Defining the Clinical Role of Topiramate in the Treatment of Alcohol Dependence in Australia

Study Overview
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Brief Summary
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To compare the clinical effectiveness, tolerability, and cost-effectiveness of topiramate to active control (naltrexone) on treatment outcomes for alcohol dependence in a double-blind randomised controlled trial.

Detailed Description
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Clinicians urgently require new treatment strategies for the treatment of alcohol dependence. Although alcohol use disorders are a leading cause of preventable death in Australia, their treatment is generally not evidence based. The medications currently approved for use in Australia for the management of alcohol dependence have limited efficacy, and existing research does not address the heterogeneity of treatment response. Targeted personalised medicine addresses this heterogeneity with better medicine selection for patients based on their genotype and clinical comorbidities. Members of our research team have recently demonstrated findings that support the use of topiramate (TOP) 200 mg/day to reduce heavy drinking and pharmacogenetic findings that implicate the GluK1 receptor subunit in the mechanism of these effects. This project will evaluate the clinical effectiveness and tolerability of topiramate relative to the active control naltrexone (NTX) in heavy drinkers. Investigators hypothesise that topiramate treated patients will be better able to achieve a reduction in heavy drinking and predict that, based on prior research, that the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1. Research personnel will utilise an innovative prospective pharmacogenetic randomisation approach to a double-blind, randomised, controlled trial. Individuals will receive 12 weeks of titrated treatment with topiramate (200 mg/day) or naltrexone (50mg/day) and medical management.

Official Title
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Defining the Clinical Role of Topiramate in the Treatment of Alcohol Dependence in Australia

Conditions
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Alcohol Dependence

Intervention / Treatment
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* Drug: Topiramate
* Drug: Naltrexone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Alcohol Use Disorder according to the Diagnostic and Statistical Manual of Mental Disorders Version V criteria Age 18-70 Average weekly alcohol consumption of >30 standard drinks for men and >25 standard drinks for women, with a weekly average of > 2 heavy drinking days during the month before screening Adequate cognition and English language skills to give valid consent and complete research interviews Willingness to give written informed consent Willingness to provide a blood sample for genotyping Written informed consent Exclusion Criteria: Active major psychological disorder associated with psychosis, significant suicide risk, and signs of impaired cognitive functioning Pregnancy or lactation Concurrent use of any psychotropic medication other than antidepressants Currently taking any tricyclic antidepressant Use of antiretroviral dolutegravir Any substance dependence other than nicotine Opioid abuse, opioid dependence, or on opioid maintenance treatment Clinically significant liver disease History of nephrolithiasis History of glaucoma Lack of stable housing and/or contact phone number Previous hypersensitivity to TOP or NTX Any alcohol pharmacotherapy within the past month

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topiramate<br>Topiramate 200mg/day | Drug: Topiramate<br>* 200mg/day 100mg b.i.d<br>|
| Experimental: Naltrexone<br>Naltrexone 50mg/day | Drug: Naltrexone<br>* 50mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of heavy drinking days, as measured by the Time Line Follow Back | Corroborated with Phosphatidylethanol (PEth) levels | Over 12 weeks | 
| Time to relapse, as measured by the Time Line Follow Back | Corroborated with PEth levels | Over 12 weeks | 
| Time to lapse, as measured by the Time Line Follow Back | Corroborated with PEth levels | Over 12 weeks | 
| Number of days abstinent, as measured by the Time Line Follow Back | Corroborated with PEth levels | Over 12 weeks | 
| Number of standard drinks per drinking day, as measured by the Time Line Follow Back | Corroborated with PEth levels | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self report of adverse events | as reported by patient during weekly medical management sessions facilitated by the treating doctor. | 12 weeks | 
| Penn Alcohol Craving Scale for alcohol craving | as measured by amount of time spent thinking and craving for alcohol, difficulty in resisting consumption of alcohol if present and hypothetical pleasure associated with consumption of alcohol. | 12 weeks | 
| DASS21 score for presence and/or severity of anxiety | as measured by cumulative score of anxiety related questions on the Depression, Anxiety Stress Scale-21 (DASS21). | 12 weeks | 
| DASS21 score for presence and/or severity of depression | as measured by cumulative score for depression related questions | 12 weeks | 
| Insomnia Severity Index for sleep disturbances | as measured by cumulative score of satisfaction with current sleep patterns and extent to which sleep disturbances interfere and impair with every day activities and daily functioning | 12 weeks | 
| Blood glucose test for diabetes | as measured by fasting blood glucose levels in blood | 12 weeks | 
| Liver function tests for clinical markers of liver injury | as measured by levels of liver enzymes, Alanine Transaminase (ALT), Alkaline Phosphatase (ALP) and Aspartate Transaminase (AST) in blood | 12 weeks | 
| Body Mass Index | as measured by weight in kilograms (kg) and height in metres (m). These two measurements will be combined together to report BMI in kg/m^2. | 12 weeks | 
| Number of cigarettes smoked daily, as measured by Time Line Follow Back |  | 12 weeks | 
| Self report of daily measures of expectancies, confidence and drinking | as measured using a scale of the likelihood of having a good time and feeling more relaxed if alcohol was consumed. | 12 weeks |