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| ID | Type | Description | Link |
|---|---|---|---|
| DAMD17-03-1-0532 | Other Grant/Funding Number | Department of Defense |
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| Name | Class |
|---|---|
| United States Department of Defense | FED |
| US Department of Veterans Affairs | FED |
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The proposed project aims to:
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.
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 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Topiramate | Experimental | Participants will be randomly assigned to either the topiramate arm or placebo arm. Neither the participant nor the researchers will know which arm the participant is in. Participants in the topiramate arm will be ingesting daily doses of topiramate that will gradually increase to a maximum, and then taper off. |
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| Placebo | Placebo Comparator | The Drug Product Services Laboratory at UCSF will purchase and supply our lab with USP or NF grade topiramate study capsules and matching placebo capsules. Randomization will be done by a consulting biostatistician, who will be the only one to know which participants are assigned to placebo. Dosing will follow the same procedures as with topiramate in that arm of the study. If adverse events occur, there will be a procedure in place for unblinding only that participant. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Topiramate | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Weekly, weeks 1-12, average |
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| Measure | Description | Time Frame |
|---|---|---|
| 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). |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Steven L. Batki, MD | University of California, San Francisco; Department of Veteran's Affairs | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| San Francisco VA Medical Center | San Francisco | California | 94121 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19336652 | Background | Alderman CP, McCarthy LC, Condon JT, Marwood AC, Fuller JR. Topiramate in combat-related posttraumatic stress disorder. Ann Pharmacother. 2009 Apr;43(4):635-41. doi: 10.1345/aph.1L578. Epub 2009 Mar 31. | |
| 16670409 | Background | Anton RF, O'Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006 May 3;295(17):2003-17. doi: 10.1001/jama.295.17.2003. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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). |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Placebo administration | Other | 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. |
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| Weeks 4, 8, 12 |
| 7771669 | Background | Anton RF, Moak DH, Latham P. The Obsessive Compulsive Drinking Scale: a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res. 1995 Feb;19(1):92-9. doi: 10.1111/j.1530-0277.1995.tb01475.x. |
| 12943017 | Background | Baker F, Johnson MW, Bickel WK. Delay discounting in current and never-before cigarette smokers: similarities and differences across commodity, sign, and magnitude. J Abnorm Psychol. 2003 Aug;112(3):382-92. doi: 10.1037/0021-843x.112.3.382. |
| 17661192 | Background | Batki SL, Dimmock JA, Wade M, Gately PW, Cornell M, Maisto SA, Carey KB, Ploutz-Snyder R. Monitored naltrexone without counseling for alcohol abuse/dependence in schizophrenia-spectrum disorders. Am J Addict. 2007 Jul-Aug;16(4):253-9. doi: 10.1080/10550490701389732. |
| 9870231 | Background | Beckham JC, Crawford AL, Feldman ME. Trail making test performance in Vietnam combat veterans with and without posttraumatic stress disorder. J Trauma Stress. 1998 Oct;11(4):811-9. doi: 10.1023/A:1024409903617. |
| 11838620 | Background | Berlant J, van Kammen DP. Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry. 2002 Jan;63(1):15-20. doi: 10.4088/jcp.v63n0104. |
| 15315714 | Background | Berlant JL. Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder. BMC Psychiatry. 2004 Aug 18;4:24. doi: 10.1186/1471-244X-4-24. |
| FG001 | 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. |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| History of combat exposure | Number | participants |
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| Comorbid substance use disorder | Number | participants |
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| Prior treatment for substance use disorder | Number | participants |
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| BDI | Depression was assessed using the Beck Depression Inventory, scores range from 0-63, with scores over 40 indicating severe depression and scores under 10 indicating normal mood symptoms. | Mean | Standard Deviation | units on a scale |
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| BAI | The Beck Anxiety Inventory (BAI) consists of twenty-one questions about how the subject has been feeling in the last week, expressed as common symptoms of anxiety (such as numbness and tingling, sweating not due to heat, and fear of the worst happening).Each question has the same set of four possible answer choices, ranging from 0 to 3 points: NOT AT ALL (0), MILDLY (1), MODERATELY (2), SEVERELY (3). Total BAI scores range from 0 - 63, with higher scores indicating greater severity. 0-7: minimal level of anxiety 8-15: mild anxiety 16-25: moderate anxiety 26-63: severe anxiety | Mean | Standard Deviation | units on a scale |
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| Alcohol Use Disorders Identification Test | The Alcohol Use Disorders Identification Test (AUDIT) score is the sum of 10 questions about alcohol consumption, each with scores ranging from 0 to 4, and total AUDIT score ranges from 0-40. Higher scores indicate greater likelihood of hazardous and harmful drinking, and may also reflect greater severity of alcohol problems and dependence, as well as a greater need for more intensive treatment. | Mean | Standard Deviation | units on a scale |
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| Percent drinking days per week | The Alcohol Timeline Followback (TLFB) is a drinking assessment interview that obtains estimates of daily drinking and has been evaluated with clinical and nonclinical populations. Using a calendar, people provided retrospective estimates of their daily drinking over the 90 day period prior to study screening. DD: day on which alcohol was consumed | Mean | Standard Deviation | percent days in a week |
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| Percent heavy drinking days per week | The Alcohol Timeline Followback (TLFB) is a drinking assessment interview that obtains estimates of daily drinking and has been evaluated with clinical and nonclinical populations. Using a calendar, people provided retrospective estimates of their daily drinking over the 90 day period prior to study screening. HDD: day on which >4 (men) or >3 (women) standard alcoholic drinks were consumed Standard alcoholic drink defined as containing 13.6 g of pure alcohol. | Mean | Standard Deviation | percent days in a week |
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| Average drinks per week | The Alcohol Timeline Followback (TLFB) is a drinking assessment interview that obtains estimates of daily drinking and has been evaluated with clinical and nonclinical populations. Using a calendar, people provided retrospective estimates of their daily drinking over the 90 day period prior to study screening. Standard alcoholic drink defined as containing 13.6 g of pure alcohol. | Mean | Standard Deviation | Drinks |
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| Average drinks per drinking day | The Alcohol Timeline Followback (TLFB) is a drinking assessment interview that obtains estimates of daily drinking and has been evaluated with clinical and nonclinical populations. Using a calendar, people provided retrospective estimates of their daily drinking over the 90 day period prior to study screening. DD: day on which alcohol was consumed Standard alcoholic drink defined as containing 13.6 g of pure alcohol. | Mean | Standard Deviation | Drinks |
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| Baseline PTSD Symptomatology | The Clinician-Administered PTSD Checklist (CAPS) was used at baseline to assess PTSD symptoms at baseline. The PTSD Checklist is a 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). | Mean | Standard Deviation | units on a scale |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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. | Posted | Mean | Standard Deviation | percent days in a week | Weekly, weeks 1-12, average |
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| 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). | Posted | Mean | Standard Deviation | units on a scale | Weeks 4, 8, 12 |
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12 Weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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). | 0 | 14 | 12 | 14 | ||
| EG001 | 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. | 4 | 16 | 13 | 16 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Suicidal ideation | Psychiatric disorders | Non-systematic Assessment | Subject was hospitalized due to alcohol relapse and self-reported suicidal ideation |
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| Chest pain | Cardiac disorders | Non-systematic Assessment | Myocardial infarction (MI) was ruled out and patient was discharged the next day |
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| Death | General disorders | Non-systematic Assessment | Research participant in 9th week of treatment died of apparent cardiac arrest |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| numbness/tingling | Nervous system disorders | Non-systematic Assessment |
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| Altered taste | Nervous system disorders | Non-systematic Assessment |
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| Difficulty with concentration/attention | Nervous system disorders | Non-systematic Assessment |
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| Difficulty with memory | Nervous system disorders | Non-systematic Assessment |
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| Slow thinking | Nervous system disorders | Non-systematic Assessment |
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| Confusion | Nervous system disorders | Non-systematic Assessment |
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| Language problems | Nervous system disorders | Non-systematic Assessment |
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| Fatigue | General disorders | Non-systematic Assessment |
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| Loss of appetite | General disorders | Non-systematic Assessment |
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| Dizziness | General disorders | Non-systematic Assessment |
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| Itching | General disorders | Non-systematic Assessment |
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| Sleepiness | General disorders | Non-systematic Assessment |
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| Nervousness | Psychiatric disorders | Non-systematic Assessment |
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| Depression | Psychiatric disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
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| Abnormal vision | Eye disorders | Non-systematic Assessment |
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| Eye pain | Eye disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David L. Pennington, PhD (Research Psychologist II) | University of California, San Francisco | 415-221-4810 | 4504 | david.pennington2@va.gov |
| ID | Term |
|---|---|
| D013313 | Stress Disorders, Post-Traumatic |
| D000437 | Alcoholism |
| ID | Term |
|---|---|
| D040921 | Stress Disorders, Traumatic |
| D000068099 | Trauma and Stressor Related Disorders |
| D001523 | Mental Disorders |
| D019973 | Alcohol-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
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| ID | Term |
|---|---|
| D000077236 | Topiramate |
| C577572 | Qnexa |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D005632 | Fructose |
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D002241 | Carbohydrates |
| D007661 | Ketoses |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| No combat exposure |
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| Comorbid substance use disorder absent |
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| Outpatient treatment |
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| No prior substance use disorder treatment |
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| Intrusion subscale |
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| Avoidance subscale |
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| Arousal subscale |
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| There were no pre hoc hypothesis regarding change within placebo group. We were only tested change within the topiramate condition. | Other | 0.00 | No | Superiority or Other |
| 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. | Negative binomial model | 0.036 | Incidence Rate Ratio (IRR) | 0.38 | 2-Sided | 95 | 0.15 | 0.94 | No | Superiority or Other |
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