Lead Investigator: Manabu Takaki, Okayama University
Title of Proposal Research: Clinical moderators of response to nalmefene in alcohol dependence: Results from a randomized controlled trial in Japan
Vivli Data Request: 7245
Funding Source: None
Potential Conflicts of Interest: Dr. Takaki has received honoraria for his participation as a speaker at educational events sponsored by Otsuka, Dainippon Sumitomo, and Takeda.
Summary of the Proposed Research:
Prior identification of patients who may respond well to nalmefene well could maximize the effectiveness of treatment. It would also provide clinicians with clinical guideline that would enable them to appropriately prescribe nalmefene to patients who could benefit from it, leading to the rise of prescription rates. The unique circumstances in Japan, where only nalmefene is the only available opioid antagonist medication that can be used for alcohol dependence justifies research to identify patients who may benefit from the medication.
The purpose of this study is to identify clinical moderators that affect treatment responsiveness of nalmefene for alcoholism by sub-analyzing the dataset from a multicenter, randomized, controlled, double-blind, phase 3 study conducted in Japanese alcohol-dependent patients19. This study showed the effect of nalmefene in reducing heavy drinking days (HDD) and average total alcohol consumption (TAC) among alcoholics with a high Drinking Risk Level (DRL) and a very high DRL, as defined by the WHO.
Statistical Analysis Plan:
The possible effect modifiers are mainly selected from the previous findings about the other therapeutic medication of alcohol dependence, e.g. acamprosate, naltrexone and baclofen. The other effect modifiers are assumed by our research team. Finally, below variables in the clinical trial ofnalmefene are included in the analysis.
i) Age [years]
ii) Gender (male= I or female=O)
iii) Body mass index [kg/m2] (continuous)
iv) Smoking status (current= ! or none/exsmoker=O)
v) Marital status (married= I or no married=O)
vi) Liver disfunction [IU/L] (ALT45 or y-GTP male>80 or female>30 = I or others=O)
vii) Baseline WHO drinking risk level (very high or high= I)
viii) Employment status (employed= ! or not employed=O)
ix) Age at onset of drinking problems [years] x) Family history of alcohol problems (yes= I or no=O)
Analyses is conducted on an intention-to-treat basis including all the randomized participants.
Firstly, we describe summary statistics (i.e., mean, standard deviation for continuous outcomes, and proportions for dichotomous outcomes) of primary/secondary outcomes in various subpopulations stratified by categorical possible effect modifiers (continuous variables (i, iii, and ix) are collapsed into some categories).
Secondly, multiple linear regression analysis is conducted for the primary outcomes. In addition to the previously conducted analysis, the interaction terms between nalmefene and possible effect modifiers were entered into the model to test effect modifications on the effect of nalmefene.
With respect to the other secondary outcome measures, we defined patients with Response Shift Drinking Risk Level (RSDRL), Response Low Drinking Risk Level (RLDRL), a 70% decrease in Total Alcohol Consumption (TAC), and 4 Heavy Drinking Days (HDD) at week 12/24 as responder group, respectively. Multiple logistic regression analysis is employed, and the statistical procedures to test possible effect modifiers were the same as primary outcomes. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. All analyses are two-tailed with a significant level at p < 0.05.
A Multicenter, Randomized, Double-blind, Placebo-controlled, 3-parallel-group Comparison Trial to Investigate the Effect of Nalmefene on Alcohol Consumption Reduction in Patients With Alcohol Dependence (Phase 3 Trial)
Data Contributor: Otsuka Pharmaceuticals
Study ID: NCT02364947
Sponsor ID: 339-14-001
Nozomu Hashimoto, Hiroshi Habu, Soshi Takao, Shinji Sakamoto, Yuko Okahisa, Keitaro Matsuo, Manabu Takaki, Yoshiki Kishi, Norihito Yamada. Clinical moderators of response to nalmefene in a randomized-controlled trial for alcohol dependence: an exploratory analysis. Drug and Alcohol Dependence, 2022, 109365, ISSN 0376-8716. doi: 10.1016/j.drugalcdep.2022.109365