Per Sørensen

Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: A 1-year, randomised controlled study

This study evaluated the long-term efficacy and safety of nalmefene treatment in reducing alcohol consumption. We randomised (1:3) 675 alcohol-dependent patients ≥ 18 years of age to 52 weeks of as-needed treatment with placebo or nalmefene 18 mg/day: A total of 112 patients (68%) in the placebo group and 310 (62%) in the nalmefene group completed the study. At month 6, the co-primary outcome variables showed no statistically-significant differences between the treatment groups; but at month 13, nalmefene was more effective than placebo, both in the reduction of the number of heavy drinking days (HDDs) (− 1.6 days/month (95% CI − 2.9; − 0.3); p = 0.017) and the reduction of total alcohol consumption (TAC) (− 6.5 g/day last month (95% CI − 12.5; − 0.4); p = 0.036). In a subgroup analysis of patients with high/very high drinking risk levels at screening and at randomisation (the target population), there was a significant effect in favour of nalmefene on TAC at month 6, and on both HDD and TAC at month 13. Improvements in Clinical Global Impression and liver enzymes were greater with nalmefene, compared to placebo. Most adverse events were mild or moderate, and transient; adverse events, including those leading to dropout, were more common with nalmefene. This study provides evidence for the long-term safety and efficacy of nalmefene as-needed in alcohol-dependent patients whom continue to drink heavily, following a brief intervention.

The Effects of as-Needed Nalmefene on Patient-Reported Outcomes and Quality of Life in Relation to a Reduction in Alcohol Consumption in Alcohol-Dependent Patients

Background The objective of this article was to investigate the effect of as-needed nalmefene on health-related quality of life (HRQoL) in patients with alcohol dependence, and to relate changes in drinking behavior and status to HRQoL outcomes. Methods This post hoc analysis was conducted on a pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) who participated in one of two randomized controlled 6-month studies, ESENSE 1 and ESENSE 2. Patients received nalmefene 18 mg or placebo on an as-needed basis, in addition to a motivational and adherence-enhancing intervention (BRENDA). At baseline and after 12 and 24 weeks questionnaires for the Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36), European Quality of life-5 Dimensions (EQ-5D) and the Drinker Inventory of Consequences (DrInC-2R) were completed. Results The pooled population consisted of 667 patients (nalmefene: 335; placebo: 332), with no notable between-group differences in baseline patient demographics/characteristics. At week 24, nalmefene had a superior effect compared to placebo in improving SF-36 mental component summary scores (mean difference [95% CI], p-value: 3.09 [1.29, 4.89]; p=0.0008), SF-36 physical component summary scores (1.23 [0.15, 2.31]; p=0.026), EQ-5D utility index scores (0.03 [0.00, 0.06]; p=0.045), EQ-5D health state scores (3.46 [0.75, 6.17]; p=0.012), and DrInC-2R scores (-3.22 [-6.12, 0.33]; p=0.029). The improvements in SF-36 mental component summary scores at week 24, and the DrInC-2R total score change from baseline to week 24, were significantly correlated to reductions in heavy drinking days and total alcohol consumption at week 24. Conclusions As-needed nalmefene significantly improved almost all patient-reported HRQoL measures included in SF-36 and EQ-5D compared with placebo. These HRQoL gains were significantly correlated to reduced drinking behavior, as determined by reductions in heavy drinking days and total alcohol consumption.

Clinical relevance of nalmefene versus placebo in alcohol treatment: reduction in mortality risk.

Reduction of long-term mortality risk, an important clinical outcome for people in alcohol dependence treatment, can rarely be established in randomized controlled trials (RCTs). We calculated the reduction in all-cause mortality risk using data from short-term (6 and 12 months) double-blind RCTs comparing as-needed nalmefene treatment to placebo, and mortality risks from meta-analyses on all-cause-mortality risk by reduction of drinking in people with alcohol dependence. A reduction in drinking in the RCTs was defined by shifts in drinking risk levels established by the European Medicines Agency. Results showed that the reduction of drinking in the nalmefene group was associated with a reduction in mortality risk by 8% (95% CI: 2%, 13%) when compared to the placebo group. Sensitivity analyses confirmed a significant effect. Thus comparing the difference between nalmefene and placebo in reduction in drinking levels with results on all-cause mortality risk from meta-analyses indicated a clinically relevant reduction in mortality risk. Given the high mortality risk of people with alcohol dependence, abstinence or a reduction in drinking have been shown to reduce mortality risk and should be considered treatment goals.

Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme

Objective: To investigate safety and tolerability of nalmefene for reduction of alcohol consumption in alcohol-dependent patients. Methods: Pooled data from three randomized, placebo-controlled studies (two 6-month; one 12-month) of 18 mg nalmefene (as-needed use) in alcohol-dependent patients looking at the total population (placebo n = 824, nalmefene n = 1123) and patients with high/very high drinking risk levels at screening and randomization (target population: placebo n = 374, nalmefene n = 450). Results: In the study, 62.7% of patients on placebo and 74.7% on nalmefene in the total population had treatment-emergent adverse events (TEAEs). Fourty-seven (5.9%) on placebo and 149 (13.0%) on nalmefene dropped out due to TEAEs. Thirty-five (4.4%) on placebo and 57 (5.0%) on nalmefene had serious adverse events. Tolerability and safety were similar in the target population and total population. Most frequent TEAEs were transient, mainly occurring at treatment initiation. There was no difference in tolerability and safety if nalmefene was taken daily or intermittently; no signal of increased risk of suicide-related behavior with nalmefene. The higher incidence of psychiatric events in the nalmefene group was mainly due to the TEAE of confusional state. Conclusions: Although there was a higher incidence of TEAEs and TEAEs leading to dropout, nalmefene was well-tolerated and no major safety issues were identified.

1105 – Long-term efficacy of nalmefene as-needed in alcohol dependent patients with high drinking risk levels: results of a subgroup analysis

Introduction We describe the efficacy and safety of as-needed use of nalmefene in the subgroup of patients with a high drinking risk level (DRL; men:>60g/day; women:>40g/day); i.e. a group of patients with a great unmet medical need for treatment. Objectives To evaluate the 1 year efficacy and safety of as-needed use of nalmefene 18mg versus placebo in a subgroup of alcohol dependent patients with high DRL from a randomised controlled trial [NCT00811941]. Methods All patients received a motivational and adherence-enhancing intervention (BRENDA) in combination with either nalmefene or placebo. Number of heavy drinking days (HDDs) and total alcohol consumption (TAC) were measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study. Results The study population consisted of 187 patients: placebo N=42; nalmefene N=145 (mean age 46.2±11.9 years; 78% men; mean HDDs 19±6.3/month; mean TAC 101±45.0 g/day). Mean number of HDDs decreased to 7 days/month and mean TAC decreased to 33g/day at 1 year in the nalmefene group. At 1 year, there was a superior effect of nalmefene compared to placebo in reducing the number of HDDs (-3.6 [95% CI:-6.5;-0.7]; p=0.0164) and TAC -17.3 [-30.9;-3.8]; p=0.0129). Improvements in clinical status and in liver enzymes from baseline were larger in the nalmefene compared to the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo. Conclusions As-needed nalmefene was efficacious in reducing alcohol consumption in patients with high risk for alcoholrelated harm.

1613 – As-needed use of nalmefene in the treatment of alcohol dependence

Introduction In the phase 3 programme on nalmefene for reduction of alcohol consumption in alcohol dependent patients, an as-needed dosing regimen was used. Patients were instructed to take one tablet on each day they perceived a risk of drinking alcohol, preferably 1 to 2 hours prior to the anticipated time of drinking. Tablets could be taken up to once daily. As-needed use is a patient-centered approach engaging patients in active and responsible management of their illness. It should be seen as an integral part of disease management, increasing awareness of drinking amount and patterns, facilitating identification of at-risk situations. Objectives Explore the feasibility of as-needed use of nalmefene in alcohol dependence. Methods The Timeline Follow-back was used to obtain estimates of daily drinking and to record daily medication intake. Pooled data (treated patients: nalmefene=643; placebo=633) from the two randomised controlled 6 month studies (ESENSE 1 [NCT00811720] and ESENSE 2 [NCT00812461]) was used. Adherence was defined as medication intake and alcohol consumption, or no alcohol consumption (with or without medication intake). Results Nalmefene was taken on approximately half of the study days; placebo was taken more often than nalmefene. In each treatment group, medication intake varied according to patients’ needs as intake correlated with baseline drinking pattern. 68% of the nalmefene treated patients (78% of the study completers) adhered to the as-needed treatment regimen on at least 80% of the study days. Conclusions These results demonstrate that patients understand, accept, and adhered to the as-needed treatment regimen.