Topiramate for the Treatment of Alcohol Dependence:

1


Topiramate for the Treatment of Alcohol
Dependence The Multi-Site Trial

Bankole A. Johnson, DSc, MD, PhD, MPhil,
FRCPsych Alumni Professor of Psychiatry and
Neurobehavioral Sciences Professor of
Neuroscience Professor of Medicine Chairman,
Department of Psychiatry and Neurobehavioral
Sciences University of Virginia Charlottesville,
VA
Main source Johnson BA, et al. JAMA
2007298(14)1641-1651.
Courtesy of Professor Bankole Johnson
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• Acute alcohol ? firing rate of inhibition of
  VTA-GABA neurons, thereby reducing their activity
  and promoting ? DA neuronal activity of
  cortico-mesolimbic neurons. Topiramate ? GABA
  inhibition at VTA and NAcc and ? GLU excitation
  at the same sites concomitantly these effects
  might attenuate alcohol-induced ? DA in
  cortico-mesolimbic neurons.
• Line weights (i.e., heavy, medium, and thin)
  denote relative strengths of neuronal activity.

Source Johnson BA. Alcohol Clin Exp Res
200428(8)1137-1144.
Courtesy of Professor Bankole Johnson
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• Chronic alcohol is associated with
  hyper-excitable VTA-GABA neurons due to ?
  GABA-ergic tone from NAcc to VTA and ? GLU
  sensitization, and relative VTA-DA hypo-function.
  Abrupt alcohol cessation would result in
  rebound ? DA neuronal activity, which could
  promote relapse. Topiramate ? GLU sensitization
  by ? AMPA GLU and ? L-type Ca2 channel currents
  and potentiating VTA-GABA neurons, thereby
  normalizing VTA-GABA neuronal activity. NAcc
  DA release is suppressed due to blockade of
  excitatory GLU afferents and facilitation of
  inhibitory GABA neuronal inputs to NAcc.
• Line weights (i.e., heavy, medium, and thin)
  denote relative strengths of neuronal activity.

Source Johnson BA. Alcohol Clin Exp Res
200428(8)1137-1144.
Courtesy of Professor Bankole Johnson
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Objective and Study Design

• Primary objective was to evaluate the safety and
  efficacy of topiramate as compared with placebo
  in the treatment of subjects with alcohol
  dependence.
• 14-week, outpatient, randomized, double-blind,
  placebo-controlled clinical trial was conducted
  at 17 sites in the United States.
• Study consisted of 4 phases a washout period
  from day ?35 (visit 1A) to day ?7 (visit 1B), a
  1-week screening period, a 6-week titration
  period, and an 8-week maintenance period.
• Written informed consent was obtained from all
  subjects before they underwent any study
  procedures, and ethical approval for the study
  was provided by the institutional review boards
  of all 17 of the participating sites.

Courtesy of Professor Bankole Johnson
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Inclusion Criteria

• Men and women between 18 and 65 years of age
• Current diagnosis of alcohol dependence as
  defined by the Diagnostic and Statistical Manual
  of Mental Disorders, 4th edition (DSM-IV)
• Drinking an average of ?28 standard drinks/ week
  (women) or ?35 standard drinks/week (men) during
  the 28 days prior to screening and during the
  7-day period between the screening visit and
  randomization
• Score of 8 on the Alcohol Use Disorders
  Identification Test
• Body mass index of gt18 kg/m2
• Negative urine toxicological screen for
  narcotics, amphetamines, antidepressants,
  propoxyphenes, and barbiturates
• Expressing a desire to stop or reduce the
  consumption of alcohol

Courtesy of Professor Bankole Johnson
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Exclusion Criteria

• Current Axis I psychiatric diagnosis on DSM-IV
  other than alcohol, nicotine, or caffeine
  dependence
• History in the last 6 months of substance abuse
  or dependence other than dependence on alcohol,
  nicotine, or caffeine
• Important alcohol withdrawal symptoms (score of
  gt10 on the revised Clinical Institute Withdrawal
  Assessment for Alcohol scale)
• More than four unsuccessful formal inpatient
  treatment attempts to curb alcohol dependence
• Clinically significant depression as defined by a
  total Montgomery-Asberg Depression Rating Scale
  score of gt24
• Suicidal ideation or suicide attempt in the past
  30 days
• Currently receiving treatment for alcohol
  dependence other than Alcoholics Anonymous

Courtesy of Professor Bankole Johnson
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Exclusion Criteria (continued)

• Clinically significant physical abnormalities on
  physical examination, electrocardiogram
  recording, hematological assessment, biochemistry
  including bilirubin concentration, and urinalysis
• History of or current renal impairment, renal
  stones, seizures, or unstable hypertension
• Progressive neurodegenerative disorders or
  clinically significant neurological disorders
  including seizures
• Currently pregnant or lactating
• Currently taking medications with a potential
  effect on alcohol consumption or a carbonic
  anhydrase inhibitor
• Compelled to receive treatment for alcohol
  dependence to avoid imprisonment, parole,
  probation, or loss of employment
• From the same household as another subject

Courtesy of Professor Bankole Johnson
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Treatment Regimen

• Patients were randomized to receive topiramate
  (n183) or placebo (n188).
• Study medication was dispensed in double-blind
  fashion for the efficacy determination period,
  which began at week 0 and finished at the end of
  week 14.
• The dose of the medication was titrated from
  weeks 0 to 6 to 300 mg/day or the maximum
  tolerated dose, and the achieved dose was
  maintained from weeks 6 to 14. Subjects must
  have achieved a minimum dose of 50 mg/day.
• All randomized subjects received brief behavioral
  compliance enhancement treatment (BBCET) as their
  psychosocial treatment. BBCET, a standardized,
  brief (i.e., delivered in about 15 minutes),
  psychosocial adherence enhancement procedure,
  emphasized that medication was crucial to
  changing the drinking behavior of
  alcohol-dependent individuals.

Courtesy of Professor Bankole Johnson
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Baseline Demographic and Psychopathological
Characteristics of Subjects
(Table continued on next slide)
Courtesy of Professor Bankole Johnson
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Baseline Demographic and Psychopathological
Characteristics of Subjects (continued)
Abbreviations SD, standard deviation CIWA-Ar,
revised Clinical Institute Withdrawal Assessment
for Alcohol scale. Self-reported alcohol
drinking reflects the average values during the
28-day period prior to the screening visit. All
other values refer to baseline (i.e., week 0).
Courtesy of Professor Bankole Johnson
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Trial Flow Diagram
707 Individuals screened  
336 Excluded 265 Did not meet inclusionor
met exclusioncriteria 31 Participant
choice 40 Lost to follow-up
371 Randomized
183 Randomized to receive topiramate
188 Randomized to receive placebo
4 Enrollment failures 2 Participant choice
2 Lost to follow-up 67 Did not complete trial
34 Limiting adverse event 16 Participant
choice 13 Lost to follow-up 3 Lack of
efficacy 1 Other
3 Enrollment failures 2 Limiting adverse
event 1 Lost to follow-up 41 Did not
complete trial 6 Limiting adverse event
19 Participant choice 7 Lost to follow-up
4 Lack of efficacy 5 Other
144 Completed trial
112 Completed trial
183 Included in primary analysis 183 Included in
safety analysis
188 Included in primary analysis 188 Included in
safety analysis
Courtesy of Professor Bankole Johnson
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Primary Efficacy Variable and Safety Assessment

• The primary efficacy variable was the percentage
  of heavy drinking days, defined as the number of
  days on which men and women consumed 5 and 4
  standard drinks/day, respectively, divided by the
  number of study days.

• The safety assessment included monitoring of
  retention and adverse events profile.
• Adverse events were coded according to the World
  Health Organization Adverse Reactions Terminology
  dictionary modified for topiramate (version 1992,
  3rd quarter).

Courtesy of Professor Bankole Johnson
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Statistical Analysis

• Data were analyzed with SAS version 9.1 (SAS
  Institute Inc., Cary, NC).
• A sample size of 184 subjects per group (N368
  total) was estimated.
• The aim was to achieve 90 power to detect a mean
  group difference of 11.5 in percentage of heavy
  drinking days at a two-sided 0.05 significance
  level.
• For the primary analysis, we tested the null
  hypothesis on the efficacy measures in all
  randomized participants by imputing data for all
  dropouts as relapse to the baseline measure
  (i.e., data from the 7-day period prior to taking
  the first dose of medication at week 0).
• This was done to provide the most conservative
  estimate for the difference in treatment effect
  between topiramate and placebo.

Courtesy of Professor Bankole Johnson
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Statistical Analysis (continued)

• For the pre-specified analysis, we tested the
  null hypothesis on the efficacy measures in all
  randomized participants who took at least one
  study medication dose and had at least one
  double-blind visit, without imputing missing data
  for dropouts.
• For both approaches, a repeated-measures model
  was used to analyze the primary efficacy measure,
  percentage of heavy drinking days. Covariates
  included treatment group, center, week, sex,
  baseline percentage of heavy drinking days,
  chronological age, age at onset of problem
  drinking, and treatment-by-week interaction.
• A fixed sequence procedure was used to control
  for type 1 error when determining the earliest
  time point at which the between-groups difference
  in percentage of heavy drinking days became
  statistically significant and was sustained for
  subsequent time points.

Courtesy of Professor Bankole Johnson
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Statistical Analysis (continued)

• The procedures basis was to test the
  between-groups difference in percentage of heavy
  drinking days at week 14 at the 0.05 significance
  level (two-tailed).
• If the difference at week 14 was significant,
  this procedure would be repeated for the
  preceding weeks until a time point was reached at
  which there was no difference.
• A finding of no significant difference at week 14
  would have stopped the comparison for the
  preceding weeks.
• The Kaplan-Meier method was used to calculate the
  cumulative probability function of reaching 28 or
  more days of continuous abstinence and 28 or more
  days of continuous non-heavy drinking for the
  topiramate and placebo groups.

Courtesy of Professor Bankole Johnson
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Percentage of Heavy Drinking Days from Study Week
1
The primary analytic approach of imputing missing
data with the baseline value is illustrated.
Courtesy of Professor Bankole Johnson
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Percentage of Heavy Drinking Days from Study Week
1
The pre-specified approach of not imputing
missing data is illustrated data were analyzed
using a repeated-measures mixed model.
Courtesy of Professor Bankole Johnson
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BBCET

• BBCET was successful at ensuring medication
  compliance
• The pill-taking rates were
• Topiramate 91.46 14.96
• Placebo 90.09 13.12

Courtesy of Professor Bankole Johnson
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Time to First Day of 28 or More Days of
Continuous Abstinence
The primary analytic approach of imputing missing
data with the baseline value is illustrated the
observed numbers of participants in the
topiramate group meeting this criterion were 27
of 183 compared with 6 of 188 in the placebo
group.
Courtesy of Professor Bankole Johnson
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Time to First Day of 28 or More Days of
Continuous Abstinence
The pre-specified approach of not imputing
missing data is illustrated the observed numbers
of participants in the topiramate group meeting
this criterion were 27 of 179 compared with 6 of
185 in the placebo group.
Courtesy of Professor Bankole Johnson
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Time to First Day of 28 or More Days of
Continuous Non-Heavy Drinking
The primary analytic approach of imputing missing
data with the baseline value is illustrated the
observed numbers of participants in the
topiramate group meeting this criterion were 54
of 183 compared with 28 of 188 in the placebo
group.
Courtesy of Professor Bankole Johnson
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Time to First Day of 28 or More Days of
Continuous Non-Heavy Drinking
The pre-specified approach of not imputing
missing data is illustrated the observed numbers
of participants in the topiramate group meeting
this criterion were 54 of 179 compared with 28 of
185 in the placebo group.
Courtesy of Professor Bankole Johnson
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Selected Adverse Events During Treatment
Occurring in 10 of Subjects in the Topiramate
Group
Plt0.05, chi-square test. If a subject
experienced more than one adverse event within a
category, the subject is counted once under that
category. Subjects with more than one occurrence
of an adverse event are summarized under the most
related category.
Courtesy of Professor Bankole Johnson
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Conclusions

• Topiramate is more efficacious than placebo in
  treating alcoholism as it
• Reduces heavy drinking
• Promotes abstinence

• Side-effect profile of topiramate is consistent
  with findings in epilepsy and migraine prevention
• The first evidence of efficacy was seen at 100
  mg/day, which was well tolerated, with few
  reported adverse events more data are needed to
  characterize the minimum effective dose
• Future studies elucidating the optimum dose that
  balances efficacy, tolerability, and compliance
  would be important

Courtesy of Professor Bankole Johnson