Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial

Abstract

Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation.

Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients.

Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3-3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period.

Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6-68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites (n = 3-66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated.

Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD.

Trial registration: ClinicalTrials.gov Identifier: NCT04648423.

Keywords: Alcohol dependence; GHB; RCT; alcohol use disorders; maintenance of abstinence; sodium oxybate.

Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Giovanni Addolorato served as a consultant for Ortho-McNeil Janssen Scientific Affairs, LLC, and D&A Pharma, and was paid for his consulting services. He has received lecture fees from D&A Pharma. Henri-Jean Aubin reports being member of advisory boards or DSMB for Bioprojet, and Ethypharm, and has received sponsorship to attend scientific meetings, speaker honoraria or consultancy fees from Bioprojet, D&A Pharma, Ethypharm, Kinnov Pharmaceuticals and Lundbeck. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative (ACTIVE), which was supported in the last 3 years by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Indivior, Lundbeck, Mitsubishi, and Otsuka. Rolland Benjamin received fees from Ethypharm and Lundbeck.

David Nutt reports personal fees from D&A Pharma and Lundbeck. Wim van den Brink reports personal fees from D&A Pharma, Kinnov Therapeutics, Bioproject, Lundbeck, Novartis, Indivior, Angelini, Mundipharma, Takeda, Opiant Inc, Recordati, and Camurus. Maurice Dematteis has provided expert advice to Camurus, Indivior, Molteni, D&A Pharma and Recordati Laboratories, and received fees for lectures from Accord Healthcare, Camurus, Indivior and Recordati Laboratories. Antony Gual reports grants from Novartis and D&A Pharma.

Otto Lesch served as a paid consultant for D&A Pharma. Icro Maremmani served as a board member for Angelini, Camurus, CT Sanremo, D&A Pharma, Gilead, Indivior, Lundbeck, Molteni, MSD, Mundipharma. Jürgen Rehm reported personal fees from D&A Pharma and Lundbeck.

Rainer Spanagel reported grants from Horizon 2020 program, Era-NET NEURON, BMBF, Deutsche Forschungsgemeinschaft (DFG), and personal fees from EMCCDA and D&A Pharma. Bruno Scherrer reported fees from D&A pharma, DNDI, HRA Pharma, and other pharmaceutical organizations. Roberto Cacciaglia is employed by Laboratorio Farmaceutico CT, San Remo, Italy. Julien Guiraud is employed by D&A Pharma, Paris, France. Roch Poulnais and Quentin Raffaillac were employed by D&A Pharma, Paris, France. None of the other authors received financial support for the current work. Bo Söderpalm and Andrea de Bejczy are founders and co-owners of Sobrera Pharma. AB, currently developing a treatment for alcohol dependence. Lorenzo Somaini served as a board member for Camurus, CT Laboratori Sanremo, GL Pharma, Gilead, Indivior, Molteni, AbbVie.

Figures

Figure 1.

Patient flow chart.

Figure 2.

Adjusted mean CAD over the study period. Bars indicate standard error; ***: p ⩽ 0.001. CAD, cumulative abstinence duration.

Figure 3.

Site-specific treatment effects (95% CI) in CAD during the 6-month treatment period. CAD, cumulative abstinence duration; CI, confidence interval; PBO: placebo; SMO: sodium oxybate.

Figure 4.

Mean difference in CAD during the 6-month treatment period and mean placebo response in each site. CAD, cumulative abstinence duration.