Nalmefene for reducing alcohol consumption in people with alcohol dependence

Nalmefene compared with psychological intervention

3.1 The company identified 3 randomised controlled trials (ESENSE1, ESENSE2 and SENSE) in adults with alcohol dependence, comparing 18 mg nalmefene (on an as‑needed basis) plus psychosocial support with placebo plus psychosocial support. ESENSE1 (n=604) and ESENSE2 (n=718) were identical efficacy studies with a follow‑up period of 24 weeks. SENSE (n=675) was primarily designed to collect safety data for up to 12 months on nalmefene, but after the study had started the protocol was amended to include efficacy analyses. SENSE had a follow‑up period of 12 months.

3.2 Psychosocial support (in the form of BRENDA), focusing on treatment adherence and reduction of alcohol consumption, was provided to all treatment groups in the 3 studies. The first part comprised a biopsychosocial evaluation, followed by sharing the results with the patient. The next stage involved expressing empathy for the patient and together identifying their needs, providing direct advice to the patient to meet those needs, assessing patient reaction to advice and adjusting the treatment plan as needed. All sessions were provided by trained professionals and were delivered at weekly intervals for the first 2 weeks and then monthly. Sessions lasted for 15–30 minutes except for the first longer session, which was 30–40 minutes.

3.3 Alcohol dependence was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM‑IV‑TR). To be included in the studies, patients must have had 14 or fewer days of abstinence in the 28 days preceding the screening visit, and have an average daily alcohol consumption of medium risk or higher: equivalent to more than 40 g per day (equivalent to more than 5 units) for men and more than 20 g per day (equivalent to more than 2.5 units) for women. Patients had at least 6 heavy drinking days in the 28 days prior to enrolment. A heavy drinking day was defined, in line with the World Health Organization classification of drinking risk levels, as alcohol consumption of more than 60 g per day (equivalent to more than 7.5 units) for men and more than 40 g per day (equivalent to more than 5 units) for women. People with severe medical comorbidities were excluded from all 3 studies, and those with severe psychiatric comorbidities were excluded from the 2 ESENSE trials. The 3 studies were conducted across different regions of Europe. In total, there were 156  sites; 5 sites in the UK were included in the SENSE trial.

3.4 The ESENSE trials contained 4 study periods. The first was a 1–2 week screening period, after which all patients were randomised 1:1 to either the nalmefene plus BRENDA group or placebo plus BRENDA group for 24 weeks. Patients were then instructed to take 1 tablet (the maximum daily dose) on an 'as‑needed' basis, preferably 1–2 hours before they perceived a risk of drinking. If the patients started to drink without taking a tablet, they were advised to take a tablet as soon as possible. The patients who completed the 24‑week trial entered a 4‑week, double‑blind, run‑out period to evaluate any treatment discontinuation effects. Those who had been initially randomised to nalmefene were re‑randomised to receive either nalmefene or placebo, and patients originally in the placebo group continued on placebo. A safety follow‑up visit was scheduled for 4 weeks after completion of the run‑out period or after withdrawal from the study.

3.5 Similar to the ESENSE studies, the SENSE study also began with a 1–2 week screening period, after which patients were randomised 3:1 to receive 52 weeks of as‑needed treatment with nalmefene plus BRENDA or placebo plus BRENDA. A safety follow‑up period was scheduled for 4 weeks after completion of the study or after withdrawal from the study.

3.6 The primary outcomes in ESENSE1 and ESENSE2 measured changes from baseline in the number of heavy drinking days per month and total alcohol consumption at month 6. The company highlighted that the primary end points of number of heavy drinking days and total alcohol consumption were in accordance with the recommendations in the European Medicines Agency guideline on the development of medicinal products for the treatment of alcohol dependence. Total alcohol consumption was defined as mean daily alcohol consumption in grams per day, over a month (28 days). Patients self‑reported their daily alcohol consumption using the timeline follow‑back method at monthly intervals. This provided retrospective estimates of the number of standard drinks consumed each day in the previous month, which were subsequently converted into grams of alcohol per day. Secondary outcomes included the effect of nalmefene on: proportion of people whose alcohol dependence responded to treatment based on different drinking measures, alcohol dependence symptoms and clinical status, liver function and other clinical safety laboratory tests, pharmaco‑economic outcomes, treatment withdrawal effects after 24 weeks, safety and tolerability of nalmefene and quality‑of‑life measures (SF‑36 and EQ‑5D).

3.7 Similar to ESENSE1 and ESENSE2, the primary outcomes for the SENSE study were change from baseline in the number of heavy drinking days per month and total alcohol consumption at month 6. These outcomes were added as an amendment to the protocol while the study was ongoing. No protocol amendments were made to outcomes to assess the safety and tolerability of nalmefene.

3.8 In ESENSE1 and ESENSE2, approximately 78% of all patients enrolled had a high or very high drinking risk level at baseline. In SENSE, 52% of the enrolled patients had a high or very high drinking risk level at baseline. In ESENSE1, ESENSE2 and SENSE, 74%, 57% and 52% respectively continued drinking at this level at randomisation. After an agreement with the Scientific Advisory Group to the European Medicines Agency, the company performed a post hoc analysis in the subgroup of patients in the 3 studies who had a high or very high drinking risk level both at baseline and at randomisation. The company stated that the Scientific Advisory Group recognised the validity of the post hoc subgroup analyses and that these analyses form the basis of the marketing authorisation for nalmefene.

3.9 Results of the post hoc analyses in the licensed population (that is, people who had a high or very high drinking risk level at baseline and maintained such a level at randomisation) showed that there were greater reductions in the number of heavy drinking days and total alcohol consumption in patients treated with nalmefene plus BRENDA, than with placebo plus BRENDA. The treatment difference in the changes from baseline to 6 months in the number of heavy drinking days, using mixed model repeated measures analysis, was −3.7 days per month (95% confidence interval [CI] −5.9 to −1.5, p=0.001) in ESENSE1, and −2.7 days per month (95% CI −5.0 to −0.3, p=0.025) in ESENSE2. The treatment difference in the changes from baseline to 6 months in total alcohol consumption was −18.3 g per day (95% CI −26.9 to −9.7, p<0.001) in ESENSE1, and −10.3 g per day (95% CI −20.2 to −0.5, p=0.040) in ESENSE2. In the SENSE study, the treatment difference in the changes from baseline to 6 months in the number of heavy drinking days was −2.6  days per month (95% CI −5.5 to 0.2, p=0.071) at 6 months, and −3.6 days per month (95% CI −6.5 to −0.7, p=0.016) at month 13. The difference in total alcohol consumption at month 6 was −15.3 g per day (95% CI −29.1 to −1.5, p=0.031) and at month 13 was −17.3 g per day (95% CI −30.9 to −3.8, p=0.013).

3.10 The company did not perform a meta‑analysis of the efficacy data for the ESENSE1, ESENSE2 and SENSE studies but pooled the primary outcomes, the change from baseline to month 6 in monthly heavy drinking days, and total alcohol consumption from ESENSE1 and ESENSE2. In the ESENSE1 and ESENSE2 studies there were 23 heavy drinking days per month at baseline in the nalmefene plus BRENDA group with a reduction to 10 heavy drinking days per month at month 6 (a reduction of 55%). In the placebo plus BRENDA group there were 22 heavy drinking days per month at baseline with a reduction to 13 heavy drinking days per month at month 6 (a reduction of 42%). At 6 months the number of heavy drinking days had been reduced by 3.01 days per month (95% CI −4.36 to −1.66, p<0.0001) and total alcohol consumption had been reduced by 14.22 g per day (95% CI −19.96 to −8.47, p<0.0001). In the ESENSE1 and ESENSE2 studies there was a total alcohol consumption of 107.7 g per day in the nalmefene plus BRENDA group, which reduced to 49.0 g per day at month 6 (a reduction of 61%). In the placebo plus BRENDA group there was a total alcohol consumption of 103.3 g per day, which reduced to 51.9 g per day at month 6 (a reduction of 50%). The odds ratio for the pooled response of drinking risk level for the ESENSE1 and ESENSE2 trials was 1.87 (95% CI 1.35 to 2.59, p<0.001).

3.11 The company reported the results for a number of secondary outcomes in the 3 nalmefene studies. Secondary outcomes included response at month 6 (response of drinking risk level defined as a downward shift from baseline in drinking risk level by 2 risk categories). The odds ratio for nalmefene for response of drinking risk level was 2.15 (95% CI 1.38 to 3.36, p<0.001) in the ESENSE1 study and 1.59 (95% CI 0.98 to 2.59, p=0.062) in the ESENSE2 study. In ESENSE1 and ESENSE2, the EQ‑5D health state and utility index score in the licensed population increased more from baseline to month 6 in the nalmefene plus BRENDA group than in the placebo plus BRENDA group. This was statistically significantly in favour of nalmefene for the health state score in ESENSE1 only. Pooled analysis of the EQ‑5D (a quality of life questionnaire) results in ESENSE1 and ESENSE2 in the licensed population produced a mean change from baseline, for the health state score and the utility index score, of 3.46 points (p=0.0124) for the health state score and 0.03 points (p=0.0445) for the utility index score. The EQ‑5D health state and utility index score in the licensed population increased more from baseline to month 6 in the nalmefene group than in the placebo group with a mean change in utility index score from baseline to month 6 of 0.03±0.02 (95% CI 0.00 to 0.06, p=0.0445) and a mean change in health state score from baseline to month 6 of 3.46±1.38 (95% CI 0.75 to 6.17, p=0.0124).

Evidence Review Group's comments

3.31 The ERG commented that the company had carried out a comprehensive systematic review and all relevant studies for nalmefene plus psychosocial support were included. It was unsure if all relevant naltrexone data had been included. The ERG also commented that the company's model was generally well constructed and had few errors.

3.32 The ERG indicated that the post hoc subgroup analyses of patients who had high or very high drinking risk level in the 3 nalmefene studies may cause the efficacy and safety data to be less robust because they were not powered for this analysis. The robustness may also be affected by the high dropout rates in the nalmefene trials. The company carried out sensitivity analyses to account for the missing data but there were some inconsistencies as to whether statistical significance was achieved or not. The ERG also indicated that patient self‑reporting of alcohol intake could bias the results.

3.33 The ERG indicated that the uncertainties in the clinical evidence related to the types and frequencies of psychosocial intervention, along with its treatment duration and generalisability to England. Psychosocial support in the form of BRENDA was used in the nalmefene trials but was delivered at different intervals to the psychosocial intervention (including behavioural therapies, cognitive behavioural therapy and behavioural couples therapies) recommended in the NICE guideline on alcohol-use disorders. The ERG stated that the evaluation carried out in the model does not meet that specified in the final scope and that it was difficult to know how the results would apply to people receiving different forms and frequencies of psychosocial intervention.

3.34 The ERG had concerns about the generalisability of the population in the 3 nalmefene studies to clinical practice in England. People with severe psychiatric comorbidities were excluded from all 3 nalmefene trials, and those with severe medical comorbidities were excluded from the ESENSE trials. The company commented in its submission that many people with alcohol dependence also have diagnosed medical conditions and/or psychiatric comorbidities. Patients were also excluded from the nalmefene trials if they were taking certain medication, such as drugs for angina, anticoagulants, anticonvulsants, insulin, sedatives and systemic steroids. The ERG stated that the safety and efficacy of nalmefene in people taking these drugs was therefore uncertain. Only a small number of trial patients were from the UK (SENSE trial only, 5 sites out of a total of 156) and the company did not provide any data on the variability of the outcomes for different European countries. The ERG stated that the generalisability of this data for England was unknown.

3.35 The ERG noted that naltrexone was not formally modelled as a comparator in the economic analysis even though it was included in the final scope issued by NICE. The model assumed that if patients stopped nalmefene treatment because of adverse events, they would switch to psychosocial support alone, but it did not account for switching to naltrexone. The ERG commented that it was unsure whether this assumption could be favourable or unfavourable to nalmefene.

3.36 The ERG stated that its clinical advisers did not agree with the assumption that people would remain on treatment (regardless of drinking level) for the full year. The ERG commented that its clinical advisers believed that GPs would not let patients drink at very high risk levels for more than 6 months without recommending intensification of psychosocial intervention and additional expert input, and that 3 months might be a more likely cut‑off point.

Evidence Review Group's exploratory analyses

3.37 The ERG formulated 4 comparisons in its exploratory analysis (see table 2).

Table 2 The 4 comparisons formulated by the Evidence Review Group

3.38 For comparison 1, the ERG carried out a number of exploratory analyses including:

3.39 The ERG's base case included assumptions 1, 2 and 5, with the additional assumption that 50% of people withdrawing from nalmefene would also withdraw from psychosocial support treatment. In the ERG base case, nalmefene plus psychosocial support still dominated psychosocial support alone. The ERG carried out a second analysis using their base case assumption but also presumed no second‑line treatment options were allowed and the ICER was £5166 per QALY gained when comparing nalmefene plus psychosocial support with psychosocial support alone. Although the ERG was critical of the fact that the company did not conduct a half‑cycle correction, the model was not adapted by the ERG to allow this for 2 reasons: the first was the time needed to carry out this adaptation and the second because after the first year (in which monthly cycles were used), there was no differential efficacy between the 2 arms apart from people drinking at medium drink risk levels. Also, any potential inaccuracy was relatively small compared with the uncertainty explored in comparisons 2 and 3.

3.40 For comparison 2, the ERG suggested that it was unlikely for people at medium risk drinking level to have treatment indefinitely and assumed in comparison 1 that these people would relapse to high and very high risk levels. The ERG was unable to carry out a threshold analysis altering the variable treatment options because this part of the model was not functioning, and also given that the impact in the ICER was small, the ERG left the assumption as it was. The threshold analysis carried out by the company in scenario 7 was reassessed in the ERG's comparison 2 (with the exception that those at a medium risk drinking level were assumed to remain on treatment). The results produced by the ERG were similar to the company's results. If the efficacy of nalmefene and psychosocial support compared with psychosocial support alone were reduced by 62.8%, then the ICER would become £20,000 per QALY gained. The reduction would have to be 71.5% for the ICER to reach £30,000 per QALY gained. When additional factors accounting for the potential cost of crime and loss of productivity were considered, the efficacy of nalmefene and psychosocial support compared with psychosocial support alone would need to be reduced by 80.4% and 83.1% for the ICER to be £20,000 and £30,000 per QALY gained respectively.

3.41 For comparison 3, the ERG highlighted that there were few data to assess the cost effectiveness of nalmefene with psychosocial intervention when using the psychosocial intervention as described in the NICE guideline on alcohol-use disorders. The time point at which psychosocial intervention alone was not successful was also unknown but the nalmefene trials indicated that when patients were treated with BRENDA alone, approximately 20% were either abstinent or of low risk drinking level at month 3. The ERG suggested a greater response may be seen with higher‑intensity psychosocial intervention and that the costs of nalmefene can be saved without incurring health losses particularly if nalmefene use was delayed. The ERG did caution that there would be uncertainty about the efficacy of nalmefene in patients whose alcohol dependence had not responded to psychosocial support alone.

3.42 For comparison 4, again the ERG suggested there were few data available and therefore did not feel comfortable estimating an ICER for this comparison.

3.43 Full details of all the evidence are available.