Clinical trial NCT04648423: Evaluation of the Efficacy of Sodium Oxybate in the Long-term Maintenance of Abstinence in Alcoholic Patients
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Alcohol Use Disorder (AUD)
Alcohol Dependence
Keywords: alcoholism
alcohol
alcohol dependence
relapse prevention
Lead sponsor: Laboratorio Farmaceutico Ct S.r.l.
Sponsor class: INDUSTRY
First posted: 2020-12-01
Enrollment: 314
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: double-blind, placebo-controlled study with parallel group
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Cumulative Abstinence Duration (CAD)
timeFrame: 6-month treatment period
Secondary outcomes:
measure: CAD stratified
timeFrame: 6-month treatment period
measure: Assessment of the exposure-corrected CAD
timeFrame: 6-month treatment period
measure: CAD during the whole study
timeFrame: 12 months: 6-month treatment period + 6-month follow-up
measure: Proportion of abstinent patients
timeFrame: 12 months: 6-month treatment period + 6-month follow-up
measure: Time to the first relapse
timeFrame: 6-month treatment period
measure: Change from baseline in the craving for alcohol intensity and frequency by the Lubecker Craving Risiko Ruckfall (LCRR) questionnaire.
timeFrame: 12 months: 6-month treatment period + 6-month follow-up
measure: Assessment of the time course of γ-GT as biological marker of alcohol abuse, during treatment and at the end of follow-up.
timeFrame: Month 6
measure: Adverse events
timeFrame: 6-month treatment period
measure: Number of participants with Adverse Events (AEs)
timeFrame: 6-month treatment period
measure: Risk of Secondary Dependence - treatment period
timeFrame: 6-month treatment period
measure: Assessment of the time course of MCV as biological marker of alcohol abuse, during treatment and at the end of follow-up.
timeFrame: Month 6
Other outcomes:
Locations:
Study officials:
affiliation: Laboratorio Farmaceutico C.T.
name: Roberto Cacciaglia
role: STUDY_CHAIR
References:
citation: Skala K, Caputo F, Mirijello A, Vassallo G, Antonelli M, Ferrulli A, Walter H, Lesch O, Addolorato G. Sodium oxybate in the treatment of alcohol dependence: from the alcohol withdrawal syndrome to the alcohol relapse prevention. Expert Opin Pharmacother. 2014 Feb;15(2):245-57. doi: 10.1517/14656566.2014.863278. Epub 2013 Nov 28.
citation: van den Brink W, Addolorato G, Aubin HJ, Benyamina A, Caputo F, Dematteis M, Gual A, Lesch OM, Mann K, Maremmani I, Nutt D, Paille F, Perney P, Rehm J, Reynaud M, Simon N, Soderpalm B, Sommer WH, Walter H, Spanagel R. Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level. Addict Biol. 2018 Jul;23(4):969-986. doi: 10.1111/adb.12645.
citation: Guiraud J, Addolorato G, Antonelli M, Aubin HJ, de Bejczy A, Benyamina A, Cacciaglia R, Caputo F, Dematteis M, Ferrulli A, Goudriaan AE, Gual A, Lesch OM, Maremmani I, Mirijello A, Nutt DJ, Paille F, Perney P, Poulnais R, Raffaillac Q, Rehm J, Rolland B, Rotondo C, Scherrer B, Simon N, Skala K, Soderpalm B, Somaini L, Sommer WH, Spanagel R, Vassallo GA, Walter H, van den Brink W. Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2022 Oct;36(10):1136-1145. doi: 10.1177/02698811221104063. Epub 2022 Jul 7.