A Controlled Trial of Topiramate Treatment for Alcohol Dependence in Veterans With PTSD

Study Overview
=================
Brief Summary
-----------------
The goal of this project is to improve the treatment of veterans with co-occurring alcohol dependence and posttraumatic stress disorder (PTSD). The PI and co-investigators will conduct a controlled clinical trial of topiramate for the treatment of these co-occurring disorders.

Detailed Description
-----------------
This project consists of a controlled clinical trial of topiramate treatment to reduce alcohol use and PTSD symptoms in veterans with these co-occurring disorders. This is a prospective randomized double-blind controlled parallel groups clinical trial of topiramate or or placebo up to 300 mg per day, combined with weekly alcohol counseling, over a 12-week treatment period with a week 16 follow-up. The study population consists of 150 male and female veterans between the ages of 18-69 who have concurrent diagnoses of alcohol use disorder and PTSD. Subjects meet with research staff weekly to receive study medication, manualized alcohol counseling, and research assessments. The primary treatment outcome is the percent of days of drinking; the secondary outcome is PTSD symptom severity. Exploratory measures include assessments of impulsivity and decision-making.

Official Title
-----------------
A Controlled Trial of Topiramate Treatment for Alcohol Dependence in Veterans With PTSD

Conditions
-----------------
Alcohol Dependence, Posttraumatic Stress Disorder (PTSD)

Intervention / Treatment
-----------------
* Drug: Topiramate
* Drug: placebo
* Behavioral: Medical Management


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female veterans Ages18 to 69 (inclusive) Current DSM-IV diagnosis of PTSD Current (past month) DSM-IV diagnosis of an Alcohol Dependence Level of drinking must meet criteria for at-risk  or heavy drinking by NIAAA threshold (NIAAA 2007): at least 15 standard drinks per week on average over the 4 weeks prior to study entry for men and at least 8 standard drinks per week on average for women. Subjects must express a desire to reduce alcohol consumption with the possible long-term goal of abstinence. Female subjects must have a negative urine pregnancy test and must be either postmenopausal for at least one year, or practicing an effective method of birth control (e.g., surgically sterile, spermicide with barrier, male partner sterilization; or abstinent and agrees to continue abstinence or to use an acceptable method of contraception, as listed above, should sexual activity commence) Subjects must have a Breath Alcohol Concentration (BAC) of < 0.02% when signing informed consent. Exclusion Criteria: Psychotic disorders, bipolar disorder, dementia, or other psychiatric disorders judged to be unstable. Subjects known to have clinically significant unstable medical conditions, including but not limited to: Clinically significant renal disease and/or impaired renal function as defined by clinically significant elevation of blood urea nitrogen (BUN) or creatinine or an estimated creatinine clearance of < 60 mL/min AST and/or ALT >5 times the upper limit of the normal range and/or an increased serum bilirubin >2 times the upper limit of normal. Seizure disorders History of glaucoma. History of kidney stones. Concurrent participation in another treatment study. Female patients who are pregnant or lactating. Current Topiramate use or use within the past 4 weeks. Current medications for alcohol dependence (disulfiram, naltrexone, or acamprosate) or use in the past week. Needing acute medical detoxification from alcohol based on a score of 12 or more on the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-AD); Subjects who are legally mandated to participate in an alcohol treatment program. Subjects who have had a suicide attempt in the past 6 months or suicidal ideation in the 90 days prior to enrollment. Subjects who have previously been treated with topiramate for any reason and discontinued treatment due to an adverse event or due to a hypersensitivity reaction to topiramate, Subjects with seizure disorders that require anticonvulsant medications Subjects currently being treated with another anticonvulsant. Subjects who in the opinion of the investigator should not be enrolled in the study because of the precautions, warnings or contraindications outlined in the topiramate package insert.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topiramate<br>Topiramate capsules daily - up to 300 mg | Drug: Topiramate<br>* Experimental study drug<br>Behavioral: Medical Management<br>* Brief alcohol counseling<br>|
| Placebo Comparator: Placebo<br>Placebo capsules daily - up to 300 mg | Drug: placebo<br>* Placebo comparator<br>Behavioral: Medical Management<br>* Brief alcohol counseling<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percentage of Heavy Drinking Days Over the 12 Weeks of Study Treatment as Assessed by the Timeline Followback (TFLB) | Timeline Followback (TLFB) data was recorded using a calendar, with participants providing retrospective reports of daily drinking over the past week(s). The percent of heavy drinking days per week was calculated from the calendar data. The change in percentage of heavy drinking days was calculated by subtracting Week 0 (baseline) data from Week 12. Negative scores indicate improvement. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PTSD Symptom Severity as Assessed by the PTSD Checklist (PCL) | The PCL is a 17-item self-report measure reflecting DSM-IV symptoms of PTSD. A total symptom severity score (range = 17-85) can be obtained by summing the scores from each of the 17 items that have response options ranging from 1 Not at all to 5 Extremely. It was calculated by subtracting the data collected at Week 0 (baseline) from data collected at Week 12. Negative scores indicate improvement. | Baseline to Week 12 | 
| Change in Impulsivity as Assessed by Delay Discounting (DD) | DD measures impulsivity by evaluating discount rates for delayed rewards. On a computer screen, the participant is shown hypothetical dollar amounts that could be received immediately, while a hypothetical $100 reward is displayed continuously. The delay duration is the waiting period for the $100 delayed reward. The computer randomly presents each immediate reward dollar amount, one at a time and participants are asked to choose between each immediate reward or the delayed $100. The same procedure will be repeated for each of the delay periods. Delay discounting quantifies the devaluation of rewards over time, which allows for an index of overall discounting rate (k). Higher k values indicate greater discounting and therefore greater impulsivity. DD score change was measured by subtracting Week 0 (baseline) scores from Week 12 scores, with negative scores representing improvement. | Baseline to Week 12 | 
| Change in Risk-taking Behavior as Assessed by the Balloon Analogue Risk Task (BART) | BART is a computerized measure of risk taking behavior that displays a computer-generated balloon on a computer monitor. Participants gradually pump (inflate) the balloon. Each pump adds 5 cents to a temporary bank. After each pump, participants have 2 options, 1) continue to pump the balloon and risk bursting it, losing all the money from that balloon, or 2) saving the accumulated money to a permanent bank. Whenever a balloon bursts or the participant chooses to bank money, they start with a new balloon. Participants respond to 30 balloons, each having a different bursting point. With each pump, participants weigh the potential gain of collecting more money against the risk of losing all money accumulated with that balloon. Greater number of pumps indicates greater risk taking. Change was calculated by subtracting Week 12 scores from Week 0 (baseline), with negative scores representing improvement and positive scores representing worsening risk taking. | Baseline to Week 12 | 
| Change in Decision-making Behavior as Assessed by the Iowa Gambling Task (IGT) | The Iowa Gambling Task (IGT) is a computerized assessment that evaluates decision-making by tracking the selection of advantageous or disadvantageous electronic cards from four decks. Subjects are presented the 4 decks of cards on a computer screen and are told that they can win money by picking cards from the most advantageous deck. After each deck selection, subjects are provided feedback as to whether their selection resulted in a win or a loss and the dollar amount of the win/loss. Data indicate change from baseline in mean number of cards selected from advantageous decks minus number of cards selected from disadvantageous decks as a function of drug condition. Change measured by substracting Week 0 (baseline) scores from Week 12 scores. Higher numbers indicate better decision making regarding advantageous cards. | Baseline to Week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pharmacotherapy, alcohol dependence, Veterans