A Randomized, Double-blind Placebo-Controlled Pharmacogenetic Study of Topiramate in European-American Heavy Drinkers

• Status: Completed
• Trial end date: 2020-02-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Pennsylvania
• Collaborators: Corporal Michael J. Crescenz VA Medical Center; Department of Health and Human Services; National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institutes of Health (NIH)
• Treatments: Topiramate

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