Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial
Julien Guiraud, Giovanni Addolorato, Mariangela Antonelli, Henri-Jean Aubin, Andrea de Bejczy, Amine Benyamina, Roberto Cacciaglia, Fabio Caputo, Maurice Dematteis, Anna Ferrulli, Anna E Goudriaan, Antoni Gual, Otto-Michael Lesch, Icro Maremmani, Antonio Mirijello, David J Nutt, François Paille, Pascal Perney, Roch Poulnais, Quentin Raffaillac, Jürgen Rehm, Benjamin Rolland, Claudia Rotondo, Bruno Scherrer, Nicolas Simon, Katrin Skala, Bo Söderpalm, Lorenzo Somaini, Wolfgang H Sommer, Rainer Spanagel, Gabriele A Vassallo, Henriette Walter, Wim van den Brink, Julien Guiraud, Giovanni Addolorato, Mariangela Antonelli, Henri-Jean Aubin, Andrea de Bejczy, Amine Benyamina, Roberto Cacciaglia, Fabio Caputo, Maurice Dematteis, Anna Ferrulli, Anna E Goudriaan, Antoni Gual, Otto-Michael Lesch, Icro Maremmani, Antonio Mirijello, David J Nutt, François Paille, Pascal Perney, Roch Poulnais, Quentin Raffaillac, Jürgen Rehm, Benjamin Rolland, Claudia Rotondo, Bruno Scherrer, Nicolas Simon, Katrin Skala, Bo Söderpalm, Lorenzo Somaini, Wolfgang H Sommer, Rainer Spanagel, Gabriele A Vassallo, Henriette Walter, Wim van den Brink
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.
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