A multi-centre, placebo-controlled, 2x2 factorial, randomised clinical trial of combined lisdexamphetamine and mirtazapine for cocaine use disorder. The MEDications for COcaine Use Disorder (MEDCO) study.

RESEARCH QUESTION. The MEDications for COcaine Use Disorder (MEDCO) study will determine the efficacy of an 18-week pharmacotherapy with a stimulant and an anti-depressant (evaluated singly and in combination) to help adults with cocaine addiction abstain from cocaine and recover. BACKGROUND. Cocaine is a powerful, addictive stimulant. In the UK last year around 116,000 people with cocaine use disorder (CUD; DSM-5) sought help, but clinicians had no medication to offer. CUD is complex and hard-to-treat. The MEDCO study hypothesises that a combination pharmacotherapy is needed. The accumulated evidence points to two medication candidates: lisdexamphetamine (LDX), a prodrug taken once daily in the morning to attenuate cocaine withdrawal symptoms, boost cognition and control cravings; and mirtazapine (MZP), an atypical antidepressant taken once daily at nighttime to improve sleep and attenuate psychological distress. In combination, LDX and MZP could be highly efficacious. AIMS AND OBJECTIVES. The study is a Patient and Public Involvement and Engagement co-designed, multi-centre, 2x2 factorial, placebo-controlled, double-blind, phase 2b randomised clinical trial, with 3-week induction, 12-week stabilisation, 3-week taper, and a week-24 endpoint. The study will be conducted in England and Scotland in urban, rural and coastal areas of high need. An internal pilot assesses recruitment, adherence, and outcome data collection. Participants are randomly assigned (1:1:1:1) to one of 4 groups: (1) Active LDX and Active MZP; (2) Placebo LDX and Active MZP; (3) Active LDX and Placebo MZP; (4) Placebo LDX and Placebo MZP. The primary outcome measure is the count of cocaine-abstinent days from randomisation to study endpoint (range: 0–168 days) using the addiction field gold standard Time-Line Follow-Back (TLFB) interview with a Urine Drug Screen (UDS) to detect benzoylecgonine (cocaine’s primary metabolite). The TLFB and UDS procedure will be conducted at each of 13 clinic visits. The treatment effect is an adjusted interval rate ratio from a mixed-effects Poisson regression, with multiple-imputation to manage missing data. Planning for 20% attrition per group, 400 participants (randomly allocated 1:1:1:1) to the 4 groups will give 95% power to detect this effect. The project includes 2 clinical objectives (CO) and 3 mechanistic objectives (MO) to investigate: duration and timing of cocaine abstinence; retention; other drug use; craving and withdrawal symptoms; remission; patient reported outcome; sleep quality; ADHD symptoms; cognitive impairment; social functioning; and psychological distress (CO1); safety (CO2); treatment effect modification (MO1); craving, sleep quality, cognition, ADHD symptoms, and psychological distress mediation of cocaine abstinence (MO2); specific and combined effects of LDX and MZP in reducing activation of craving, affect and cognition circuitry via fMRI cue-reactivity paradigm (MO3). TIMELINES FOR DELIVERY. From June 2025, project delivered is 49 months. First and last participants are enrolled in June 2026 (pilot) and September 2028 (full trial), respectively. DISSEMINATION AND ANTICIPATED IMPACT. Primary findings (full disaggregation by demographic and clinical characteristics), will be submitted within 12 weeks after review by study committees and partners, to a high-impact medical journal, with engaging summaries for general audiences. Meeting endpoint will secure progression support for HTA phase 3 project.