Alcohol Abuse, Alcoholism, PTSD
Conditions
Keywords
PTSD, Alcohol abuse, Alcoholism, Topiramate, Stress Disorder, Post Traumatic, Chronic Post-Traumatic Stress Disorder
Brief summary
The proposed project aims to: 1. Obtain a preliminary assessment of the efficacy of topiramate treatment in reducing alcohol use in veterans with Post Traumatic Stress Disorder (PTSD) and alcohol dependence; 2. Obtain preliminary assessments of safety/tolerability of topiramate in these patients; 3. Assess the feasibility of recruitment and retention for topiramate treatment in this comorbid population; and 4) to inform the design of a planned subsequent larger controlled trial of topiramate. PRIMARY HYPOTHESIS: Topiramate treatment combined with Medical Management alcohol counseling will be associated with a significant decrease in percent drinking days from baseline to end of treatment. SECONDARY HYPOTHESIS: There will be significantly less percent drinking days in the topiramate treatment group compared to the placebo group.
Detailed description
The goal of the proposed project is to improve the treatment of veterans with co-occurring Post Traumatic Stress Disorder (PTSD) and alcohol dependence. Exposure to the stresses of combat is known to be associated with risk for both PTSD and alcohol and other substance use. PTSD and alcohol use disorders occur frequently among returning OEF/OIF veterans. Alcohol and substance use are risk factors for the development of PTSD, moderators of PTSD symptom severity, and potential consequences of PTSD. Alcohol is by far the most common substance of abuse in patients with PTSD, and its use may represent an attempt by PTSD patients to self-medicate symptoms such as hyperarousal. However, to date there has been little research to develop pharmacotherapies that would, ideally, reduce both alcohol use and PTSD symptoms. Topiramate is one of the few medications for alcohol dependence that has also been tested as a potential medication to treat PTSD. Topiramate's efficacy in alcohol dependence has been shown in two recent large controlled trials. Several open trials have suggested that topiramate may be effective in reducing PTSD symptoms while the results of two small controlled trials have been mixed. A clinical trial of topiramate is therefore indicated in order to achieve the following specific aims: The primary aim is to obtain a preliminary assessment of the efficacy of topiramate in increasing the percent of days abstinent from alcohol use from baseline to the end of treatment in veterans with PTSD and alcohol abuse/dependence who are drinking heavily. The secondary aim is to obtain a preliminary assessment of the efficacy of topiramate in increasing the percent of days abstinent from alcohol as compared to placebo. Additional aims include the following: * To obtain a preliminary assessment of the efficacy of topiramate in reducing other measures of alcohol use such as percent heavy drinking days, number of drinks per week, number of drinks per drinking day, and alcohol craving. * To obtain a preliminary assessment of the efficacy of topiramate in reducing PTSD symptom severity in veterans with chronic PTSD and alcohol abuse/dependence. * Informing the design of a planned subsequent larger controlled trial of topiramate in veterans with chronic PTSD and alcohol abuse/dependence * To obtain an estimate of topiramate vs. placebo effect size for future studies. B. To obtain a preliminary assessment of the effects of topiramate treatment on measures of risk-taking behavior in veterans with chronic PTSD and alcohol abuse/dependence. To achieve these aims, we will conduct a prospective, parallel groups, randomized, double-blind, placebo-controlled flexible-dose pilot clinical trial of topiramate in veterans with PTSD and alcohol abuse/dependence who are already receiving standard treatment for PTSD but still drink heavily. The primary treatment outcome will be percent days abstinent from alcohol; secondary outcomes will include other alcohol use measures, PTSD symptom severity, adverse effects, recruitment and retention rates.
Interventions
DRUGTopiramate
After random assignment, topiramate will be titrated up over 5 weeks. Dosing begins at 25 mg per day, and increase in the second week to 25 mg twice per day; in the third week to 50 mg twice/day; in the fourth week to 75 mg twice/day; in the 5th week to 100 mg twice/day; and in weeks 6-11 increased to and maintained at 100 mg in the morning and 200 mg at night. Patients will receive the highest dose tolerated, not to exceed 300 mg per day. Adjustments are permitted throughout titration. Once maximum tolerated dosage is reached, subjects will be asked to maintain dosage for remainder of the treatment phase. Upon completing the 6 week maintenance period subjects will taper off over a 7-day period (Week 12). If subjects experience significant side effects, the dosage may be adjusted.
OTHERPlacebo administration
Placebo pills will be prepared by the UCSF pharmacy which will be indistinguishable from the topiramate pills used in that arm. Both topiramate and placebo will then be delivered to the VA pharmacy. A consulting biostatistician will randomly assign participants to either the topiramate or placebo group. The dosing of placebo pills will follow the same regimen as outlined for the topiramate arm. In the event of a safety issue, there will be a procedure for unblinding only that participant.
Sponsors
United States Department of Defense
US Department of Veterans Affairs
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and female outpatient veterans. * Current DSM-IV diagnosis of PTSD. * Current (past month) DSM-IV diagnosis of an Alcohol Use Disorder. * Must meet criteria for heavy or at-risk drinking by NIAAA thresholds. * Receiving treatment for PTSD. * Must express desire to reduce alcohol consumption. * Female subjects must have negative urine pregnancy test and must be either postmenopausal for at least one year, or practicing an effective method of birth control. * Must have a BAC of less than 0.02% when signing the 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 BUN or creatinine or an estimated creatinine clearance of \< 60 mL/min; AST (SGOT) and/or ALT (SGPT) \>3 times the upper limit of the normal range and/or an increased serum bilirubin \>2 times the upper limit of normal; seizure disorders. * Subjects with glaucoma. * Subjects with a history of kidney stones. * Subjects with a history of renal disease. * 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 or use within the past 4 weeks. * 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 or suicidal ideation in the 6 months 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Drinking Days (%DD) | Weekly, weeks 1-12, average | Alcohol consumption was assessed at baseline and weekly during the treatment phase (12 weeks) using the Time Line Follow Back (TLFB) interview which yields number of days of alcohol use (DD). DD: day on which alcohol was consumed Standard alcoholic drink defined as containing 13.6 g of pure alcohol. |
Other
| Measure | Time frame | Description |
|---|---|---|
| PTSD Symptom Severity | Weeks 4, 8, 12 | The average PTSD symptom severity score during treatment (weeks 4, 8, 12). The PTSD Checklist (PCL) is a self-report measure of the 17 DSM-IV symptoms of PTSD. Respondents rate on a scale from 1 (not at all) to 5 (extremely) how much they were bothered by each symptom in the past month. A total symptom severity score (range = 17 - 85) can be obtained by summing the scores from the 17 items, with higher scores indicating greater severity of PTSD symptoms. Mean scores may be calculated for subscales of intrusion (range 5-25), avoidance (range 7-35), and arousal (range 5-25). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Topiramate Topiramate: topiramate titrated up over 5 weeks, beginning at 25 mg per day, and increased in the second week to 25 mg twice per day; in the third week to 50 mg twice/day; in the fourth week to 75 mg twice/day; in the 5th week to 100 mg twice/day; and in weeks 6-11 increased to and maintained at 100 mg in the morning and 200 mg at night. Upon completing the 6 week maintenance period dosage was tapered off over a 7-day period (Week 12). | 14 |
| Placebo Placebo: Placebo pills prepared by the UCSF pharmacy were indistinguishable from the topiramate pills used in that arm. The dosing of placebo pills followed the same regimen as outlined for the topiramate arm. In the event of a safety issue, there would be a procedure for unblinding only that participant. | 16 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Topiramate | Total |
|---|---|---|---|
| Age, Continuous | 50.4 years STANDARD_DEVIATION 12.8 | 49.5 years STANDARD_DEVIATION 13.9 | 50 years STANDARD_DEVIATION 13.1 |
| Alcohol Use Disorders Identification Test | 23.0 units on a scale STANDARD_DEVIATION 7.5 | 27.1 units on a scale STANDARD_DEVIATION 7.9 | 24.9 units on a scale STANDARD_DEVIATION 7.8 |
| Average drinks per drinking day | 10.9 Drinks STANDARD_DEVIATION 4.7 | 11.1 Drinks STANDARD_DEVIATION 6.1 | 11.0 Drinks STANDARD_DEVIATION 5.3 |
| Average drinks per week | 58.2 Drinks STANDARD_DEVIATION 25.4 | 52.4 Drinks STANDARD_DEVIATION 34.2 | 55.5 Drinks STANDARD_DEVIATION 29.4 |
| BAI | 27.4 units on a scale STANDARD_DEVIATION 13.3 | 20.4 units on a scale STANDARD_DEVIATION 12.7 | 24.0 units on a scale STANDARD_DEVIATION 13.3 |
| Baseline PTSD Symptomatology Arousal subscale | 26.4 units on a scale STANDARD_DEVIATION 4.1 | 23.5 units on a scale STANDARD_DEVIATION 6.7 | 25.0 units on a scale STANDARD_DEVIATION 5.6 |
| Baseline PTSD Symptomatology Avoidance subscale | 34.8 units on a scale STANDARD_DEVIATION 8.9 | 31.1 units on a scale STANDARD_DEVIATION 6.1 | 33.1 units on a scale STANDARD_DEVIATION 7.8 |
| Baseline PTSD Symptomatology Intrusion subscale | 21.9 units on a scale STANDARD_DEVIATION 6.9 | 18.2 units on a scale STANDARD_DEVIATION 4.3 | 20.2 units on a scale STANDARD_DEVIATION 6 |
| Baseline PTSD Symptomatology PTSD total score | 83.1 units on a scale STANDARD_DEVIATION 17.3 | 72.8 units on a scale STANDARD_DEVIATION 14.3 | 78.3 units on a scale STANDARD_DEVIATION 16.6 |
| BDI | 26.3 units on a scale STANDARD_DEVIATION 12.3 | 23.4 units on a scale STANDARD_DEVIATION 11.6 | 24.9 units on a scale STANDARD_DEVIATION 11.9 |
| Comorbid substance use disorder Comorbid substance use disorder absent | 11 participants | 9 participants | 20 participants |
| Comorbid substance use disorder Comorbid substance use disorder present | 5 participants | 5 participants | 10 participants |
| History of combat exposure Combat exposure | 12 participants | 10 participants | 22 participants |
| History of combat exposure No combat exposure | 4 participants | 4 participants | 8 participants |
| Percent drinking days per week | 80.4 percent days in a week STANDARD_DEVIATION 21.5 | 73.3 percent days in a week STANDARD_DEVIATION 30.3 | 77.1 percent days in a week STANDARD_DEVIATION 25.8 |
| Percent heavy drinking days per week | 72.6 percent days in a week STANDARD_DEVIATION 28.5 | 58.5 percent days in a week STANDARD_DEVIATION 33.7 | 66.0 percent days in a week STANDARD_DEVIATION 31.3 |
| Prior treatment for substance use disorder No prior substance use disorder treatment | 6 participants | 3 participants | 9 participants |
| Prior treatment for substance use disorder Outpatient treatment | 8 participants | 7 participants | 15 participants |
| Prior treatment for substance use disorder Residential treatment | 2 participants | 4 participants | 6 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment United States | 16 participants | 14 participants | 30 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 14 | 13 / 16 |
| serious Total, serious adverse events | 0 / 14 | 4 / 16 |
Outcome results
Primary
Percent Drinking Days (%DD)
Alcohol consumption was assessed at baseline and weekly during the treatment phase (12 weeks) using the Time Line Follow Back (TLFB) interview which yields number of days of alcohol use (DD). DD: day on which alcohol was consumed Standard alcoholic drink defined as containing 13.6 g of pure alcohol.
Time frame: Weekly, weeks 1-12, average
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate | Percent Drinking Days (%DD) | 19.5 percent days in a week | Standard Deviation 34.2 |
| Placebo | Percent Drinking Days (%DD) | 39.7 percent days in a week | Standard Deviation 36.5 |
Comparison: Our primary protocol-defined analysis was to examine the within-group efficacy of topiramate to reduce percent drinking days (%DD).p-value: 0.01995% CI: [0.89, 0.98]negative binomial regression
Comparison: There were no pre hoc hypothesis regarding change within placebo group. We were only tested change within the topiramate condition.p-value: 0Other
Comparison: A secondary analysis was powered to detect a Signal or statistical trend (p\<0.10) for a difference between the topiramate and placebo condition. We compared percent drinking days per week between groups averaged over the active phase of the trial (weeks 1-12). The negative binomial model included fixed effect for week, treatment group, and the interaction between treatment group and week. We covaried for baseline %DD averages to control for prestudy and study enrollment effects.p-value: 0.03695% CI: [0.15, 0.94]Negative binomial model
Other Pre-specified
PTSD Symptom Severity
The average PTSD symptom severity score during treatment (weeks 4, 8, 12). The PTSD Checklist (PCL) is a self-report measure of the 17 DSM-IV symptoms of PTSD. Respondents rate on a scale from 1 (not at all) to 5 (extremely) how much they were bothered by each symptom in the past month. A total symptom severity score (range = 17 - 85) can be obtained by summing the scores from the 17 items, with higher scores indicating greater severity of PTSD symptoms. Mean scores may be calculated for subscales of intrusion (range 5-25), avoidance (range 7-35), and arousal (range 5-25).
Time frame: Weeks 4, 8, 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Topiramate | PTSD Symptom Severity | PCL-C Avoidance (Weeks 1-12 Average) | 17.6 units on a scale | Standard Deviation 7.4 |
| Topiramate | PTSD Symptom Severity | PCL Total Score (Weeks 1-12 Average) | 42.3 units on a scale | Standard Deviation 16.4 |
| Topiramate | PTSD Symptom Severity | PCL-D Arousal (Weeks 1-12 Average) | 12.4 units on a scale | Standard Deviation 4.9 |
| Topiramate | PTSD Symptom Severity | PCL-B Intrusion (Weeks 1-12 Average) | 12.3 units on a scale | Standard Deviation 5.5 |
| Placebo | PTSD Symptom Severity | PCL-D Arousal (Weeks 1-12 Average) | 14.9 units on a scale | Standard Deviation 5 |
| Placebo | PTSD Symptom Severity | PCL-C Avoidance (Weeks 1-12 Average) | 19.9 units on a scale | Standard Deviation 6.9 |
| Placebo | PTSD Symptom Severity | PCL-B Intrusion (Weeks 1-12 Average) | 14.3 units on a scale | Standard Deviation 5.5 |
| Placebo | PTSD Symptom Severity | PCL Total Score (Weeks 1-12 Average) | 49.0 units on a scale | Standard Deviation 16.5 |
Comparison: We planned to explore the efficacy of topiramate in reducing PTSD symptom severity. We used random-intercept linear mixed models to explore the efficacy for topiramate related reduction in PTSD symptomatology. We looked for an effect of week within TOP. Baseline scores for PTSD symptoms were used as covariates in group comparisons. All analyses were intent-to-treat and used all observations from all weeks.p-value: <0.026Mixed Models Analysis
Comparison: There was not a pre hoc hypothesis regarding change within placebo group. We only examined within group change in the topiramate condition.p-value: 0Other