Topiramate to Reduce Heavy Drinking in HIV-Positive Heavy Drinkers

A. General Design: This study will employ an 11-week, parallel-groups design (TOP vs.
placebo) to test the effects of topiramate (TOP) on HD by HIV+ individuals with a current
alcohol use disorder. We will gradually increase the dosage of TOP from 25 mg/day to 150
mg/day over a 6-week period to minimize adverse events. Random assignment to treatment group
and double-blind conditions will be maintained throughout the study.

B. Recruiting: HIV+ men and women will be recruited through advertisements and by
collaboration with physicians in the University of Pennsylvania Health System (UPHS) who
will be invited to refer patients for whom heavy drinking in their HIV+ patients has created
medical concerns. Patients will be recruited using the following methods: through referrals
to the research center at the University of Pennsylvania (UPenn); by posting/distributing
recruitment materials in community settings with public posting areas or other means of
providing community access to materials (such as hospitals, town halls, public libraries,
YMCA, health fairs/organizations); and through advertisements in local media (including text
ads in newspapers, magazines; radio ads on local radio stations; web ads on internet sites
and web postings on community message boards and research listings). These methods have been
successful for Dr. Kranzler at the University of Pennsylvania and for many investigators at
the Treatment Research Center (TRC) at UPenn. The TRC is an active center for clinical
investigation and the staff and faculty there are highly experienced and capable in the
conduct of clinical trials such as this. We will use institution-approved recruitment
materials to advertise for regular or daily drinkers who are HIV+ and want to reduce their
drinking. We will obtain permission at selected locations before distributing or posting the
approved recruitment materials (to ensure that we comply with other institutions'
guidelines). We anticipate that approximately 40% of patients will be women and that
minority patients will be represented at least in proportion to the general population in
Philadelphia. Based upon the large number of potential patients and our success in
recruitment for prior studies, including those involving heavy drinkers, we are confident of
our ability to achieve our recruitment goals.

C. Study Visits: At the screening visit, patients will provide informed consent and their
reading ability will be evaluated, a medical and psychiatric history obtained. Blood and
urine samples will be taken for routine clinical laboratory evaluations (including GGTP),
drug screening, and pregnancy testing in females of reproductive potential. Patients will be
interviewed with the Structured Clinical Interview for DSM-IV (SCID). Patients who are
excluded will be referred to treatment.

The baseline visit will occur 1-14 days after the screening visit. Eligible patients will
undergo a research evaluation, complete a packet of questionnaires, complete cognitive
testing, and be interviewed by the research assistant. A physical examination will be
performed by a study physician or nurse practitioner. Eligible patients will receive their
first counseling session and first supply of study medication during a subsequent treatment
session the same day. We will use urn randomization, a probabilistic balancing procedure to
assign patients to medication group so that groups are balanced on key variables (Wei 1978):
sex, race (white or non-white), number of HD days in past month.

During the 11-week treatment period, patients will return to the clinic weekly for five
weeks while the dosage of the medication is gradually increased and then biweekly for six
weeks. For patient safety during travel, they will be instructed not to drink prior to study
visits. At each visit, the patient's breath alcohol level, weight, and vital signs will be
measured. They will complete questionnaires and cognitive testing, and be interviewed by the
research nurse about their use of concurrent medications, the occurrence of adverse events,
and protocol compliance and then receive the medical management intervention. During visit 9
(end of treatment week 11), patients will complete questionnaires and cognitive testing and
be interviewed by the research evaluator concerning their alcohol consumption. Patients will
be compensated for this end-of-treatment visit. Patients will also be interviewed by the
research nurse about their use of concomitant medications, occurrence of adverse events,
compliance with the protocol, and their assessment of the effectiveness and acceptability of
the treatment procedures (through the Medication Questionnaire; MED-Q). The nurse will
dispense 4 days of medication for the taper and instruct the patient on how to take the
medication during this period. Blood samples to measure serum GGTP will be obtained to
assess the validity of self-reported drinking. A study nurse or research coordinator will
call the patient one week after the endpoint visit to confirm that the subject completed the
medication taper. Continuing adverse events will be followed by the study nurse and
physician to their conclusion, as is feasible. Patients requesting (or clearly needing)
additional treatment for alcohol problems will be referred to local treatment centers. All
patients (including those who discontinue treatment prematurely) will be asked to complete
an end-of-treatment evaluation and to complete all scheduled assessments to facilitate
intention-to-treat (ITT) analyses. For patients who withdraw early and do not wish to
continue with study visits/procedures, all end-of-treatment procedures will be administered
at the time of withdrawal. Such patients will also be asked to undergo in-person or
telephone follow-up at end-of-treatment for collection of the remaining treatment-phase
Timeline Followback (TLFB) data.

D. Compensation: Patients will be compensated for their time and transportation.

E. Study Treatments: Throughout the study, we will maintain double-blind conditions with
respect to medication administration. The research nurse, who is experienced in the conduct
of alcohol pharmacotherapy trials, will deliver the medical management and monitor the
medication, including capsule counts to measure adherence. The physician will meet with the
patient initially, meet at least weekly with the nurse to discuss progress, and evaluate the
patient in the event of severe or persistent adverse effects. The nurse will dispense study
medications prescribed by the physician. Patients with severe psychological symptoms (e.g.,
suicidal thoughts) will be withdrawn from treatment and referred for appropriate clinical
care. An effort will be made to obtain outcome information on all randomized patients for
ITT analysis. In the medication condition, TOP will be administered at a maximum of 150
mg/day in two divided doses. TOP will be purchased commercially and formulated in opaque
capsules by the Investigational Drug Service (IDS) at the University of Pennsylvania School
of Medicine, which will purchase the TOP commercially and formulate the medication in
capsules. Placebo will be formulated to match the active medication, such that inspection of
the capsules will not permit the two to be differentiated.

F. Assessments:

Laboratory/Medical Assessments: These assessments are included to screen patients for
medical exclusion criteria, assess potential adverse effects of medications, and corroborate
self-reported drinking. Prior to entrance into the study, each patient will receive:

- A physical examination

- Urinalysis and urine toxicology

- Complete Blood Count (CBC)

- Gamma-Glutamyl Transferase Levels (GGTP)

- A chemistry panel (which includes electrolytes, liver enzymes, bilirubin, uric acid)

- Pregnancy testing in women of reproductive age (conducted at screening and then at the
midpoint of the trial).

At the midpoint and end of the 11-week treatment phase, GGTP will be repeated to corroborate
self-reported alcohol consumption. In addition to eliciting self-reported adverse events,
weight and vital signs (blood pressure and pulse) will be obtained at each treatment visit.

Psychological/Behavioral Assessments:

- Sociodemographic information and alcohol dependence family history will be obtained at
baseline.

- Locator information: At baseline, the research assistant will obtain information on
patient locators nominated by the patient, which helps to maintain patients in
treatment and enhances follow-up data collection.

- Psychiatric diagnosis: The Structured Clinical Interview(SCID-I/P; First et al. 2001)
for the Diagnostic and Statistical Manual-IV (DSM-IV) will be used at baseline to
classify patients according to the presence or absence of standard psychiatric
disorders according to DSM-IV (American Psychiatric Association 1994).

- Alcohol use patterns and medication adherence: The Timeline Followback (TLFB; Sobell
and Sobell 1992) will be used to estimate current medication adherence and alcohol
consumption and drinking at intake and at each subsequent study visit. This interview
procedure will provide quantity/frequency of alcohol consumption data for the period
prior to the interview and since the last interview.

- Cogstate computerized battery: To examine the cognitive effects of changes in drinking
behavior and of TOP treatment, we will administer the 20-minute battery biweekly. We
will use these tasks: Detection Task, Identification Task, One Card Learning Task, One
Back Memory Task, Shopping List Task, Groton Maze Learning Test.

- Iowa Gambling Task (IGT) (Decision Making and Impulsivity) [15 minutes]: The IGT
(Bechara et al. 1994) is a computerized gambling task intended to simulate real-world
decision making. Prior research indicates that it is sensitive to cognitive impairment
in HIV populations (Martin et al. 2004) as well as substance users. Because practice
effects are possible, the IGT will only be administered at baseline, midpoint (Visit
6), and endpoint (Visit 9).

- Depressive symptoms: Beck Depression Inventory (BDI)

- Medication adverse effects: Patients will provide subjective reports of adverse effects
at each study visit using a list of adverse medication effects derived from completed
studies of TOP for AD.

- Adherence to antiretroviral medication: We will use the Timeline Followback method to
determine the percentage of ART doses taken each day as prescribed.

- Checklist of Cognitive Complaints: Individuals will rate their perceived impairment in
everyday function in the domains of attention, memory, and decision making.

- General intellectual function: The Wechsler Test of Adult Reading (WTAR; Pearson
Education, Inc.)

- Dementia screening: The Mini Mental State Exam (MMSE)

Inclusion Criteria:

- Seropositive for HIV

- Age 18-70

- Report average of at least twice weekly heavy drinking

- Willing to reduce drinking to non-hazardous levels

- Verbal Intelligence Quotient (Verbal IQ) of 80 or higher

- Willing to provide signed informed consent

- Willing to nominate an individual to help locate the participant's whereabouts for
follow-up

- If female: non-lactating and practicing a reliable method of birth control

Exclusion Criteria:

- Current clinically significant and/or uncontrolled physical disease (e.g.,
pancreatitis, diabetes)

- History of nephrolithiasis

- Severe psychiatric illness (i.e., psychosis or mania)

- Current diagnosis of drug abuse or dependence (other than nicotine abuse/dependence
and cannabis abuse)

- Current diagnosis of alcohol dependence (AD) too severe for participation in a trial
in which the goal is reduced drinking

- Gross cognitive impairment

- Glaucoma

- Serious/confounding neurological disease (e.g, stroke, seizure)

- Pregnancy