Health Technology Assessment (Oct 2023)
Adjunctive Medication Management and Contingency Management to enhance adherence to acamprosate for alcohol dependence: the ADAM trial RCT
Abstract
Background Acamprosate is an effective and cost-effective medication for alcohol relapse prevention but poor adherence can limit its full benefit. Effective interventions to support adherence to acamprosate are therefore needed. Objectives To determine the effectiveness of Medication Management, with and without Contingency Management, compared to Standard Support alone in enhancing adherence to acamprosate and the impact of adherence to acamprosate on abstinence and reduced alcohol consumption. Design Multicentre, three-arm, parallel-group, randomised controlled clinical trial. Setting Specialist alcohol treatment services in five regions of England (South East London, Central and North West London, Wessex, Yorkshire and Humber and West Midlands). Participants Adults (aged 18 years or more), an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of alcohol dependence, abstinent from alcohol at baseline assessment, in receipt of a prescription for acamprosate. Interventions (1) Standard Support, (2) Standard Support with adjunctive Medication Management provided by pharmacists via a clinical contact centre (12 sessions over 6 months), (3) Standard Support with adjunctive Medication Management plus Contingency Management that consisted of vouchers (up to £120) to reinforce participation in Medication Management. Consenting participants were randomised in a 2 : 1 : 1 ratio to one of the three groups using a stratified random permuted block method using a remote system. Participants and researchers were not blind to treatment allocation. Main outcome measures Primary outcome: self-reported percentage of medication taken in the previous 28 days at 6 months post randomisation. Economic outcome: EuroQol-5 Dimensions, a five-level version, used to calculate quality-adjusted life-years, with costs estimated using the Adult Service Use Schedule. Results Of the 1459 potential participants approached, 1019 (70%) were assessed and 739 (73 consented to participate in the study, 372 (50%) were allocated to Standard Support, 182 (25%) to Standard Support with Medication Management and 185 (25%) to Standard Support and Medication Management with Contingency Management. Data were available for 518 (70%) of participants at 6-month follow-up, 255 (68.5%) allocated to Standard Support, 122 (67.0%) to Standard Support and Medication Management and 141 (76.2%) to Standard Support and Medication Management with Contingency Management. The mean difference of per cent adherence to acamprosate was higher for those who received Standard Support and Medication Management with Contingency Management (10.6%, 95% confidence interval 19.6% to 1.6%) compared to Standard Support alone, at the primary end point (6-month follow-up). There was no significant difference in per cent days adherent when comparing Standard Support and Medication Management with Standard Support alone 3.1% (95% confidence interval 12.8% to −6.5%) or comparing Standard Support and Medication Management with Standard Support and Medication Management with Contingency Management 7.9% (95% confidence interval 18.7% to −2.8%). The primary economic analysis at 6 months found that Standard Support and Medication Management with Contingency Management was cost-effective compared to Standard Support alone, achieving small gains in quality-adjusted life-years at a lower cost per participant. Cost-effectiveness was not observed for adjunctive Medication Management compared to Standard Support alone. There were no serious adverse events related to the trial interventions reported. Limitations The trial’s primary outcome measure changed substantially due to data collection difficulties and therefore relied on a measure of self-reported adherence. A lower than anticipated follow-up rate at 12 months may have lowered the statistical power to detect differences in the secondary analyses, although the primary analysis was not impacted. Conclusions Medication Management enhanced with Contingency Management is beneficial to patients for supporting them to take acamprosate. Future work Given our findings in relation to Contingency Management enhancing Medication Management adherence, future trials should be developed to explore its effectiveness and cost-effectiveness with other alcohol interventions where there is evidence of poor adherence. Trial registration This trial is registered as ISRCTN17083622 https://doi.org/10.1186/ISRCTN17083622. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 22. See the NIHR Journals Library website for further project information. Plain language summary What is the problem? Many people who are trying to stop drinking alcohol can find it difficult to remain alcohol free. There is a medication called acamprosate (Campral) that can reduce cravings thereby increasing the likelihood of abstinence. However, some people have trouble taking the right amount of acamprosate tablets needed every day at the right time, preferably at mealtimes. This means the medication is not as effective. We have tested some new ways to help support people taking acamprosate. What did we do? We tested three different strategies to find the best way to support people taking acamprosate. We recruited 739 people aged 18 and over who were receiving alcohol treatment to stop drinking and were taking acamprosate. We randomly allocated these people to three groups. The first was Standard Support, the usual support people receive when taking acamprosate. The second group received Standard Support plus Medication Management. This consisted of 12 telephone calls over 6 months with a trained pharmacist to discuss the importance of taking the right amount of the medication, how the medication works and strategies to help people take the medication correctly. The third group received Standard Support, Medication Management and Contingency Management. This involved giving people shopping vouchers for participating with Medication Management calls. The maximum value of vouchers per person was £120. What did we find out? People who were in the group receiving Medication Management and Contingency Management took a greater number of acamprosate tablets. We also found that Medication Management plus Contingency Management was more cost-effective; there were greater gains in health with a smaller cost per person compared to Standard Support alone. This shows that there is likely to be a benefit to patients of Medication Management plus Contingency Management for supporting people taking acamprosate. Scientific summary Background Alcohol is a significant risk factor for morbidity and mortality. In the UK there has been an increase in harm related to alcohol while also a reduction in funding to public health budgets, including alcohol services. While some individuals do successfully complete alcohol treatment, the majority will undergo frequent episodes of relapse. Providing effective treatment can reduce relapse rates and associated harms thus having a positive impact on cost-effectiveness. The National Institute for Health and Care Excellence (NICE) recommends acamprosate in combination with psychological intervention as a first-line treatment for relapse prevention in alcohol dependence, however, acamprosate adherence poses a problem for its effectiveness in clinical practice. The reasons for non-adherence are complex and often due to multiple influences. Currently there is insufficient evidence as to which forms of intervention are effective in increasing adherence. Psychosocial interventions to support medication adherence have the potential to promote positive beliefs about medication and any concerns. Medication Management (MM) is a psychosocial intervention which aims to improve medication and treatment adherence by providing education, support, and practical advice about drinking behaviour and medication. There has also been an increasing focus on extending the role of the community pharmacist and the delivery of MM to improve medication adherence compliments this expanding role. Engagement in psychological interventions and retention in treatment is often poor in alcohol dependence but there is evidence that Contingency Management (CM) improves engagement and retention in substance use disorder treatment. There is currently limited evidence of its effectiveness within alcohol treatment but if shown to be effective it has the potential to also be adopted within the NHS and community pharmacies. Objectives Our aim was to evaluate the effectiveness and cost-effectiveness of adjunctive MM with and without CM in improving adherence to acamprosate for relapse prevention in alcohol dependence. To conduct a definitive three-arm, randomised controlled trial (RCT) of the effectiveness of MM with and without CM compared to Standard Support (SS) alone in enhancing adherence to acamprosate in alcohol dependence relapse prevention. To estimate the cost-effectiveness of MM with and without CM compared to SS alone in enhancing adherence to acamprosate in alcohol dependence relapse prevention. To assess the impact of adherence to acamprosate for alcohol dependence relapse prevention on abstinence and reduced alcohol consumption. Methods Trial design This was a three-arm, parallel-group, pragmatic RCT, which began with an internal pilot phase to demonstrate recruitment, randomisation and interventions could be implemented as planned. Eligibility and recruitment Participants presenting to alcohol services in one of the trial sites (London, Southampton, Birmingham, Yorkshire and Humber) who met the trial inclusion criteria were recruited via service staff. Participants Inclusion criteria were: (1) adults, aged 18 years and over; (2) an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of alcohol dependence; (3) abstinent from alcohol at baseline assessment; (4) in receipt of a prescription of acamprosate; and (5) willing and able to provide informed consent. Exclusion criteria were: (1) a diagnosis of a severe physical/mental illness likely to preclude active participation in treatment or follow-up, (2) unable to understand verbal English at a level necessary to engage in the intervention and follow-up and (3) concurrent dependence on an illicit substance (other than cannabis). Randomisation and interventions Participants were randomised in a 2 : 1 : 1 ratio to SS, SS + MM or SS + MM + CM using a stratified random permuted block method using a remote system. Participants and researchers were not blind to treatment allocation. SS typically comprised of monthly dispensing of prescribed acamprosate, monthly monitoring of the service user for 3 months by the specialist alcohol service, and then returned to the care of their GP for monthly monitoring in accordance with NICE guidelines and current clinical NHS clinical practice. SS + MM participants followed the same care pathway as those in SS, with the addition of MM delivered by a central telephone support service by trained pharmacists. MM was delivered once a week for the first 6 weeks, reducing to once a fortnight for the following 6 weeks, and then monthly for 3 months. SS + MM + CM participants followed the same care pathway as those in the SS + MM arm but with the addition of CM. Incentives in the form of vouchers were provided to reinforce attendance at MM sessions, up to a total of £120. Outcomes The primary outcome measure was the self-reported per cent of medication taken as prescribed during the 6-month target phase of prescribing, post randomisation. Data collection Data were collected at baseline, 2, 4, 6 and 12 months. Following an amendment, the 12-month follow-up was removed to maximise participant recruitment, and the recruitment period was extended without extending the trial end date. Data that had been collected at the 12-month follow-up were still included in the trial analysis plan. The primary outcome was collected at the 6-month follow-up. Sample size The sample size aimed to detect a clinically important effect size difference of 0.3, about 13% difference in per cent adherence. In order to make the study cost-efficient, we proposed to allocate twice as many to the SS group than to the SS + MM and SS + MM + CM groups. With power at 80%, alpha of 0.05 and a two-sided test, this required 524 to be followed up at the primary end point, 262 in the SS group and 131 in each of the other groups. We anticipated a loss to follow-up at month 6 of 30% and inflated the required sample at baseline to 748 to account for this. Sample sizes were calculated using Stata 12 (StataCorp LP, College Station, TX, USA). Statistical methods The primary analysis was an analysis by treatment allocated (ATA) and was based on all available data for participants who were randomised, irrespective of whether they complied with their allocation or not. The primary analysis was based on the ATA. Secondary analyses examined treatment effects under different scenarios for compliance with allocation/treatment: complier average causal effects (CACE). Two scenarios of compliance were defined in this trial. The first compliance for those in the SS + MM and SS + MM + CM group was defined as adhering to at least 50% of the MM calls. In the second, the threshold was increased to 100%. Both scenarios are modelled in the analysis. We considered missing data as being missing at random (MAR) or missing not at random (MNAR). We conducted a multiple imputation to address MAR and a sensitivity analysis to address MNAR. Fractional regression was conducted to model the relationship between pre-randomisation factors and per cent adherence to acamprosate and per cent days abstinent from alcohol at month 6. Interaction terms with treatment allocation were included in the model and a significance level of 0.1 was used as a threshold to determine which variables were maintained in the final model reported. Baseline variables included initially in the model include age, gender, marital status, ethnicity, employment status, number of children, age of first drink, weekly and daily drinking, frequency and quantity of alcohol consumption, severity of alcohol dependence, alcohol urges and alcohol-related problems. This analysis was augmented with an additional analysis for the SS + MM and SS + MM + CM groups where the same dependent variable was assessed with the same independent variables with the addition of therapeutic alliance. Method of economic evaluation The primary economic analysis was a cost-utility analysis where outcomes were expressed as quality-adjusted life-years (QALYs), as recommended by NICE. A secondary analysis explored cost-effectiveness in terms of the primary clinical outcome which was adherence to relapse prevention medication. The primary economic perspective was the NHS and personal social services (NHS/PSS) perspective preferred by NICE. The primary time horizon of the economic analyses using both QALYs and relapse medication adherence was the 6-month follow-up, consistent with the primary clinical analysis. A secondary analysis was carried out at the 12-month follow-up using QALYs. The primary economic outcome was QALYs calculated using the EuroQol-5 Dimensions, a five-level version measure of health-related quality-of-life scores at baseline, 6- and 12-month follow-ups. The primary economic analysis was composed of two separate comparisons: (1) SS + MM + CM versus SS alone; and (2) SS + MM versus SS alone, both at 6 months post randomisation, and assessed cost-effectiveness in terms of cost per QALY using the EuroQol-5 Dimensions measure of quality of life. Two secondary economic evaluations were carried out, a cost-utility analysis at 12 months post randomisation and a cost-effectiveness analysis using adherence to relapse medication which was the primary clinical outcome. Cost-effectiveness was explored using incremental cost-effectiveness ratios (difference in mean cost divided by difference in mean effect) and cost-effectiveness acceptability curves (CEACs), which show the probability that SS + MM + CM or SS + MM are cost-effective compared to SS alone for different levels of willingness to pay for improvements in outcome. Sensitivity analyses were carried out to test the impact of varying methods and assumptions on the relative cost-effectiveness of the interventions being compared. We planned three sensitivity analyses: (1) a broader analytical perspective to include the cost of crime (which was not completed as no crimes were reported), (2) a complete case analysis for comparison with the results that used multiple imputation for missing data and (3) a cost-utility analysis using QALYs calculated from EuroQol-5 Dimensions, three-level version tariffs. Results A total of 1459 potential participants were approached of whom 1019 (70%) were assessed. Of these 739 (73%) were eligible and consented to participate in the study. Allocation was in the ratio of 2 : 1 : 1, 372 (50%) were allocated to SS, 182 (25%) to SS + MM and 185 (25%) to SS + MM + CM. At the primary end point, 6 months post randomisation, 518 (70%) were successfully followed up with 255 (68.5%) allocated to SS, 122 (67.0%) to SS + MM and 141 (76.2%) to SS + MM + CM. There were no serious adverse events related to the trial interventions reported. The mean difference in per cent adherence to acamprosate at month 6 between those allocated to SS and SS + MM + CM versus SS was 10.6% [95% confidence interval (CI) 19.6% to 1.6%]; this difference was statistically significant. When the SS + MM group was compared to SS alone, the SS + MM group had a lower per cent days adherent than the SS group, mean difference 3.1% (95% CI 12.8% to −6.5%); this was not significant. A similar non-significant finding was seen when we compared the SS + MM and SS + MM + CM groups, mean difference 7.9% (95% CI 18.7% to −2.8%). Our secondary analysis included per cent days abstinent from alcohol at month 6. The ATA found differences favouring both intervention groups over SS alone but neither of these was significant. When a CACE analysis was conducted using scenario 2, both intervention groups had a significantly greater per cent days abstinent than SS alone. This analysis also highlighted the relationship between adherence to acamprosate and better outcomes, something additionally highlighted by a significant correlation between adherence to acamprosate and increased per cent days abstinent at month 6. CACE analysis: Under scenario 1, 50% adherence, the mean difference in per cent adherence increases from 10.6% (95% CI 19.6 to 1.62) to 12.4% (95% CI 17.8% to 7.1%) in the SS + MM + CM versus SS comparison, indicating that at 50% compliance those allocated to SS + MM + CM have a mean of 12.44% more adherence to acamprosate at month 6 than those allocated to SS alone. When comparing the SS + MM versus the SS group, a previous non-significant difference 3.14% (95% CI 12.8% to −6.5%) becomes a significant difference of 13.2% (25.4–1.15%). Under scenario 2, the differences are larger in magnitude, the SS + MM + CM group having 22.2% (95% CI 29.7% to 14.7%) more adherent days than the SS group alone. At the same time, the magnitude of difference is larger for the SS + MM versus SS comparison 31.8% (95–60.5% vs. 3.10%), although this comparison is based on a small number of participants, 20, and should be interpreted with caution. For SS + MM + CM versus SS, the primary economic analysis at 6-month follow-up using QALYs, the secondary economic analysis at 6-month follow-up using medication adherence and the economic modelling over a 20-year time horizon using QALYs all found SS + MM + CM to dominate SS (better outcomes at lower cost). At 12-month follow-up, although SS + MM + CM was not dominant, it generated more QALYs at an additional cost that was below the NICE cost per QALY threshold. CEACs also showed there was a higher probability of SS + MM + CM being cost-effective compared to SS alone in all analyses and at all time points. For SS + MM versus SS, at 6- and 12-month follow-up and when modelled over 20 years, SS + MM achieved better outcomes at higher cost compared to SS. In terms of cost-effectiveness, SS + MM was not found to be cost-effective at 6-month follow-up but had a higher probability of being cost-effective compared to SS at both the 12-month follow-up (using the higher £30,000 per QALY NICE threshold) and when modelled over 20 years (over the full £20,000–30,0000 cost per QALY threshold). Conclusions When comparing SS + MM + CM versus SS alone, we observed a significantly higher per cent adherence to acamprosate in the SS + MM + CM group, and the differences were of the magnitude that would indicate a clinically important difference. Differences were also observed when comparing SS + MM versus SS and SS + MM + CM versus SS + MM, but these were not significant. We explored how robust these findings were to assumptions about the nature of any missing data and we explored a missing data imputation model to explore the impact of data that may be MAR and a sensitivity analysis to explore data that may not be MAR. Neither of these analyses found any significant deviation from the analysis based on observed values, we can be confident that our findings from the ATA analysis are robust. To explore the effect of compliance to MM we conducted a CACE analysis using two scenarios of compliance, 50% and 100%. In both scenarios, we found greater benefits associated with SS + MM + CM and SS + MM versus SS alone and these benefits were significant and clinically important. There were several limitations to the current trial that should be taken into consideration. The trial’s primary outcome measure changed substantially due to data collection difficulties and therefore relied on a measure of self-reported adherence. A lower than anticipated follow-up rate at 12 months may have lowered the statistical power to detect differences in the secondary analyses, although the primary analysis was not impacted. The results of the primary economic analysis at the 6-month follow-up point suggest that MM was only cost-effective when supported by incentives to encourage support session uptake. This finding was heavily influenced by lower total costs in the SS + MM + CM group as a result of lower use of residential rehabilitation facilities compared to both SS + MM and SS alone, which may be related to the significantly higher medication adherence seen in the CM group. Over the medium (12 months) and longer term (20 years), SS + MM + CM remained cost-effective compared to SS and there was a higher probability of SS + MM being cost-effective compared to SS. These results support the addition of MM to SS for alcohol dependence, with or without CM. However, the economic benefit was stronger when CM was included. Trial registration This trial is registered as ISRCTN17083622 https://doi.org/10.1186/ISRCTN17083622. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 22. See the NIHR Journals Library website for further project information.
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