METRIC trial: METfoRmin In psyChosis (METRIC) for weight gain prevention

RESEARCH QUESTION: What is the clinical and cost effectiveness of metformin plus usual care compared to placebo plus usual care for preventing antipsychotic-induced weight gain in people experiencing their first episode of psychosis? BACKGROUND: Antipsychotics (AP), although effective for managing psychosis, are typically associated with weight gain which may be accompanied by an increase in blood lipids and glucose, increasing long-term risk of cardiovascular disease & type 2 diabetes. Implementing lifestyle change to prevent weight gain is challenging. A 2023 Cochrane Review evaluated pharmacological strategies to prevent weight gain in schizophrenia. Low certainty evidence exists that metformin can prevent AP-weight gain. AIM: To determine the clinical and cost effectiveness of metformin plus usual care compared to placebo plus usual care for preventing AP-induced weight gain in people with first episode psychosis (FEP). Primary Objective: To undertake a randomised controlled trial powered to test if metformin plus usual care reduces weight gain by at least 4 kg (equivalent to 5% of the expected baseline body weight) at 1 year compared to placebo plus usual care. Secondary objectives include an economic evaluation to guide cost effectiveness modelling and a process evaluation to understand issues of acceptability and implementation. METHODS: Adults with FEP will be recruited within 1 month of starting AP-treatment. Participants will be randomised to receive either modified-release metformin (up to 2g/day) plus usual care or matching placebo (up to 2g/day) plus usual care for 12 months. Follow up post treatment will be for up to six months to evaluate the effect of the metformin cessation. Primary outcome will be absolute change in weight from baseline to 1 year follow-up. Secondary outcomes: Absolute change in BMI; waist circumference; lipids profile; HbA1c; number and percentage of participants who, by 12 months, have gained >5% and >10% of their body weight; and the number of participants who have a body mass index (BMI) =25 kg/m2; or BMI =30 kg/m2; number who have changed BMI category. Adherence to metformin and APs, psychiatric symptoms, adverse effects, quality of life, cost-effectiveness, resource use. Effect of medication withdrawal over 3-6 months. Acceptability and qualitative evaluation of impact and factors influencing adherence will be assessed through the process evaluation. Health economic analysis will be a cost-utility analysis comparing differences in costs with differences in QALYs generated from EQ-5D-5L. A sample size of 340 participants (170 per arm) allows for 15% loss to follow up, with 90% power (5% significance) to detect a difference of 4kg between groups i.e. a standardised effect size of 0.33, and deemed clinically relevant by clinicians and patients. TIMELINE: 48-month duration including 12m setup, 15m recruitment (including 7m internal pilot), 12 follow-up on-treatment, 3 to 6 m follow-up post treatment, 6m analysis and writeup. IMPACT/DISSEMINATION: Results will inform commissioners on the optimal timing of metformin treatment and if it should be prescribed before weight gain has occurred in people with FEP on AP-treatment. We will engage with networks, professional societies, and patient charities throughout the trial and will share results with all relevant stakeholders.