A Randomized, Double-blind Placebo-Controlled Pharmacogenetic Study of Topiramate in European-American Heavy Drinkers
Condition: Alcoholism; Alcohol Use Disorder (AUD)
MeSH terms: Alcoholism; Alcoholic Intoxication
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to advance the effort to develop personalized pharmacotherapy
      for alcohol use disorders (AUDs). The investigators propose to conduct a 12-week,
      prospective, randomized clinical trial of the moderating effect of rs2832407 on the efficacy
      of TOP in reducing heavy drinking (HD) in 200 individuals of European descent with DSM-5 AUD.
      The investigators will stratify the randomization on genotype and oversample rs2832407*C
      homozygotes, the most TOP-responsive genotype, to ensure comparable numbers of patients in
      the four medication x genotype groups. The investigators will use daily data collection to
      examine changes in relevant process variables (e.g., alcohol expectancies) and their
      interaction with genotype and medication group as predictors of HD. The proposed study is
      innovative in that it will be the first prospective test of a pharmacogenetic hypothesis
      involving TOP; it will use daily reports to examine expectancies and how they interact with
      medication and genotype to predict HD; and it will enroll DSM-5 AUD patients whose goal is
      either to reduce or stop drinking, which will increase the study's external validity.
    

Detailed description: 
      This is a 12-week, prospective, randomized clinical trial of the moderating effect of
      rs2832407 on the efficacy of topiramate in reducing HD in 200 individuals of European descent
      with DSM-5 AUD. The investigators will stratify the randomization on genotype and oversample
      rs2832407*C homozygotes, the most topiramate-responsive genotype, to ensure comparable
      numbers of subjects in the four medication x genotype groups. The investigators will compare
      the efficacy of topiramate to placebo in reducing the frequency of HDDs in subjects with AUD
      using a two-arm, parallel-groups design. Subjects will either have a goal of reducing their
      drinking to safe levels or abstinence.

      The investigators will use daily data collection to examine changes in relevant process
      variables and their interaction with genotype and medication group as predictors of HD. At
      each visit, all subjects will receive Medication Management (Pettinati, Weiss et al. 2004),
      which was developed for the COMBINE Trial and which the investigators modified to be relevant
      for both reducing heavy drinking and promoting abstinence. Random assignment to treatment
      group and double-blind conditions will be maintained throughout the study. Raters will be
      trained in the reliable use of all assessments. The investigators will use serum GGTP and
      percent disialotransferrin (%dCDT), an improved assay for carbohydrate deficient transferrin,
      to validate subject reports. Following a one-week pre-treatment assessment period, subjects
      will receive 12 weeks of treatment, after which there will be a 6-day taper period, during
      which subjects will reduce their dosage of topiramate gradually and then discontinue it
      completely. Daily reports during the treatment period will be obtained using interactive
      voice response (IVR) to identify subjective correlates of medication effects and to monitor
      medication use. Following the 12-week treatment period, subjects will be asked to return to
      the clinic for 3-month and 6-month post-treatment follow-up visits to evaluate the durability
      of treatment effects.

      Two hundred men and women of European descent will be randomized to study medication.
      Subjects will be recruited using referrals from treatment programs throughout Philadelphia;
      IRB-approved advertisements on mass transit, on local radio and television stations and in
      newspapers, social media, and broadcast email messages at institutions that offer such a
      service and by posting/distributing recruitment materials in community and college settings.
      Respondents will initially be evaluated by telephone prior to an in-person visit to the
      Treatment Research Center of the University of Pennsylvania Perelman School of Medicine. The
      investigators will select subjects based on their genotype to ensure comparable numbers of
      individuals who are rs2832407*C-allele homozygotes and A-allele carriers. The investigators
      will block randomize subjects to balance the groups on treatment goal (i.e., reduced drinking
      or abstinence).
    

Intervention name(s): Topiramate; Medical Management; Inactive Placebo
Intervention type(s): Drug; Behavioral; Drug
Intervention description(s): Max therapeutic dose of 200mg/day; Medical Management (MM; Pettinati, 2004) will support subjects' efforts to reduce or stop their drinking. The study nurse makes direct recommendations for reducing drinking to sensible levels. The first session will use the brochure A Guide to Sensible Drinking (WHO 1996). The subject is provided with information about pharmacotherapy and the importance of adherence to topiramate/placebo. Subsequent treatment sessions (15-25 minutes) will be conducted at each study visit, during which the nurse will perform an assessment of the subject's drinking, monitor his/her medication adherence, and make recommendations to follow until the next visit. Men will be advised to consume no more than 3 drinks 4 times per week; women will be advised to consume no more than 2 drinks 4 times per week.; In capsules indistinguishable from topiramate capsules and gradually increased to a maximum equivalent of 200 mg of topiramate/day
Other intervention name(s): Topamax; MM
Intervention MeSH terms: Topiramate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Topiramate; Pharmacogenetics; Personalized Medicine