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Cited by 23Substance Abuse Treatment and OutcomesAlcohol Consumption and Health EffectsOpioid Use Disorder Treatment

Gabapentin enacarbil extended-release versus placebo: a likely responder reanalysis of a randomized clinical trial

Open access
Laska, Eugene M., Siegel, Carole E., Lin, Ziqiang, Bogenschutz, Michael, Marmar, Charles R.·2020·Alcoholism: Clinical and Experimental Research
DOI 10.1111/acer.14414PMC PMC7540534
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Abstract

Background: We reanalyzed a multisite 26‐week randomized double‐blind placebo‐controlled clinical trial of 600 mg twice‐a‐day Gabapentin Enacarbil Extended‐Release (GE‐XR), a gabapentin prodrug, designed to evaluate safety and efficacy for treating alcohol use disorder. In the original analysis (n = 338), published in 2019, GE‐XR did not differ from placebo. Our aim is to advance precision medicine by identifying likely responders to GE‐XR from the trial data and to determine for likely responders if GE‐XR is causally superior to placebo. Methods: The primary outcome measure in the reanalysis is the reduction from baseline of the number of heavy drinking days (ΔHDD). Baseline features including measures of alcohol use, anxiety, depression, mood states, sleep, and impulsivity were used in a random forest (RF) model to predict ΔHDD to treatment with GE‐XR based on those assigned to GE‐XR. The resulting RF model was used to obtain predicted outcomes for those randomized to GE‐XR and counterfactually to those randomized to placebo. Likely responders to GE‐XR were defined as those predicted to have a reduction of 14 days or more. Tests of causal superiority of GE‐XR to placebo were obtained for likely responders and for the whole sample. Results: For likely responders, GE‐XR was causally superior to placebo (p < 0.0033), while for the whole sample, there was no difference. Likely responders exhibited improved outcomes for the related outcomes of percent HDD and drinks per week. Compared with unlikely responders, at baseline likely responders had higher HDDs; lower levels of anxiety, depression, and general mood disturbances; and higher levels of cognitive and motor impulsivity. Conclusions: There are substantial causal benefits of treatment with GE‐XR for a subset of patients predicted to be likely responders. The likely responder statistical paradigm is a promising approach for analyzing randomized clinical trials to advance personalized treatment.

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  • A recent overall-negative study with a gabapentin prodrug was reported, but the consensus was that the dose was low, and secondary analyses showed some efficacy in some subgroups.

    “A recent overall-negative study with a gabapentin prodrug has been reported, but the consensus was that the dose was low, and secondary analyses showed some efficacy in some subgroups of subjects in the study (Falk et al., 2019;Laska et al., 2020).”

    From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Laska et al., 2020

    The Introduction reports that the original gabapentin enacarbil trial found no significant difference from placebo, and the Discussion reports better outcomes for some subgroups in this reanalysis. The paper gives the dose as 600 mg twice daily but does not say there was a consensus that it was low. (LLM, conf=0.88)

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Research works printed but not linked: 2

  1. Imbens GW and Rubin DB, 2015 Causal inference in statistics, social, and biomedical sciences. Cambridge University Press.
  2. Neyman J, 1923 Sur les applications de la theorie des probabilites aux experiences agricoles: essai des principes (Masters Thesis); Justification of applications of the calculus of probabilities to the solutions of certain questions in agricultural experimentation. Excerpts English translation (Reprinted). Stat Sci, 5, pp. 463– 472.

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Authors
Laska, E. M., Siegel, C. E., Lin, Z., Bogenschutz, M., & Marmar, C. R.
Affiliations
New York University (US)
Corresponding author
Laska, Eugene M.
ORCID
Venue
Alcoholism: Clinical and Experimental Research
Publisher
Wiley
Published
2020-07-31
Volume
44
Issue
9
Pages
1875-1884
ISSN
  • 0145-6008 (ISSN-L)
  • 1530-0277
DOI
10.1111/acer.14414
PMC
PMC7540534
OpenAlex
W3043313766
Cited by
23
References
27
Citations by year
2026: 4 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 2 · 2020: 1
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Alcoholism Clinical and Experimental Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute on Alcohol Abuse and Alcoholism (PO1AA027057‐01)
Topics
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
Keywords
alcoholism, precision medicine, heavy drinking days, impulsivity, anxiety and depression, random forest prediction, personalized treatment
MeSH terms
Machine Learning, Adult, Alcoholism, Carbamates, Female, gamma-Aminobutyric Acid, Humans, Male, Middle Aged, Outcome Assessment, Health Care, Precision Medicine

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