Mental Imagery to Reduce Alcohol-related harm in patients with alcohol use disorder and alcohol-related liver damaGE: the MIRAGE randomised pilot trial results.

OBJECTIVE: The healthcare burden of alcohol-related liver disease (ARLD) is increasing. ARLD and alcohol use disorder (AUD) is best managed by reduction or cessation of alcohol use, but effective treatments are lacking. We tested whether people with ARLD and AUD admitted to hospital could be recruited to and retained in a trial of Functional Imagery Training (FIT), a psychological therapy that uses mental imagery to reduce alcohol craving. We conducted a multicentre randomised pilot trial of treatment as usual (TAU) versus FIT+TAU in people admitted to hospital with ARLD and AUD. DESIGN: Participants were randomised to TAU (a single session of brief intervention) or FIT+TAU (TAU with one hospital-based FIT session then eight telephone sessions over 6 months). Pilot outcomes included recruitment rate and retention at day 180. Secondary outcomes included fidelity of FIT delivery, alcohol use, and severity of alcohol dependence. RESULTS: Fifty-four participants (mean age 49; 63% male) were recruited and randomised, 28 to TAU and 26 to FIT+TAU. The retention rate at day 180 was 43%. FIT was delivered adequately by most alcohol nurses. 50% of intervention participants completed FIT sessions 1 and 2. There were no differences in alcohol use or severity of alcohol dependence between treatment groups at day 180. CONCLUSION: Participants with ARLD and AUD could be recruited to a trial of FIT versus FIT+TAU. However, retention at day 180 was suboptimal. Before conducting a definitive trial of FIT in this patient group, modifications in the intervention and recruitment/retention strategy must be tested. TRIAL REGISTRATION NUMBER: ISRCTN41353774.

Motivational support intervention to reduce smoking and increase physical activity in smokers not ready to quit: the TARS RCT.

Background: Physical activity can support smoking cessation for smokers wanting to quit, but there have been no studies on supporting smokers wanting only to reduce. More broadly, the effect of motivational support for such smokers is unclear. Objectives: The objectives were to determine if motivational support to increase physical activity and reduce smoking for smokers not wanting to immediately quit helps reduce smoking and increase abstinence and physical activity, and to determine if this intervention is cost-effective. Design: This was a multicentred, two-arm, parallel-group, randomised (1 : 1) controlled superiority trial with accompanying trial-based and model-based economic evaluations, and a process evaluation. Setting and participants: Participants from health and other community settings in four English cities received either the intervention (n = 457) or usual support (n = 458). Intervention: The intervention consisted of up to eight face-to-face or telephone behavioural support sessions to reduce smoking and increase physical activity. Main outcome measures: The main outcome measures were carbon monoxide-verified 6- and 12-month floating prolonged abstinence (primary outcome), self-reported number of cigarettes smoked per day, number of quit attempts and carbon monoxide-verified abstinence at 3 and 9 months. Furthermore, self-reported (3 and 9 months) and accelerometer-recorded (3 months) physical activity data were gathered. Process items, intervention costs and cost-effectiveness were also assessed. Results: The average age of the sample was 49.8 years, and participants were predominantly from areas with socioeconomic deprivation and were moderately heavy smokers. The intervention was delivered with good fidelity. Few participants achieved carbon monoxide-verified 6-month prolonged abstinence [nine (2.0%) in the intervention group and four (0.9%) in the control group; adjusted odds ratio 2.30 (95% confidence interval 0.70 to 7.56)] or 12-month prolonged abstinence [six (1.3%) in the intervention group and one (0.2%) in the control group; adjusted odds ratio 6.33 (95% confidence interval 0.76 to 53.10)]. At 3 months, the intervention participants smoked fewer cigarettes than the control participants (21.1 vs. 26.8 per day). Intervention participants were more likely to reduce cigarettes by ≥ 50% by 3 months [18.9% vs. 10.5%; adjusted odds ratio 1.98 (95% confidence interval 1.35 to 2.90] and 9 months [14.4% vs. 10.0%; adjusted odds ratio 1.52 (95% confidence interval 1.01 to 2.29)], and reported more moderate-to-vigorous physical activity at 3 months [adjusted weekly mean difference of 81.61 minutes (95% confidence interval 28.75 to 134.47 minutes)], but not at 9 months. Increased physical activity did not mediate intervention effects on smoking. The intervention positively influenced most smoking and physical activity beliefs, with some intervention effects mediating changes in smoking and physical activity outcomes. The average intervention cost was estimated to be £239.18 per person, with an overall additional cost of £173.50 (95% confidence interval -£353.82 to £513.77) when considering intervention and health-care costs. The 1.1% absolute between-group difference in carbon monoxide-verified 6-month prolonged abstinence provided a small gain in lifetime quality-adjusted life-years (0.006), and a minimal saving in lifetime health-care costs (net saving £236). Conclusions: There was no evidence that behavioural support for smoking reduction and increased physical activity led to meaningful increases in prolonged abstinence among smokers with no immediate plans to quit smoking. The intervention is not cost-effective. Limitations: Prolonged abstinence rates were much lower than expected, meaning that the trial was underpowered to provide confidence that the intervention doubled prolonged abstinence. Future work: Further research should explore the effects of the present intervention to support smokers who want to reduce prior to quitting, and/or extend the support available for prolonged reduction and abstinence. Trial registration: This trial is registered as ISRCTN47776579. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 4. See the NIHR Journals Library website for further project information.

NHS pharmacological and behavioural support helps smokers wanting to quit, and physical activity may also help. It is unclear if behavioural support for those not ready to quit may lead to more quit attempts and abstinence from smoking. A total of 915 smokers who wanted to reduce their smoking, but who had not yet quit, were recruited and randomised to receive an intervention or brief support as usual (brief advice to quit), in Plymouth, London, Oxford and Nottingham. The intervention involved up to eight sessions (by telephone or in person) of motivational support to reduce smoking and increase physical activity (and more sessions to support a quit attempt). Participants self-reported smoking and physical activity information at the start of the trial and after 3 and 9 months. Self-reported quitters confirmed their abstinence with a biochemical test of expired air or saliva. Our main interest was in whether or not the groups differed in the proportion who remained abstinent for at least 6 months. Overall, only 1­2% remained abstinent for 6 months. Although it appeared that a greater proportion did so after receiving the intervention, because few participants were abstinent, the results are not conclusive. However, the intervention had beneficial effects on less rigorous outcomes, including a reduction in the self-reported number of cigarettes smoked, and a greater proportion of intervention than control participants with self-reported and biochemically verified abstinence at 3 months. The intervention also helped participants to reduce, by at least half, the number of cigarettes they smoked at 3 and 9 months, and to report more physical activity, but only at 3 months. Despite reasonable intervention engagement and some short-term changes in smoking and physical activity, the trial does not provide evidence that this intervention would help smokers to quit for at least 6 months nor would it be cost-effective, with an average cost of £239 per smoker.

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. Design, Setting, and Participants: This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Interventions: Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. Main Outcomes and Measures: The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Results: Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. Conclusions and Relevance: In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. Trial Registration: ISRCTN Identifier: 16108482.

Mental Imagery to Reduce Alcohol-related harm in patients with alcohol dependence and alcohol-related liver damaGE: the MIRAGE pilot trial protocol.

INTRODUCTION: In the UK, alcohol use is the main driver of chronic liver disease and each year results in over 1 million unplanned hospital admissions and over 25 000 deaths from alcohol-related liver disease (ArLD). The only effective treatment to prevent progression of liver damage is reducing or ceasing alcohol consumption. Psychological and pharmacological therapies for alcohol misuse are ineffective in patients with ArLD. Functional imagery training (FIT) is a novel psychological therapy that builds on motivational interviewing techniques with multisensory imagery. This pilot trial aims to test the feasibility of training alcohol liaison nurses to deliver FIT therapy and of recruiting and retaining patients with ArLD and alcohol dependence to a randomised trial of FIT and treatment as usual (TAU) versus TAU alone. METHODS AND ANALYSIS: This is a randomised pilot trial of FIT and TAU versus TAU alone in 90 patients with ArLD and alcohol dependence admitted to one of four UK centres. The primary objectives are to estimate rates of screening, recruitment, randomisation, retention, adherence to FIT/TAU and a preliminary assessment of the FIT intervention in the ArLD population. Data from the pilot study will be used to finalise the design of a definitive randomised controlled trial to assess the effectiveness and cost-effectiveness of FIT. The proposed primary outcome measure for the definitive trial is self-reported alcohol use assessed using timeline follow-back. ETHICS AND DISSEMINATION: Research ethics approval was given by the Yorkshire and Humber-Bradford Leeds Research Ethics Committee (reference: 21/YH/0044). Eligible patients will be approached and written informed consent obtained prior to participation. Results will be disseminated through peer-reviewed open access journals, international conferences and a lay summary published on the Trials Unit website and made available to patient groups. TRIAL REGISTRATION NUMBER: ISRCTN41353774.