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
Intervention: Topiramate; Medical Management; Inactive Placebo
Intervention description: 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
Intervention MeSH terms: Topiramate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 320.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Topiramate; Pharmacogenetics; Personalized Medicine

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Determined to be physically healthy, based on medical history and physical examination
             and approval of the study physician

          2. Age 18 to 70 years, inclusive

          3. Self-identified European ancestry

          4. Meets DSM-5 criteria for AUD

          5. Average weekly ethanol consumption of >24 standard drinks for men and >18 standard
             drinks for women, with a weekly average of > 2 HDDs during the month before screening

          6. Stated goal to reduce drinking to safe levels or to stop drinking

          7. Able to read English at an 8th grade or higher level and no gross cognitive impairment

          8. Willingness to nominate an individual who will know the subject's whereabouts to
             facilitate follow up during the study

          9. Women of child-bearing potential (i.e., who have not had a hysterectomy, bilateral
             oophorectomy, tubal ligation or is less than two years postmenopausal): must be
             non-lactating and practicing a reliable method of birth control, and have a negative
             urine pregnancy test prior to the initiation of treatment. Examples of medically
             acceptable methods for this protocol include: the birth control pill, intrauterine
             device, injection of Depo-Provera, Norplant, contraceptive patch, contraceptive ring,
             double-barrier methods (such as condoms and diaphragm/spermicide), male partner
             sterilization, abstinence (and agreement to continue abstinence or to use an
             acceptable method of contraception, as listed above, should sexual activity commence),
             and tubal ligation.

         10. Willingness to provide signed, informed consent and commit to completing the
             procedures in the study

        Exclusion Criteria:

          1. A current, clinically significant physical disease or abnormality on the basis of
             medical history, physical examination, or routine laboratory evaluation, including
             direct bilirubin elevations of >110% or a transaminase elevation >300% of normal

          2. A history of nephrolithiasis

          3. A history of glaucoma

          4. Current treatment with carbonic anhydrase inhibitors, due to the added risk of
             metabolic acidosis.

          5. Current, serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe or
             psychotic major depression, panic disorder, borderline or antisocial personality
             disorder, organic mood or mental disorders, eating disorder, or imminent suicide or
             violence risk)

          6. Current DSM-IV diagnosis of dependence on a drug other than alcohol or nicotine

          7. A history of hypersensitivity to topiramate

          8. Current regular treatment with a psychotropic medication (e.g., benzodiazepines,
             antidepressants), which affect neurotransmitter systems, or a medication to treat
             alcohol dependence

          9. Currently taking any tricyclic antidepressant (e.g., Adapin (doxepin), Anafranil
             (clomipramine), Elavil (amitryptyline), Pamelor (nortryptyline), Tofranil
             (imipramine), Sinequan (doxepin)

         10. Urine drug screen positive for recent use of opioids, cocaine, or amphetamines (may be
             repeated once and if the result is negative on repeat it is not exclusionary)

         11. Because co-administration of topiramate with dolutegravir reduced plasma
             concentrations of the antiretroviral through induction of CYP3A, the use of
             dolutegravir is exclusionary.

         12. Judged by the principal investigator or his designee to be an unsuitable candidate for
             receipt of an investigational drug