Topiramate versus naltrexone for alcohol use disorder: study protocol for a genotype-stratified, double-blind randomised controlled trial (TOP study)

Kirsten C Morley, Henry R Kranzler, Natasha Luquin, Andrew Baillie, Marian Shanahan, Ronald Trent, Maree Teesson, Paul S Haber, Kirsten C Morley, Henry R Kranzler, Natasha Luquin, Andrew Baillie, Marian Shanahan, Ronald Trent, Maree Teesson, Paul S Haber

Abstract

Background: Current treatments for alcohol use disorders have limited efficacy and there is a high degree of variability in treatment response. In a randomised, placebo-controlled clinical trial, there was a large effect size for topiramate in people homozygous for the GRIK1 rs2832407*C allele. The primary aim of the TOP study is to examine prospectively the therapeutic and cost-effectiveness of topiramate versus an active control (naltrexone) in improving treatment outcomes for alcohol dependence. Participants will be stratified on rs2832407 to compare C-allele homozygotes with A-allele carriers to examine the moderating effect of rs2832407 on drinking outcomes. An exploratory aim is to examine the moderating effects of rs1799971, a polymorphism in OPRM1, on the response to naltrexone by comparing Asn40 homozygotes with Asp40 carriers.

Methods/design: This double-blind trial will randomise 180 alcohol-dependent participants to a 12-week regime of either topiramate (titrating the dose up to 200 mg/day) or naltrexone (50 mg/day). Participants will be stratified on the two polymorphisms before randomisation. All participants will receive medical management. The primary drinking outcome will be the number of heavy drinking days per week and secondary drinking outcomes will include the time to relapse, the time to lapse and the percentage of abstinent days. Other secondary outcomes will include body mass index, tobacco use, anxiety symptoms and depressive symptoms.

Discussion: If successful, the TOP study will improve management strategies for alcohol dependence by providing support for the use of genetic biomarkers to inform medication selection.

Trial registration: ClinicalTrials.gov, NCT03479086 . Registered on 27 March 2018.

Keywords: Alcohol dependence; Alcohol use disorder; GRIK1; Naltrexone; OPRM1; Pharmacogenetics; Topiramate.

Conflict of interest statement

Ethics approval and consent to participate

Ethics approval for the study has been granted by the Sydney Local Health District Ethics Review Committee (X16–0231 and HREC/16/RPAH/283). Participants are provided with an approved plain language information sheet and provide written consent to participate. The protocol is version 8 (X16–0231, 16 February 2018). The study involves off-label use of a registered medication in Australia. Approval for this trial has been given under the Clinical Trial Notification scheme of the Therapeutics Goods Administration (2013/0060). The trial is sponsored by Sydney Local Health District and was registered with the National Institutes of Health clinical trials registry retrospectively on 27 March 2018 (NCT03479086; https://ichgcp.net/clinical-trials-registry/NCT03479086). Participants are advised of their right to seek compensation from the study sponsor in the event of harm arising from trial participation. Protocol amendments to the clinical protocol will be updated at the clinical trials registry following approval by the corresponding ethics review committee.

Consent for publication

There are no restrictions on publication from the sponsor or other parties. Publications will be authored by the investigators and authorship offered according to NHMRC criteria.

Competing interests

Dr Kranzler has been a consultant, advisory board member or continuing medical education speaker for Alkermes, Lundbeck and Otsuka. He is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative (ACTIVE), which in the last 3 years was supported by AbbVie, Alkermes, Amygdala Neurosciences, Arbor, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka and Pfizer. Dr Kranzler is named as an inventor on PCT patent application 15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” which was filed on 24 January 2018.

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
SPIRIT figure of the TOP study protocol.

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