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

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).

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