribution differed between the Acamprosate group and the
placebo group. Given censoring was differential between the Acamprosate
and the placebo groups, the mean time to first relapse could be
misleading. In addition, 45% with Acamprosate and 25% with placebo
estimated from the survival curve refers to the probability of patients
who would continue to be abstinent by week-48.

###### **COMPLETE ABSTINENCE RATE (or CONTINUOUS ABSTINENCE RATE)** {#complete-abstinence-rate-or-continuous-abstinence-rate .unnumbered}

####### Table 4. Distribution of no relapse during the treatment phase -- PRAMA Trial^§^ {#table-4.-distribution-of-no-relapse-during-the-treatment-phase-prama-trial .unnumbered}

+----------------+-----------------+------------------+---------------+
|                | Method I        | Method II        | Method II     |
|                | (RELAPITT)      | (RELFLAGU)       |               |
|                |                 |                  | (final study  |
|                | (same as        | no relapse and   | report        |
|                | RELFLAGC)       | completed the    | amendments)   |
|                |                 | trial            |               |
|                | No relapse to   |                  |               |
|                | drinking        |                  |               |
+----------------+-----------------+------------------+---------------+
| Placebo        | 40% (54)        | 12% (16)         | 11% (15)      |
| (n=136)        |                 |                  |               |
+----------------+-----------------+------------------+---------------+
| Acamprosate    | 51% (70)        | 29% (39)         | 27% (37)      |
| (n=136)        |                 |                  |               |
+----------------+-----------------+------------------+---------------+
| p-value        | 0.052           | 0.0005           | 0.0007        |
|                |                 | (\<0.001)\*      |               |
+----------------+-----------------+------------------+---------------+

^§^ Extracted from the sponsor In-text Table 8.7.2.7.3:1

This reviewer analyzed the efficacy outcome of continuous abstinence
rate during the treatment phase. Results are summarized in Table 4.
Similar to time to first relapse analysis, both the censored approach
(Method I) and uncensored approach (Method II) were analyzed. For the
Method I, percentage of patients without relapse to drinking
irrespective of their completing the trial was borderline significantly
higher with Acamprosate (51%) than with placebo (40%), p=0.052. The
sponsor reported results using the Method II, the most conservative
analysis. That is, when incompleted patients without relapsed to
drinking was considered as relapsed, such percentages were 29% with
Acamprosate and 12% with placebo, p=0.0005. This reviewer also performed
a robustness analysis of Method II using the reclassified completer
status reported in the sponsor's final study report amendment.
Consistent statistical evidence was observed, p=0.0007.

To understand further the distribution of patients in terms of their
status of completing the trial and relapse to drinking, this reviewer
performed an analysis in which patients were classified into the
following four categories: (1) completer and no relapse, (2) completer
and relapse, (3) incompleter and no relapse, and (4) incompleter and
relapse. Table 5 summarized the results using the Method I. The
abstinence rate was twice higher with Acamprosate (31%) as compared to
placebo (15%) in patients who completed the trial, and no apparent
difference in patients who did not complete the trial (21% with
Acamprosate and 25% with placebo). In contrast, the lower relapse rate
with Acamprosate was primarily observed in the incompleter subgroup (21%
with Acamprosate and 35% with placebo) and not in the completer subgroup
(27% with Acamprosate and 26% with placebo).

It is noted that placebo patient (pid=273) was classified as relapsed
completer. This patient should be a relapsed incompleter. One
Acamprosate patient (pid=280) was classified as not relapsed completer.
This patient should be a not relapsed incompleter. Including/excluding
these two patients in the appropriate categories, the results in terms
of nominal statistical significance remained. The following table
provides a clean picture with imputation on the dropout patients.

####### Table 5. Summary of patients based on their status completing the trial and their status 'abstinence' during the entire 48 weeks treatment period {#table-5.-summary-of-patients-based-on-their-status-completing-the-trial-and-their-status-abstinence-during-the-entire-48-weeks-treatment-period .unnumbered}

+---------------+-----------+-------------+-------------+-------------+
| Method I      | **        | Completer   | Incompleter | **          |
| (RELFLAGC)    | Completer | and         | and         | Incompleter |
|               | and**     |             |             | and         |
|               |           | Relapse     | no relapse  | relapse**   |
|               | **No      |             |             |             |
|               | relapse** |             |             |             |
+---------------+-----------+-------------+-------------+-------------+
| Placebo       | **20      | 35 (26%)    | 34 (25%)    | **47        |
| (n=136)       | (15%)**   |             |             | (35%)**     |
+---------------+-----------+-------------+-------------+-------------+
| Acamprosate   | **42      | 37 (27%)    | 28 (21%)    | **29        |
| (n=136)       | (31%)**   |             |             | (21%)**     |
+---------------+-----------+-------------+-------------+-------------+

When the Method II was applied, not relapsed incompleters were combined
into the relapsed incompleters. Significantly higher abstinence rate in
Acamprosate (29%) than in placebo (12%) was observed, i.e., the results
shown in the column with a label heading "Method II" of Table 4 above.
This reviewer further investigated the dropout reasons among the
relapsed dropouts and the no relapsed dropouts. It appeared that among
those dropouts who did not relapse, there was little difference in the
reason of discontinuation. However, of the dropouts with relapse, the
distribution of the reasons of discontinuation appeared to differ
between two treatment groups, noticeably, in patients refusal (7% with
Acamprosate and 24% with placebo). It appeared that differential (or
informative) dropouts were observed between the relapsed placebo
patients vs. relapsed Acamprosate patients.

###### **CUMULATIVE DURATION OF ABSTINENCE** {#cumulative-duration-of-abstinence .unnumbered}

####### Table 6. Cumulative abstinence duration in days {#table-6.-cumulative-abstinence-duration-in-days .unnumbered}

+---------------+--------------------+---------------------+---------+
| CAD           | Placebo            | Acamprosate         | p-value |
|               |                    |                     |         |
|               | (n=136)            | (n=136)             |         |
+---------------+--------------------+---------------------+---------+
| Mean (SD) in  | 162.03 (132.19)    | 224.62 (136.61)     | 0       |
| days          |                    |                     | .0002\* |
|               | 135 (6, 364)       | 270 (15, 360)       |         |
| Median        |                    |                     |         |
| (range) in    |                    |                     |         |
| days          |                    |                     |         |
+---------------+--------------------+---------------------+---------+
| CADITT ≥ 360  | 13% (17)           | 29% (39)            | 0.001   |
| days          |                    |                     |         |
+---------------+--------------------+---------------------+---------+

\* Wilcoxon 2-sample test, extracted from sponsor Table 6, p.28 of
vol.1.079.

Cumulative duration of abstinence during the treatment phase was a
secondary efficacy endpoint. It measured the total time the patient was
abstinent by the sum of all periods of complete abstinence. The sponsor
reported a significantly longer average CAD with Acamprosate (224.62
days) than with placebo (162.03 days), p=0.0002. This reviewer confirmed
the results, see Table 6. This reviewer also reported the median
cumulative abstinence duration days since the distribution appeared to
be not normally distributed. These medians of the CAD were 135 days with
placebo and 270 days with acamprosate.

Given that the placebo treated patients had less exposure to the
treatment, it is likely that had the 60% placebo treated patients
compared to the 42% Acamprosate treated patients continued the treatment
longer, the already lower abstinence rate in placebo (40% vs. 51% with
Method I, 12% vs. 29% with Method II, and 11% vs. 27% with Method III)
would probably continue to be lower if not much lower.

To assess CAD as a fraction of the duration of treatment, the sponsor
calculated the corrected cumulative abstinence duration (CCAD). The CCAD
analysis reported by the sponsor was consistent with the CAD analysis.

#### • REVIEWER'S SUMMARY {#reviewers-summary-2 .unnumbered}

The sponsor concluded in the study report "Acamprosate tablets,
administered over 48 weeks were consistently more efficacious than
placebo in maintaining abstinence in alcoholic patients previously
weaned from alcohol." This reviewer confirmed the findings. The early
discontinuation rates were marginally different (60% vs. 48%), whereas
the corresponding times to discontinuation difference were 169 days
(\~5.6 weeks) with placebo and 337 days (\~11.2 weeks) with acamprosate,
which was nominally statistically significantly with p=0.006.

In summary, Acamprosate was shown to have longer time to first relapse,
higher percentage of continuous abstinence during the treatment phase
and higher percentage of cumulative abstinence rate as compared to
placebo. Further investigation suggested that a higher percentage of
patients completed the study without relapsed to drinking with
Acamprosate (31%) compared to placebo (15%), and that among those who
discontinued the study early, a lower percentage of Acamprosate treated
patients (21%) relapsed compared to placebo treated patients (35%).

## US96.1  {#us96.1 .unnumbered}

#  {#section-3 .unnumbered}

Acamprosate in patients with alcohol dependence: a double-blind, placebo
controlled safety and efficacy study at two active dose levels

#### • STUDY SYNPOSIS {#study-synposis .unnumbered}

This was a multicenter (21 US centers), double-blind, randomized,
placebo controlled 3-arm 24-week study. The study was initiated in May
1997 and completed in January 1999 (\~1.7 years). Eligible ambulatory
patients aged 18 or older, who were alcohol dependent according to the
DSM-IV criteria of the American Psychiatric Association and who had been
withdrawn from alcohol or who had completed medicated detoxification
within ≥2 to ≤10 days of study entry, were passively stratified on the
basis of medicated (inpatient or outpatient) detoxification vs.
non-medicated withdrawal and then randomized to receive placebo or
Acamprosate 2000 mg/day (median dose) or Acamprosate 3000 mg/day (high
dose) for 24 weeks. Subsequent to the 24 weeks treatment phase (but with
continued study blinding), all subjects were to be followed for an
additional two months (follow-up phase).

During the treatment phase, all patients were given standardized
medication management/supportive psychotherapy at each visit by a
qualified therapist and according to a protocol-specific manual,
entitled "Brief Intervention and Medication Compliance Procedures". The
alcohol measurement collection according to the Alcohol Timeline Follow
Back (TLFB) schedule during the 24 weeks treatment phase (bolded)
followed by an additional 2 months without Acamprosate therapy was as
follows.

  ---------- -------------- --------- --------- --------- ---------- ---------- ---------- ---------- ----------- ------
  Visit0     **V1**         **V2**    **V3**    **V4**    **V5**     **V6**     **V7**     **V8**     V9          V10

  Baseline   **Wk1**        **Wk2**   **Wk4**   **Wk8**   **Wk12**   **Wk16**   **Wk20**   **Wk24**   Wk25        Wk32

  Baseline   **Treatment                                                                              Follow-up   
             (6-months)**                                                                             (2mon)      
  ---------- -------------- --------- --------- --------- ---------- ---------- ---------- ---------- ----------- ------

It is noted that after the first month of treatment, patients were
contacted by telephone at weekly intervals to reinforce compliance and
for supportive purposes in between their monthly regular visits. The
study schema can be found in page 15 of the original protocol (p.18 of
vol.1.102; also p.47 of vol.1.099).

The protocol has a section on summarizing drinking measures and related
assessments. Specifically, if inconsistencies remain unresolved on
alcohol consumption between sources, the most negative outcome was to be
assumed. Alcohol consumption was recorded in standardized drinks. In
addition, a number of efficacy assessments were usually self-reports,
but for the purposes of this study, unless so-specified, the majority of
the questionnaires were administered to the patient by study personnel.

**The objectives** were (1) to confirm efficacy and safety of oral
Acamprosate tablets in US alcohol-dependent patients, at a total daily
dose of 2000 mg/day (1000 mg bid) in association with standardized but
minimal psychosocial support, guided by a protocol-specific manual; (2)
to explore the efficacy and safety of Acamprosate at a total daily dose
of 3000 mg/day (1500 mg bid); (3) to explore the efficacy and safety of
Acamprosate therapy when initiated within ≥2 to ≤10 days of any
hazardous drinking (\>2 drinks/day for females, \>3 drinks per day for
males) or completion of medicated detoxification.

**The primary efficacy endpoints** were (1) time to first day of any
drinking[^2]; (2) time to first day of heavy drinking[^3] ( ≥6 drinks
for men, ≥4 drinks for women); (3) cumulative abstinence duration[^4];
and (4) rate of complete abstinence[^5]. Secondary efficacy endpoints
were alcohol consumption, alcohol craving, gamma-glutamyl transpeptidase
(GGT), clinical global impression and study retention. The primary
safety endpoints were (1) review and evaluation of all treatment
emergent signs and symptoms, (2) evaluation of effects on laboratory
parameters, to include hematology, blood chemistries, and routine
urinalysis, and (3) evaluation of any medical changes.

For sample size estimation, the sponsor indicated in the protocol that
'sample size is based on an evaluation of CAD and abstinence rates from
European trials of Acamprosate. This sample size is projected to have
80% power to show a significant difference of approximately 23 days in
CAD between Acamprosate 2000 mg/day and placebo." The only parameter
specified in the sample size estimation was the difference in CAD of 23
days. The sponsor planned 198 patients per group in Acamprosate 2000
mg/day arm and placebo arm and 64 patients in Acamprosate 3000 mg/day
exploratory dose arm. In the sponsor's NDA report, it was stated that
"the study was originally projected to have 80% power to show a
significant difference of 23 abstinent days (80 days versus 103 days,
SD=78) between Acamprosate 2000 mg/day and placebo, assuming a 10%
dropout rate." However, the dropout rates were 45% (placebo) and 59%
(Acamprosate 2000 mg/day) after the trial completion.

**Handling of missing data**: lost-to-follow-up patients were considered
"treatment failures." "Unavailable data for patients who terminate the
study early for reasons other than lost to follow-up or treatment
failure (e.g., patient's decision, sponsor's decision) will remain
missing in all analyses."

After the final protocol (dated February 22, 1997), there were two
amendments: amendment #1 related to the exclusion criteria modification
and amendment #2 related to modification of the inclusion criteria.

#### • OVERVIEW OF THE STUDY RESULTS AND REVIEWER'S EVALUATION AND COMMENTS {#overview-of-the-study-results-and-reviewers-evaluation-and-comments-2 .unnumbered}

The NDA report was dated November 19, 2001. Of those 741 patients
screened, 601 patients were randomized to receive Acamprosate 2000
mg/day (n=258) (median dose), Acamprosate 3000 mg/day (n=83) (high dose)
or placebo (n=260). The intent-to-treat population or the all efficacy
population was based on 592 patients. The main interest was the
comparison between Acamprosate 2000 mg/day vs. placebo and Acamprosate
3000 mg/day group was a dosage exploratory arm. The mean age at entry
was 44 years and 68% of the patients were males. Baseline
characteristics were comparable between the treatment groups.

##### - PATIENT ACCOUNTABILITY {#patient-accountability-3 .unnumbered}

Patient accountability during the treatment phase was summarized in
Table 1. No death occurred in any of the three treatment arms.

Acamprosate 2000 mg/day group (41%=106/258) had the lowest percentage of
patients who completed the study followed by Acamprosate 3000 mg/day
(52%=43/83) and placebo (55%=143/260), nominal global p=0.0054.
Numerically more patients discontinued the study early with Acamprosate
than with placebo. 'Patient decision' and 'lost to follow-up' appeared
to be the major reasons of discontinuation that showed an imbalance
between placebo and Acamprosate 3000 mg/day group vs. Acamprosate 2000
mg/day group. Distribution of percent of patients available over the
treatment period can be found in **Figure 1**.

####### Table 1. Patient Accountability of early discontinued patients during treatment phase -- US 96.1 Trial^§^ {#table-1.-patient-accountability-of-early-discontinued-patients-during-treatment-phase-us-96.1-trial .unnumbered}

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td>AE</td>
<td>IMP</td>
<td>AEC</td>
<td>PV</td>
<td>TF</td>
<td><strong>PD</strong></td>
<td>IV</td>
<td>SP</td>
<td>LFU</td>
<td>Othr</td>
</tr>
<tr class="even">
<td><p>Placebo</p>
<p>n=260</p></td>
<td><p>6</p>
<p>2%</p></td>
<td><p>1</p>
<p>&lt;1%</p></td>
<td><p>2</p>
<p>&lt;1%</p></td>
<td><p>1</p>
<p>&lt;1%</p></td>
<td><p>13</p>
<p>5%</p></td>
<td><p><strong>54</strong></p>
<p><strong>21%</strong></p></td>
<td><p>3</p>
<p>1%</p></td>
<td><p>2</p>
<p>&lt;1%</p></td>
<td><p><strong>33</strong></p>
<p><strong>13%</strong></p></td>
<td><p>2</p>
<p>&lt;1%</p></td>
</tr>
<tr class="odd">
<td><p>A2000mg</p>
<p>N=258</p></td>
<td><p>6</p>
<p>2%</p></td>
<td><p>4</p>
<p>2%</p></td>
<td><p>4</p>
<p>2%</p></td>
<td><p>0</p>
<p>0%</p></td>
<td><p>13</p>
<p>5%</p></td>
<td><p><strong>71</strong></p>
<p><strong>28%</strong></p></td>
<td><p>4</p>
<p>2%</p></td>
<td><p>1</p>
<p>&lt;1%</p></td>
<td><p><strong>47</strong></p>
<p><strong>18%</strong></p></td>
<td><p>2</p>
<p>&lt;1%</p></td>
</tr>
<tr class="even">
<td><p>A3000mg</p>
<p>N=84</p></td>
<td><p>2</p>
<p>2%</p></td>
<td><p>1</p>
<p>1%</p></td>
<td><p>0</p>
<p>0%</p></td>
<td><p>0</p>
<p>0%</p></td>
<td><p>4</p>
<p>5%</p></td>
<td><p><strong>18</strong></p>
<p><strong>22%</strong></p></td>
<td><p>4</p>
<p>5%</p></td>
<td><p>0</p>
<p>0%</p></td>
<td><p><strong>10</strong></p>
<p><strong>12%</strong></p></td>
<td><p>1</p>
<p>1%</p></td>
</tr>
</tbody>
</table>

^§^ Extracted from sponsor in-text Table 6.1 of vol.1.099 (p.77);
confirmed by this reviewer.

![](media/image7.wmf)AE: adverse event; IMP: intercurrent
medical/psychological event; AEC: appearance of exclusion criteria; PV:
Protocol violation; TF: treatment failure; **PD: patient decision**; IV:
investigator decision; SP: sponsor decision; **LFU: lost to follow-up**;
Othr: other.

####### Figure 1. % of patients available over time -- US 96.1 Trial {#figure-1.-of-patients-available-over-time-us-96.1-trial .unnumbered}

##### - TIME TO DISCONTINUATION {#time-to-discontinuation-2 .unnumbered}

This reviewer performed an analysis of time to discontinuation using the
electronic data information on days on study. Results are summarized in
Table 2. The estimated median times were 168 days (5.6 months) with
placebo and 136 days (4.5 months) with Acamprosate 2000 mg/day.
Acamprosate 3000 mg/day had similar treatment exposure time (164 days)
as that of placebo. A longer and similar time to discontinuations were
observed for high dose Acamprosate (220 days) and placebo (211 days),
but the median dose Acamprosate had the median time to discontinuation
(136 days).

####### Table 2. Time to discontinuation in days -- US96.1 Trial^§^ {#table-2.-time-to-discontinuation-in-days-us96.1-trial .unnumbered}

+---------------------+--------------+---------------+---------------+
|                     | Placebo      | Acamp 2000    | Acamp 3000    |
|                     |              | mg/d          | mg/d          |
|                     | N=260        |               |               |
|                     |              | N=258         | N=83          |
+---------------------+--------------+---------------+---------------+
| Treatment phase     | 168 (1, 271) | 136 (1, 249)  | 164 (1, 218)  |
| only                | days         | days          | days          |
|                     |              |               |               |
| Median (95% CI)     |              |               |               |
+---------------------+--------------+---------------+---------------+
| Treatment +         | 211 (1, 316) | 136 (1, 299)  | 220 (1, 294)  |
| Follow-up phase     | days         | days          | days          |
|                     |              |               |               |
| Median (range)      |              |               |               |
+---------------------+--------------+---------------+---------------+

^§^ based on the electornic data information on days on study

In summary, the placebo arm and Acamprosate 3000 mg/day arm had one
month longer exposure to the treatment than Acamprosate 2000 mg/day arm
during the treatment phase and a total of two months longer exposure
including the follow-up phase. In addition, the dropout rates were
significantly higher with Acamprosate 2000 mg/day arm (59%) than with
placebo (45%), nominal p=0.0015. It appeared that data indicated an
informative censoring and differential dropout pattern.

##### - PRIMARY EFFICACY ENDPOINTS {#primary-efficacy-endpoints .unnumbered}

The sponsor summarized the results of the protocol specified primary
efficacy endpoints, see the sponsor's In-Text Table 8.7.4.1:1. This
reviewer confirmed the sponsor's analysis results in the In-Text Table
8.7.4.1:1 with two minor differences. The median time to first heavy
drinking was 15 days. The mean was 45.8% and the median was 39% for CCAD
with Acamprosate 2000 mg/day treatment. These analysis results were
based on the intent-to-treat population. The resulting p-values for the
comparison between placebo and Acamprosate 2000 mg/day were 0.253 (χ2
test) for percentage of patients who relapsed to drinking (or who were
completely abstinent during the treatment period), 0.596 (log-rank test)
for time to first drink, 0.238 (log-rank test) for time to first heavy
drink, 0.071 (Wilcoxon rank sum test) for CAD analysis, and 0.134
(Wilcoxon rank sum test) for CCAD analysis, respectively.

The median dose Acamprosate (2000 mg/day) failed to show a superior
treatment effect on all the protocol specified efficacy endpoints.

According to the sponsor's report, "for the ITT Population, the
proportion of patients who had undergone alcohol detoxification prior to
randomization and the overall proportion of patients who were abstinent
prior to starting study medication was low. The percentage of patients
who had detoxification prior to randomization was 12% in the Acamprosate
1998/2000 mg/day group, 7% in the Acamprosate 3000 mg/day group, and 10%
in the placebo group. In contrast to the European studies, only about
50% of the patients in all 3 groups were abstinent at Baseline." The
percents of patients having a treatment goal of total abstinence were
40%, 32%, and 45% in the Acamprosate 1998/2000, Acamprosate 3000 and
placebo groups.

####### In‑Text Table 8.7.4.1:1 Summary of Originally Planned Efficacy Analyses -- ITT Population -- US Short-Term Supportive Efficacy Study {#intext-table-8.7.4.11-summary-of-originally-planned-efficacy-analyses-itt-population-us-short-term-supportive-efficacy-study .unnumbered}

+------------------------+--------+-----------+----------+-----------+
| **\                    | **\    | **ACAMP\  | **ACAMP\ | **\       |
| Parameter**            | Stati  | 2000      | 3000     | Placebo** |
|                        | stic** | mg/day**  | mg/day** |           |
+------------------------+--------+-----------+----------+-----------+
| Number of Patients     | N      | 255       | 82       | 258       |
| Randomized             |        |           |          |           |
+------------------------+--------+-----------+----------+-----------+
| Number of Patients Who | n (%)  | 233 (92%) | 74 (90%) | 227 (89%) |
| Relapsed to Drinking   |        |           |          |           |
+------------------------+--------+-----------+----------+-----------+
| Time to First Drink    | Median | 4         | 4        | 4         |
| (days)                 |        |           |          |           |
+------------------------+--------+-----------+----------+-----------+
| Time to Heavy Drinking | Median | 14        | 17       | 12        |
| (days)                 |        |           |          |           |
+------------------------+--------+-----------+----------+-----------+
| Cumulative Abstinence  | N\     | 253\      | 82\      | 256\      |
| Duration (CAD) (days)  | Mean   | 72.3      | 81.5     | 83.3      |
|                        | (SE)   | (3.7)\    | (7.1)\   | (3.9)\    |
|                        |        | 56        | 75       | 78        |
|                        | Median |           |          |           |
+------------------------+--------+-----------+----------+-----------+
| CCAD (%)               | N      | 253\      | 82\      | 256\      |
|                        |        | 45.5      | 49.9     | 51.2      |
|                        | Mean   | (2.2)\    | (4.1)\   | (2.2)\    |
|                        | (SE)   | 38        | 47       | 53        |
|                        |        |           |          |           |
|                        | Median |           |          |           |
+------------------------+--------+-----------+----------+-----------+
| Data Source: Final     |        |           |          |           |
| Study Report, Appendix |        |           |          |           |
| I.10.8, Tables 5.1.1,  |        |           |          |           |
| 5.2.1, 5.3.1, 5.4.1.   |        |           |          |           |
+------------------------+--------+-----------+----------+-----------+

Note: Percentages are based on the number of patients randomized.

##### - CHANGE OF PRIMARY EFFICACY ENDPOINT {#change-of-primary-efficacy-endpoint .unnumbered}

The sponsor argued the need to restructure the intended statistical
analysis plan because European outcome parameters that were contingent
on a population abstinent at baseline (e.g., time to first drink and
rate of complete abstinence) were not relevant in the largely
non-abstinent US sample. In the US population, patients neither achieved
total abstinence at the time of randomization, nor were the expectations
regarding detoxification fulfilled. In other words, 50% of the patients
had not discontinued drinking at randomization (100% in European trials)
and only 10% of patients underwent medicated detoxification (primarily
outpatient) (100% in European trials). Details of the differences
between the three European pivotal trials (Paille, Pelc II and PRAMA)
and the US 96.1 Trial can be found in the Appendix -- US96.1 of this
review.

##### - NEW PRIMARY EFFICACY ENDPOINT  {#new-primary-efficacy-endpoint .unnumbered}

The sponsor's post-hoc defined new primary efficacy endpoint was
cumulative abstinence duration[^6] (CAD). The actual endpoint used for
the analysis was CCAD, the corrected cumulative abstinence duration. New
secondary efficacy endpoints were categorization of CAD (good, partial
and poor responders), rate of complete abstinence during the last
treatment phase visit interval, the change from baseline in number of
standard drinks per week and number of drinking days per week, and
average alcohol consumption during the treatment phase relative to
baseline. **Note that for all efficacy parameters, information on daily
drinking was based primarily on the patient's Alcohol Timeline Follow
Back Interview.**

The sponsor defined five populations of interest. They are (1) **ITT
population** (all randomized patients who took at least one dose of
double-blind study medication), (2) **safety population** (all patients
in the safety population but for whom some post-baseline efficacy data
were recorded), (3) **efficacy evaluable population** (EFF, 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,
and were at least 75% compliant for the duration of their participation
in the treatment phase, (4) **motivated ITT population** (all patients
in the ITT population who had a treatment goal of complete abstinence),
(5) **motivated EFF population** (all patients in the EFF population who
had a treatment goal of complete abstinence).

###### **CCAD (Corrected Cumulative Abstinence Duration)** {#ccad-corrected-cumulative-abstinence-duration .unnumbered}

According to the sponsor, "For the purposes of statistical testing of
CCAD, models were fit via ANCOVA \[Neter J, Wasserman W, Kutner M.
Applied linear statistical models. Richard D. Irwin, Inc, Homewood,
Illinois, 1990:861‑906\] to ranked data because of the nonnormal
distribution of CCAD. All reported p‑values are from analyses of the
ranked response values. CCAD was statistically significantly greater
(p≤0.044) in the Acamprosate 1998/2000 mg/day group compared to the
placebo groups in all 4 analysis

populations after adjusting for baseline covariates (pooled site,
baseline CGI-severity, stage of readiness to change, psychological
antecedent, addiction index, and goal of abstinence) and treatment
exposure (defined as study drug compliance multiplied by treatment
duration divided by 100). In a second model excluding treatment
exposure, the difference between the Acamprosate 1998/2000 mg/day and
placebo groups approached statistical significance for the Motivated ITT
and Motivated EFF populations (p=0.100

and p=0.068, respectively). Differences between the Acamprosate
1998/2000 mg/day and placebo groups for the least-squares means from
both models were greater for the Motivated ITT and Motivated EFF
populations compared to the ITT and EFF populations."

####### In-Text Table 8.7.4.7:2 Corrected Cumulative Abstinence Duration (CCAD) (%): Treatment Group Comparisons and Adjusted Means -- US Short-Term Supportive Efficacy Study -- All Efficacy Popns {#in-text-table-8.7.4.72-corrected-cumulative-abstinence-duration-ccad-treatment-group-comparisons-and-adjusted-means-us-short-term-supportive-efficacy-study-all-efficacy-popns .unnumbered}

+-----------------------+-----------+----------+----------+----------+
| **\                   | **\       | **ACAMP\ | **\      | **\      |
| \                     | \         | 1        | \        | \        |
| Population**          | St        | 998/2000 | P        | P        |
|                       | atistic** | mg/day** | lacebo** | -Value** |
+-----------------------+-----------+----------+----------+----------+
| Intent-to-Treat       | n\        | 253      | 256\     | 0.044\*  |
|                       | LSMean    |          | 52.3     |          |
|                       | (1)       | 58.2\    |          | 0.296    |
|                       |           | 56.8     | 53.4     |          |
|                       | LSMean    |          |          |          |
|                       | (2)       |          |          |          |
+-----------------------+-----------+----------+----------+----------+
| Efficacy Evaluable    | n\        | 177\     | 198\     | 0.023\*  |
|                       | LSMean    | 62.3     | 54.8     |          |
|                       | (1)       |          |          | 0.157    |
|                       |           | 60.6     | 55.8     |          |
|                       | LSMean    |          |          |          |
|                       | (2)       |          |          |          |
+-----------------------+-----------+----------+----------+----------+
| Motivated             | n\        | 100\     | 115\     | 0.021\*  |
| Intent-to-Treat       | LSMean    | 70.0     | 58.1     |          |
|                       | (1)       |          |          | 0.100    |
|                       |           | 68.3     | 59.0     |          |
|                       | LSMean    |          |          |          |
|                       | (2)       |          |          |          |
+-----------------------+-----------+----------+----------+----------+
| Motivated Efficacy    | n\        | 71\      | 86\      | 0        |
| Evaluable             | LSMean    | 75.5     | 59.4     | .008\*\* |
|                       | (1)       |          |          |          |
|                       |           | 73.0     | 61.3     | 0.068    |
|                       | LSMean    |          |          |          |
|                       | (2)       |          |          |          |
+-----------------------+-----------+----------+----------+----------+
| Data Source: Table    |           |          |          |          |
| 8.7.3.5.1, US study   |           |          |          |          |
| report Tables 5.1.1   |           |          |          |          |
| and 5.1.3.            |           |          |          |          |
+-----------------------+-----------+----------+----------+----------+

\* Significant at the 0.050 level; \*\* significant at the 0.010 level.
The test was based on the ranked ANCOVA.

Note: LSMean (1) was obtained from an ANCOVA model including treatment
exposure, pooled site, Baseline CGI-

severity, stage of readiness to change, psychological antecedent,
addiction index, and goal of abstinence.

LSMean (2) was obtained from the same model with the exclusion of
treatment exposure. P‑values from both models

were based on a rank ANCOVA with the specified effects.

#### REVIEWER'S EVALUATION AND COMMENTS

The post-hoc ANCOVA model#1 chosen by the sponsor included seven
covariates. In a subsequent submission dated March 20, 2002, the sponsor
provided a detailed explanation of the covariates. They were

\(1\) treatment exposure -- compliance x treatment duration / 100

\(2\) pooled site (identified in the analysis plan), 3 sites which
randomized \<15 patients were pooled into one

\(3\) baseline CGI-severity -- CGI severity at baseline ranges from 1 to
7

\(4\) stage of readiness to change -- composed of 3 scales:
precontemplation, contemplation and action

\(5\) psychological antecedent -- dependent on 3 questions from the
Psychiatric History in CRF, 1: at least one of the antecedents had
occurred, 0: otherwise

\(6\) addiction index -- FTND5CAT x IDUICAT. FTND5CAT was based on the
baseline total for the Fagerstrom Test for Nicotine Dependence, for
which possible values range from 0 to 10 and was recoded to 0 to 4.
IDUICAT, based on the Illicit Drug Use Index (ranged from 0 to \>1000)
was recoded to 0 to 3

\(7\) goal of abstinence -- 1: if a patient's treatment goal was
complete abstinence, 0: otherwise

The post-hoc ANCOVA model#2 chosen by the sponsor contained six
covariates, which excluded treatment exposure from model#1 stated above.

Significant contributions of the covariates in the ANCOVA Model#1 were
Treatment (global p-value=0.02), RCQSTAGE (nominal p=0.01), PSYANT2L
(p=0.01), ABSGOAL (p\<0.0001) and treatment exposure (p\<0.0001). In
contrast, in addition to those significant covariates observed in
Model#1, ADDICIN5 (addiction index) (p=0.003) became significant but the
treatment effect (global p=0.0669) disappeared in the ANCOVA Model#2,
which excluded the treatment exposure covariate that is potentially
related to outcome measures.

Appropriateness of the Model #1 is of concern. First, the CCAD (or the
PDA percent duration of abstinence) was calculated by adjusting the
cumulative abstinence days (CAD) for the discontinuation of alcohol.
Thus, treatment exposure has been accounted for in the CCAD derivation.
By including in the model the treatment exposure as an independent
covariate (while it should not be because it is potentially treatment
related because of differential time of discontinuation and differential
dropout), it is questionable whether the resulting estimated treatment
difference can be unambiguously interpreted. The inclusion of the seven
covariates was not pre-specified in the protocol. In addition, how the
cutoff values of these derived covariates (excluding pooling centers,
which were pre-specified in the protocol) were selected was not
discussed in the protocol either. It is noted that the patient numbers
were reasonably balanced across the centers, e.g., 3% to 4% were from
Volpicelli site, and 4% to 5% were from O'Malley site, 6% to 7% from
Anton site, 7% from Mason site, etc. The original Naltrexone drug
approval was based on Volpicelli et al. trial and O'Malley et al. trial.

####### Table 3. Corrected Cumulative Abstinence Duration (CCAD) (%): Treatment Group Comparisons and Adjusted Means -- US Short-Term Supportive Efficacy Study -- All Efficacy Populations (ITT) {#table-3.-corrected-cumulative-abstinence-duration-ccad-treatment-group-comparisons-and-adjusted-means-us-short-term-supportive-efficacy-study-all-efficacy-populations-itt .unnumbered}

+-------------------+--------+-----------+----------+---------+-------+
| **Intent-to-treat | **Pla  | **Ac      | **Aca    | **p-    | **p-  |
| Population**      | cebo** | amprosate | mprosate | value** | value |
|                   |        | 2000      | 3000     |         | **^¦^ |
|                   |        | mg/d**    | mg/d**   | **      |       |
|                   |        |           |          | median: | **    |
|                   |        | **(median | **(high  | pbo**   | high: |
|                   |        | dose)**   | dose)**  |         | pbo** |
+-------------------+--------+-----------+----------+---------+-------+
| N                 | 256    | 253       | 82       |         |       |
+-------------------+--------+-----------+----------+---------+-------+
| Unadjusted        | 54.3   | 56.1      | 60.7     | 0.703   | 0.205 |
| mean^§^           |        |           |          |         |       |
+-------------------+--------+-----------+----------+---------+-------+
| Unadjusted        | 59     | 59        | 63       |         |       |
| median^§^         |        |           |          |         |       |
+-------------------+--------+-----------+----------+---------+-------+
| LS Means #1^§^    | 52.3   | 58.2      | 62.7     | 0.044   | 0.009 |
+-------------------+--------+-----------+----------+---------+-------+
| LS Means #2^§^    | 53.4   | 56.8      | 63.1     | 0.296   | 0.021 |
+-------------------+--------+-----------+----------+---------+-------+

^§^ Extracted from the In-Text Sponsor Table 6.12 and Table 6.13 of
vol.1.099 based on ranked ANCOVA, confirmed by this reviewer.

^¦^ The nominal p-value under the column heading "p-value high:pbo" was
provided by this reviewer

Excluding the treatment exposure, as those labeled "the Model #2", the
treatment effect was no longer statistically significant (p-value is
large). This reviewer further explored the ANCOVA analyses by always
including the treatment effect term and the pooled center term in the
model. When one covariate was included, none of the models showed a
significant Acamprosate median dose effect, even adjusted only for the
potentially outcome related treatment exposure or only for the treatment
goal. It was the combination of treatment goal and treatment exposure
that began to appear to show a significant Acamprosate median dose
effect. In fact, inclusion of a subset of the five covariates would
sometimes appear to show a statistically significant median dose effect,
but not always so.

The Acamprosate 2000 mg/d group and the placebo group had the same raw
median value of CCAD, see Table 3. Although there was only 1/3 of the
sample size for Acamprosate 3000 mg/day group as compared to the
Acamprosate 2000 mg/d and the placebo, the estimated median CCAD was
numerically higher. Patients treated with Acamprosate 3000 mg/day began
to show a significantly higher percentage CAD after adjustment for the
treatment goal. The effect became clearer after adjustment for treatment
goal in addition to the stage of readiness to change, the psychological
antecedent, and the addiction index individually.

This reviewer also explored repeated measure analysis and GEE analysis
on the total heavy drinking days and on the total any drinking days
efficacy outcomes. There was no significant Acamprosate 2000 mg/day
effect over time. An apparently significant Acamprosate 3000 mg/day
effect was observed based on the heavy drinking days, but not on the any
drinking days.

####### Figure 2. Observed mean on heavy drinking days at each study visit --US 96.1 Trial {#figure-2.-observed-mean-on-heavy-drinking-days-at-each-study-visit-us-96.1-trial .unnumbered}

![](media/image8.wmf)

When the data were summarized at each visit alone on the observed data,
as shown in the Figure 2 (heavy drinking days), it appeared that the
Acamprosate 2000 mg/day group showed a consistently larger mean heavy
drinking days and a numerically similar or larger median heavy drinking
days as compared to the placebo group. Although the Acamprosate 3000
mg/day group had only 1/3 of the patient size compared to the
Acamprosate 2000 mg/day and placebo groups, a much lower number of heavy
drinking days across all the visits appeared to be evident. In contrast,
the distribution of any drinking days at each visit was comparable among
all the 3 treatment groups although the Acamprosate 3000 mg/day group
seemed to have numerically lower number of any drinking days, as
depicted in Figure 3.

####### Figure 3. Observed mean on any drinking days at each study visit -- US 96.1 Trial {#figure-3.-observed-mean-on-any-drinking-days-at-each-study-visit-us-96.1-trial .unnumbered}

####  {#section-4 .unnumbered}

#### ![](media/image9.wmf) {#section-5 .unnumbered}

#### • SAFETY {#safety .unnumbered}

According to the sponsor, no deaths occurred. The overall incidence of
adverse events, serious adverse events, and premature withdrawals due to
adverse events was similar among treatment groups. Overall, the most
frequent adverse events were **diarrhea** and **headache**, but **only
diarrhea had a higher incidence in the Acamprosate treatment groups**.
Diarrhea was reported by 18% in placebo, 33% in Acamprosate 2000 mg/day
group and 40% in Acamprosate 3000 mg/day group, nominal p\< 0.001.
Diarrhea, as either a primary or secondary reason, resulted in premature
study termination in 2% with low dose acamprosate, 2% with high dose
acamprostae, and \<1% with placebo. Details of the safety evaluation can
be found in the medical safety reviewer's review and evaluation
document.

#### • REVIEWER'S SUMMARY {#reviewers-summary-3 .unnumbered}

There were significantly more dropouts in the primary treatment
comparison arm (Acamprosate 2000 mg/day) as compared to placebo or
Acamprosate 3000 mg/day exploratory treatment arm. These dropout rates
were 59%, 48% and 45% for the Acamprosate median dose, high dose and
placebo, respectively. In addition, treatment exposure time was one
month shorter with the primary treatment group than with the high dose
and placebo groups during the treatment period and two months shorter
through the follow-up period. Acamprosate 2000 mg/day treatment failed
to show a significant treatment effect based on the originally defined
primary efficacy endpoints. The post-hoc defined CCAD adjusted for the
discontinuation of alcohol and the post-hoc defined and included
covariates (baseline CGI-severity, stage of readiness to change,
psychological antecedent, addiction index, and goal of complete
abstinence) or potentially treatment related treatment exposure were
carefully assessed. It appeared that partial inclusion of the post-hoc
covariates may or may not reach a statistically significant effect with
Acamprosate 2000 mg/day compared to placebo. It is noted that the
primary comparison of interest in this US trial was the median dose
Acamprosate (2000 mg/day) versus the placebo. This study did not show an
effect of Acamprosate 2000 mg/day treatment without any adjustment on
the covariates. Adjustment of treatment goal alone (a subjective
covariate) or treatment exposure alone (an outcome related covariate)
still failed to demonstrate a significant Acamprosate 2000 mg/day
effect.

From the repeated measure analysis, the GEE analysis and the cross
sectional analysis of the total heavy drinking days and the total any
drinking days, no statistically significant Acamprosate 2000 mg/day
effect was observed. Acamprosate 2000 mg/day appeared to have
numerically similar or more heavy drinking days than the placebo. The
details were provided on page 32.

Although Acamprosate 3000 mg/day treatment was only an exploratory arm
and had only 1/3 of the patient size, it has comparable dropout rate and
treatment exposure compared to the placebo. It appeared that this high
dose arm might have a favorable (often statistically significant) higher
percent of cumulative abstinence duration, lower number of heavy
drinking days over time and have similar number of any drinking days
over time.

# 3 CONCLUSION {#conclusion .unnumbered}

Four placebo controlled studies (Pelc II, Paille, PRAMA and US 96.1)
were considered pivotal trials by FDA. All four studies appeared to show
differential dropouts. In particular, all three European studies had
higher dropout rates in the placebo group than the Acamprosate group(s).
In contrast, the US study had significantly more dropouts and shorter
treatment exposure in the primary comparison treatment arm (Acamprosate
2000 mg/day) as compared to placebo and the exploratory treatment arm
(Acamprosate 3000 mg/day).

The European trials did not have the timeline follow back drinking data.
The 3-month study (Pelc II) showed a significant Acamprosate (1332 mg/d
and 1998 mg/d) effect on abstinence rates based on both the LOCF type
and the conservative type analyses.

The 1-year (360 days) study (Paille) failed to show a significant
Acamprosate effect on 1332 mg/d dose group (the primary comparison
group) for most main efficacy criteria (also stated in the sponsor's
conclusion), although a seeming Acamprosate effect on 1998 mg/d dose
group was observed). It is noted that the second objective of showing a
superior complete abstinence rate with Acamprosate (1332 mg/d and 1998
mg/d) was not achieved through the observation phase.

The 48-weeks (1-year) study (PRAMA) showed that Acamprosate had a longer
time to first relapse, a higher percentage of continuous abstinence
during the treatment phase and a higher percentage of cumulative
abstinence rate as compared to placebo. Further investigation suggested
that there appeared to be a higher percentage of patients completing the
study without relapsed to drinking with Acamprosate (31%) compared to
placebo (15%), and that among those who discontinued the study early
there appeared to be a lower percentage of Acamprosate treated patients
(21%) relapsed compared to placebo treated patients (35%). The
Acamprosate arm included patients administered with 1332 mg/d dosage and
1998 mg/d dosage, depending on patients' baseline weight ( ≥60 kgs vs.
\< 60 kgs), in this study.

The 24-weeks (6-months) study (US 96.1), however, had the timeline
follow back drinking data. Not all patients were abstinent at baseline.
About 50% of the patients had not discontinued drinking at randomization
(100% in European trials) and only 10% of patients underwent medicated
detoxification (primarily outpatient) (100% in European trials). It
appeared that data indicated an informative censoring and differential
dropout pattern. The median dose Acamprosate (2000 mg/day) (the primary
comparison treatment arm) failed to show a superior treatment effect on
all the protocol specified efficacy endpoints.

This study did not show an effect of Acamprosate 2000 mg/day treatment
without any adjustment on the covariates. Post-Hoc adjustment of
treatment goal (a subjective covariate) alone or treatment exposure (a
potential treatment related variable because of differential time to
discontinuation and differential dropout) alone still failed to
demonstrate a significant Acamprosate 2000 mg/day effect. It appeared
that partial inclusion of the post-hoc covariates may or may not reach a
statistically significant effect with Acamprosate 2000 mg/day compared
to placebo. The insignificant results were further supported by the
repeated measure analysis and the GEE analysis and the cross sectional
analysis of the total heavy drinking days and the total any drinking
days.

Although Acamprosate 3000 mg/day treatment was only an exploratory arm
and had only 1/3 of the patient size, it has comparable dropout rate and
treatment exposure compared to the placebo. It appeared that this high
dose arm might have a favorable (often statistically significant) higher
percent of cumulative abstinence duration, lower number of heavy
drinking days over time and have similar number of any drinking days
over time.

> Sue-Jane Wang, Ph.D.

Senior Mathematical Statistician

Statistics Leader in alcohol treatment trials

Concur: S. Edward Nevius, Ph.D.

Division Director, HFD-715

cc:

HFD-170/McCormick, Winchell, Sevka, Basham

HFD-715/Anello, Nevius, Permutt, Wang

SWANG/04-03-2002/acamprosate_nda.doc

This review consists of 37 pages including the Appedix

# 4 APPENDIX  {#appendix .unnumbered}

######## US 96.1 {#us-96.1 .unnumbered}

####### Table 8.7.4.4:1 Demographic Characteristics at Baseline -- US Short-Term Supportive Efficacy Study ITT Pop. {#table-8.7.4.41-demographic-characteristics-at-baseline-us-short-term-supportive-efficacy-study-itt-pop. .unnumbered}

+---------------------+---------+----------+-------------+------------+
| **\                 | **\     | **ACAMP\ | **\         | **\        |
| \                   | \       | 1        | ACAMP\      | \          |
| \                   | \       | 998/2000 | 3000        | Placebo\   |
| Characteristic**    | Stat    | mg/day\  | mg/day\     | (N=257)**  |
|                     | istic** | (        | (N=82)**    |            |
|                     |         | N=253)** |             |            |
+---------------------+---------+----------+-------------+------------+
| Gender              | n       | 253      | 82          | 257        |
+---------------------+---------+----------+-------------+------------+
| > Males             | n (%)   | 176      | 59 (72%)    | 166 (65%)  |
|                     |         | (70%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| > Females           | n (%)   | 77 (30%) | 23 (28%)    | 91 (35%)   |
+---------------------+---------+----------+-------------+------------+
| Age (years)         | n       | 253      | 82          | 257        |
+---------------------+---------+----------+-------------+------------+
|                     | Mean    | 44.9     | 43.6 (1.0)  | 44.4 (0.6) |
|                     | (SE)    | (0.7)    |             |            |
+---------------------+---------+----------+-------------+------------+
|                     | Min.,   | 23, 72   | 21, 66      | 22, 69     |
|                     | Max.    |          |             |            |
+---------------------+---------+----------+-------------+------------+
| Age Distribution    | n       | 253      | 82          | 257        |
| (years)             |         |          |             |            |
+---------------------+---------+----------+-------------+------------+
| > 16-39             | n (%)   | 82 (32%) | 27 (33%)    | 88 (34%)   |
+---------------------+---------+----------+-------------+------------+
| > 40-59             | n (%)   | 143      | 50 (61%)    | 139 (54%)  |
|                     |         | (57%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| > ≥ 60              | n (%)   | 28 (11%) | 5 ( 6%)     | 30 (12%)   |
+---------------------+---------+----------+-------------+------------+
| Weight (kg)         | n       | 252      | 82          | 257        |
+---------------------+---------+----------+-------------+------------+
|                     | Mean    | 80.7     | 80.9 (1.9)  | 78.9 (1.0) |
|                     | (SE)    | (1.0)    |             |            |
+---------------------+---------+----------+-------------+------------+
|                     | Min,    | 51, 134  | 48, 136     | 46, 134    |
|                     | Max     |          |             |            |
+---------------------+---------+----------+-------------+------------+
| Marital Status      | n       | 253      | 82          | 257        |
+---------------------+---------+----------+-------------+------------+
| > Married           | n (%)   | 117      | 34 (41%)    | 133 (52%)  |
|                     |         | (46%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| > Not Married       | n (%)   | 136      | 48 (59%)    | 124 (48%)  |
|                     |         | (54%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| Detoxification      | n       | 253      | 82          | 257        |
| Prior to            |         |          |             |            |
| Randomization       |         |          |             |            |
+---------------------+---------+----------+-------------+------------+
| > Yes               | n (%)   | 31 (12%) | 6 (7%)      | 25 (10%)   |
+---------------------+---------+----------+-------------+------------+
| > No                | n (%)   | 222      | 76 (93%)    | 232 (90%)  |
|                     |         | (88%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| Abstinent at        | n       | 253      | 82          | 257        |
| Baseline            |         |          |             |            |
+---------------------+---------+----------+-------------+------------+
| > Yes               | n (%)   | 132      | 40 (49%)    | 127 (49%)  |
|                     |         | (52%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| > No                | n (%)   | 121      | 42 (51%)    | 130 (51%)  |
|                     |         | (48%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| Duration of Alcohol | n       | 253      | 82          | 257        |
| Dependence/Abuse    |         |          |             |            |
| (years)             |         |          |             |            |
|                     |         |          |             |            |
| > \<10              |         |          |             |            |
| >                   |         |          |             |            |
| > ≥10               |         |          |             |            |
+---------------------+---------+----------+-------------+------------+
|                     | Mean    | 13.0     | 12.5 (1.0)  | 12.6 (0.5) |
|                     | (SE)    | (0.6)    |             |            |
+---------------------+---------+----------+-------------+------------+
|                     | Min.,   | 1, 42    | 1, 40       | 1, 41      |
|                     | Max.    |          |             |            |
+---------------------+---------+----------+-------------+------------+
|                     | n (%)   | 101      | 30 (37%)    | 107 (42%)  |
|                     |         | (40%)    |             |            |
+---------------------+---------+----------+-------------+------------+
|                     | n (%)   | 152      | 52 (63%)    | 150 (58%)  |
|                     |         | (60%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| Average Standard    | n       | 253      | 82          | 257        |
| Drinks per day in   |         |          |             |            |
| Recent Past         |         |          |             |            |
+---------------------+---------+----------+-------------+------------+
| > \<5               | n (%)   | 62 (25%) | 32 (39%)    | 71 (28%)   |
+---------------------+---------+----------+-------------+------------+
| > 5-10              | n (%)   | 115      | 25 (30%)    | 111 (43%)  |
|                     |         | (45%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| > \>10              | n (%)   | 76 (30%) | 25 (30%)    | 75 (29%)   |
+---------------------+---------+----------+-------------+------------+
| Prior treatments or | n       | 253      | 82          | 257        |
| detoxes for         |         |          |             |            |
| Alcoholism          |         |          |             |            |
+---------------------+---------+----------+-------------+------------+
| > 0                 | n (%)   | 171      | 59 (72%)    | 192 (75%)  |
|                     |         | (68%)    |             |            |
+---------------------+---------+----------+-------------+------------+
| > 1                 | n (%)   | 35 (14%) | 11 (13%)    | 27 (11%)   |
+---------------------+---------+----------+-------------+------------+
| > 2                 | n (%)   | 21 ( 8%) | 7 ( 9%)     | 8 ( 3%)    |
+---------------------+---------+----------+-------------+------------+
| > 3                 | n (%)   | 7 ( 3%)  | 2 ( 2%)     | 16 ( 6%)   |
+---------------------+---------+----------+-------------+------------+
| > \>3               | n (%)   | 19 ( 8%) | 3 ( 4%)     | 14 ( 5%)   |
+---------------------+---------+----------+-------------+------------+
| Data Source: Table  |         |          |             |            |
| 8.7.3.2.1, Table    |         |          |             |            |
| 8.7.3.3.1           |         |          |             |            |
+---------------------+---------+----------+-------------+------------+

Note: Percentages are based on the number of patients in the ITT
population with an assessment.

######## DIFFERENCES BETWEEN THE US AND EUROPEAN (PAILLE, PRAMA, PELC II) STUDIES {#differences-between-the-us-and-european-paille-prama-pelc-ii-studies .unnumbered}

Comparing the ITT population of the US study to the ITT population in
the 3 pivotal efficacy studies with regard to these characteristics,
several observations are worth noting. The percentage of males was
smaller in the US (68%) study compared to the 3 pivotal efficacy studies
(80% across the studies). Patients in the US study were of a similar age
to patients in the 3 pivotal efficacy studies (mean age of 45 years in
the US compared to 42 years in the pivotal studies). Patients in the US
study were heavier (mean body weight of 80 kg) than patients in the 3
pivotal efficacy studies (mean body weight of 71 kg). Only 10% of
patients in the US study had undergone detoxification prior to
randomization compared to 100% of patients in the pivotal efficacy
studies (by virtue of the recruitment process). The mean duration of
alcohol dependence was greater in the US study (13 years) than in the
pivotal efficacy studies (10 years), but patients in the US study drank
much less at Baseline (30% drank more than 10 standard drinks \[12 g of
pure alcohol per standard drink\] per day) than patients in the pivotal
efficacy studies (73% drank more than 10 standard drinks per day). Fewer
patients in the US study (29%) had at least 1 prior treatment or
detoxification for alcoholism than in the pivotal efficacy studies
(58%). Another very important difference in the Baseline characteristics
in this study compared to the pivotal efficacy studies was that only 51%
of patients in the US study were abstinent at Baseline, while virtually
all of the patients in the pivotal efficacy studies were abstinent at
Baseline. Summary of the differences are listed below.

**[Dosage form]{.underline}**

\- In European trials, Acamprosate was administered as a 333 mg tablet
formulation given 3 times daily, primarily at a total daily dose of 1998
mg/d (two 333 mg tablets tid) or 1332 mg/d (one 333 mg tablets tid);

\- In the US trial, Acamprosate was administered as a 500 mg tablet
formulation given twice daily, primarily at a total daily dose of 2000
mg/day (two 500 mg tablets bid) or 3000 mg/day (three 500 mg tablets
bid).

**[Criteria of total abstinence at study entry]{.underline}**

\- In European trials, total abstinence was explicitly required for
admission to the study

\- In the US trial, ambulatory outpatients with alcohol dependence who
had no hazardous drinking (\> 2 drinks per day for females; \>3 drinks
per day for males) or who had completed medicated detoxification without
≥2 to ≤10 days of randomization and who expressed a desire to cut down
or stop drinking" were enrolled

**[Medicated detoxification]{.underline}**

\- In European trials, patients were required to undergo medicated
detoxification typically inpatient

\- In the US trial, not all patients were undergone medicated
detoxification. The study was passively stratified prior to
randomization to assure equivalent distribution of detoxified patients
across treatment groups (only 10% of patients underwent medicated
detoxification primarily outpatient)

**[Patients' baseline characteristics]{.underline}**

\- In European trials, age limit (18 to 65 years of age)

\- In the US trial, there was no upper age limit, allowance for
non-dependent cannabis use at enrollment and other illicit drug use
during the study

**[Psychosocial support]{.underline}**

\- In European trials, followed a more naturalistic approach, with
variable non-structured psychosocial therapy, reflective of the
individual practice techniques of the participating site

\- In US trial, all participating patients received standardized,
manual-guided psychosocial support, consisting of brief intervention and
medication compliance procedures of established efficacy to support
abstinence

**[Other design features of the US study which were not typical of the
European studies]{.underline}**

\- Daily drinking diaries, maintained by the patient and received with
the therapist at each visit in conjunction with returned study
medication

\- Specially designed "reminder" blister packaging of study medication

\- Advertising to recruit study participants from outside the existent
clinical practice of participating site

\- Weekly telephone contacts with study participants to supplement the
monthly visit to the site

\- Contracts with a close friend or relative specified by the patient to
evaluate the patient's progress

-   Mandatory follow-up algorithms for missed visits or missed telephone
    contacts, which included frequent attempts to contact the patient or
    collateral informant via phone and certified mail

[^1]: ^§^ A relapse was defined as follows:

    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

[^2]: First day of any drinking was defined as the earliest drinking
    episode identified by the patient or collateral informant, or by a
    positive breath alcohol concentration (\>0.003%)

[^3]: First day of heavy drinking was defined as the earliest heavy
    drinking day (≥4 drinks for women, ≥6 drinks for men) identified by
    the patient or collateral informant, or by a breath alcohol
    concentration consistent with intoxication (\>0.04%)

[^4]: CAD: the minimum number of abstinent (alcohol-free) days between
    visits, reported by the patient, collateral informant, or breath
    alcohol concentration results

[^5]: for rate of complete abstinence: non-abstinence was assumed if
    either the patient, collateral informant, or breath alcohol
    concentration indicate any alcohol consumption (≥0.003%)

[^6]: Treatment phase CAD was defined as the percentage of abstinent
    days while on study drug. For patients whose discontinuation was
    determined to be associated with alcohol use, the denominator for
    the Treatment Phase CAD was the anticipated duration of the
    Treatment Phase (the "uncensored" duration). The anticipated
    duration was calculated as the actual time on treatment plus the
    anticipated time required to complete all remaining visits per the
    protocol schedule. For patients whose discontinuation was determined
    to not be associated with alcohol use, the denominator of the
    treatment phase CAD was the actual time the

    patient participated in the study (the "censored" duration).