Evaluation of the Efficacy of Sodium Oxybate in the Long-term Maintenance of Abstinence in Alcoholic Patients

Study Overview
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Brief Summary
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Additional pharmacotherapies in the treatment of alcohol dependence are needed. Sodium oxybate showed efficacy in the maintenance of abstinence in alcohol-dependent patients in several small randomized trials of short duration. The aim of the present phase III/IV study is to confirm in a randomized-controlled study the efficacy and safety of oral sodium oxybate in the maintenance of abstinence.

Detailed Description
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Alcohol dependence (AD) is the most severe form of alcohol use disorder. It occurs in 2.6% of people aged 15+ years worldwide and can result in a reduction of life-expectancy by several years as compared with the general population. Currently, disulfiram, acamprosate and naltrexone are the main medicinal products registered for the maintenance of abstinence in AD patients. Although effective on the group level, effects sizes are limited, and many AD patients fail to respond to these medications. Therefore, additional pharmacological treatments are needed. Sodium oxybate 50mg/kg/day showed evidence of efficacy compared to placebo and naltrexone in the maintenance of abstinence in AD patients in a series of open label and blinded randomized controlled trials (RCTs). However, studies were generally small and did not investigate the sustainability of the Sodium oxybate effect post-treatment. The present phase III/IV RCT (GATE 2) aimed to confirm the efficacy and safety of oral Sodium oxybate in the maintenance of abstinence. Secondary aims included the assessment of sustained SMO effects during the 6-month medication free period immediately following the 6-month treatment period and monitoring the risk of Sodium oxybate dependence.

Official Title
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Multinational, Multicentre, Double-blind, Placebo-controlled Evaluation of the Efficacy of GHB in the Long-term Maintenance of Abstinence in Alcoholic Patients After the Initial Weaning Phase, Stratified by Lesch's Taxonomy (GATE 2)

Conditions
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Alcohol Use Disorder (AUD), Alcohol Dependence

Intervention / Treatment
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* Drug: Sodium Oxybate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The following subjects were recruited: males and females; of any ethnic group; age between 21 and 75 years at recruitment; documented alcohol dependency before weaning detected according to the CAGE instrument, classified according to the DSM-IV and ICD-10 and severity rated according to the MALT instrument; classified according to Lesch typology; having successfully undergone a detoxification program, encompassing a 10-day treatment period and a subsequent 10-day untreated follow-up; with a responsible relative or caregiver; having issued the informed consent. Exclusion Criteria: subjects who did not quit alcohol drinking after the detoxification period; subjects with history of epilepsy or epileptics seizures not properly controlled by established anti-epileptic treatment; subjects with dependence from narcotics or other drugs of abuse; subjects without a stable address; subjects without a reference relative or caregiver; subjects with renai failure (blood creatinine >2.5 mg/dL and/or documented proteinuria >500 mg/day); subjects with heart failure or severe respiratory failure; subjects with hepatic encephalopathy stage lI-IV; subjects with severe psychiatric disorders requiring treatment with psychoactive medications (excluding short-term benzodiazepine treatments); subjects under treatment with clonidine, disulfiram (after the end of the detoxification period), haloperidol, bromocryptine, serotonine re-uptake inhibitors or other serotoninergic agents; female subjects who cannot assure not to become pregnant during the 7-month period covering treatment and the first treatment-free month of follow-up; documented pre-existent hypersensitivity to GHB; subjects unable or unwilling to issue the informed consent; participating to another clinica! investigation in the previous month prior to recruitment; 15. any other medicai condition which, according to the investigator, justifies the patient's exclusion from the study.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 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
Interventional Model Description: double-blind, placebo-controlled study with parallel group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sodium oxybate<br>Sodium oxybate solution for oral administration (175 mg/mL). Dose (body weight ≤ 65 kg): 19.0 mL daily, in 3 administrations, for 6 months Dose (body weight > 65 kg): 22.5 mL daily, in 3 administrations, for 6 months | Drug: Sodium Oxybate<br>* solution for oral administration<br>* Other names: gamma-hydroxy butyrate (GHB);|
| Placebo Comparator: placebo<br>Placebo solution for oral administration. Dose (body weight ≤ 65 kg): 19.0 mL daily, in 3 administrations, for 6 months Dose (body weight > 65 kg): 22.5 mL daily, in 3 administrations, for 6 months | Drug: Placebo<br>* solution for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Abstinence Duration (CAD) | to demonstrate that sodium oxybate is superior to placebo in the CAD during the treatment period. | 6-month treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAD stratified | CAD during treatment period according to subtype patients stratified by Lesch's categories. | 6-month treatment period | 
| Assessment of the exposure-corrected CAD | assessment of the exposure-corrected cumulative abstinence duration (CCAD) during treatment. | 6-month treatment period | 
| CAD during the whole study | CAD during the whole observation period | 12 months: 6-month treatment period + 6-month follow-up | 
| Proportion of abstinent patients | proportion of abstinent patients at the end of the 6-month treatment period and at the end of the entire observation period. | 12 months: 6-month treatment period + 6-month follow-up | 
| Time to the first relapse | assessment of the time to the first relapse during the treatment period. | 6-month treatment period | 
| Change from baseline in the craving for alcohol intensity and frequency by the Lubecker Craving Risiko Ruckfall (LCRR) questionnaire. | The LCRR provides the patient's current state about his craving for alcohol. The clinician interviews the patient to rate the intensity of the desire for alcohol (item-1) on a 4-point scale ranging from 1 (no desire) to 4 (very strong desire), and to rate the frequency of the desire for alcohol (item-2) on a 6-point scale ranging from 1 (never) to 6 (nearly continuous). Higher scores mean a worse outcome. | 12 months: 6-month treatment period + 6-month follow-up | 
| Assessment of the time course of γ-GT as biological marker of alcohol abuse, during treatment and at the end of follow-up. | γ-GT values | Month 6 | 
| Adverse events | evaluation of the frequency, nature and severity of adverse clinical events, including mortality and morbidity | 6-month treatment period | 
| Number of participants with Adverse Events (AEs) | Overview of AEs. | 6-month treatment period | 
| Risk of Secondary Dependence - treatment period | Evaluation of the risk of onset of dependence from the medication, by means of a 2-item questionnaire. The first to rate the intensity of the desire for medication since the last visit in a scale ranging from 0 to 100. The second to rate the approach to the next dose in a scale ranging from 1 (I just waited for the time to come) to 6 (I took the dose sooner than planned). Higher scores mean a worse outcome. | 6-month treatment period | 
| Assessment of the time course of MCV as biological marker of alcohol abuse, during treatment and at the end of follow-up. | MCV values | Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alcoholism, alcohol, alcohol dependence, relapse prevention