Nalmefene in alcohol‐dependent patients with a high drinking risk: Randomized controlled trial

Abstract

AimsReducing alcohol consumption is one treatment approach for alcohol‐dependent patients. This study compared nalmefene 20 mg and 10 mg with placebo, combined with psychosocial support, in alcohol‐dependent Japanese patients with a high or very high drinking risk level (DRL).MethodsThis was a multicenter, randomized, double‐blind, phase 3 study conducted in alcohol‐dependent patients with a high or very high DRL. Patients were randomized to 24 weeks of treatment with as‐needed nalmefene 20 mg, 10 mg, or placebo with psychosocial support. The primary endpoint was change in heavy drinking days (HDD) from baseline to week 12. A key secondary endpoint was the change in total alcohol consumption (TAC) from baseline to week 12.ResultsAt week 12, 234, 206, and 154 patients who received placebo, nalmefene 20 mg, and 10 mg were included in the primary endpoint analysis. Compared with placebo, nalmefene was associated with significant reductions in HDD at week 12 (difference in 20 mg group, −4.34 days/month; 95% confidence interval [CI]: −6.05 to −2.62; P < 0.0001; difference in 10 mg group, −4.18 days/month; 95%CI: −6.05 to −2.32; P < 0.0001), as well as a significant reduction in TAC at week 12 (P < 0.0001). The incidence of treatment‐emergent adverse events was 87.9%, 84.8%, and 79.2% in the groups receiving nalmefene 20 mg, 10 mg, and placebo, respectively. These events were mostly of mild or moderate severity.ConclusionsNalmefene 20 mg or 10 mg effectively reduced alcohol consumption and was well tolerated in alcohol‐dependent patients with a high or very high DRL.

Response to ‘Nalmefene in alcohol‐dependent patients with a high drinking risk: A limited efficacy in reducing alcohol consumption’

“…Quality of Life was evaluated in our study, and a significant difference was found between placebo and Nalmefene groups at 12 weeks for the Alcohol Quality of Life Scale (AQOLs) evaluation . However, as Palpacuer and colleagues pointed out, no significant differences were found between placebo and Nalmefene groups at 24 weeks for AQOLs, SF‐36 and EQ‐5D evaluations .…”

“…First, we fully understand the issue of attrition bias and had mentioned this as a limitation in our paper . We also performed two kinds of imputation analyses and it was shown that heavy drinking day (HDD) and total alcohol consumption (TAC), the main analyses, were robust with sensitivity analysis complementing missing data …”

“…As such, this is the first study to validate the efficacy of Nalmefene without the use of a post-hoc analysis.On the other hand, we can understand some of the concerns that Palpacuer and colleagues raised in their letter.First, we fully understand the issue of attrition bias 2 and had mentioned this as a limitation in our paper. 3 We also performed two kinds of imputation analyses and it was shown that heavy drinking day (HDD) and total alcohol consumption (TAC), the main analyses, were robust with sensitivity analysis complementing missing data. 3 The other point raised was the study period of 12 and 24 weeks.…”

“…3 We also performed two kinds of imputation analyses and it was shown that heavy drinking day (HDD) and total alcohol consumption (TAC), the main analyses, were robust with sensitivity analysis complementing missing data. 3 The other point raised was the study period of 12 and 24 weeks. It should be noted that 12 or 24 weeks have generally been adopted as the evaluation period for alcohol dependence treatments in clinical trials 4-6 ; however, we agree that 6 months is too short to evaluate efficacy for harm reduction.In terms of the point on harm reduction, we value outcome measures including mortality or quality of life, and consider accident, injuries, and somatic alcohol-related complications as crucial endpoints, which should be included in "harm reduction" with reducing alcohol intake.…”

Nalmefene in alcohol‐dependent patients with a high drinking risk: A limited efficacy in reducing alcohol consumption

“…However, subgroup analyses are only exploratory. It is therefore reasonable to question if the new RCT assessing the efficacy of nalmefene in patients with a high drinking risk can add to the previous body of evidence. We argue that this study shares the weaknesses of the previous phase 3 trials that led to questioning the efficacy of nalmefene in reducing alcohol consumption …”