Aripiprazole/ sertraline combination: Clinical and cost-effectiveness in comparison with quetiapine for the treatment of bipolar depression. An open label randomised controlled trial. (ASCEnD)

This is a prospective, 2-arm, open label, superiority, individually randomised, controlled, pragmatic, parallel group, type A open label clinical trial in adults with bipolar disorder who are experiencing a depressive episode. The intervention arm is aripiprazole/sertraline combination and the comparator (1:1 randomisation) is quetiapine with primary outcome at 12-16 weeks and secondary outcomes at, and over, 24 weeks. Methods include remote collection of outcome measures relating to patient rated efficacy, treatment satisfaction and cost-effectiveness. Inclusion criteria include; current depressive episode of at least moderate severity, bipolar affective disorder, aged 18 or over, able to provide written informed consent, clinical uncertainty regarding the next course of treatment, judgement that both arms are clinically appropriate and represent equipoise, clinician satisfaction that the potential participant is not currently pregnant or planning to become pregnant during the trial and clinicians' opinion that the participant is able to follow trial prescription instructions, complete weekly questionnaires and engage in weekly telephone calls with study research assistants throughout the 24 week follow up period of the trial. Exclusion criteria include participation in another interventional trial that may affect the outcome of ASCEnD and DSM-5-TR (Diagnostic and Statistical Manual-5-Text Revision) defined severe substance use disorder. The primary objective is to test the hypothesis that improvement in depression will be greater in participants randomised to aripiprazole/sertraline combination than those randomised to quetiapine. This will be measured using the Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR), reported weekly 12 to 16 weeks after randomisation in the two arms. Secondary objectives include comparison of the impact of aripiprazole/sertraline combination versus quetiapine on the trajectories of symptom change, treatment satisfaction, tolerability, pattern of medication adherence, pattern of non-randomised antidepressant/antipsychotic medication use, change in anxiety symptoms, change in manic symptoms, psychosocial functioning, health-related quality of life, capability well-being and costs and incremental cost-effectiveness over 24 weeks. One informal carer (defined as a someone who provides care in an unpaid capacity e.g. spouse, family member or friend) per trial participant can also be consent and recruited to the ASCEnD trial. In these cases, health-related quality of life, capability well-being and costs of caring will be measured over the 24 week trial period. Recruitment of participants will occur via self-referral and from primary and secondary (mental health) NHS services using care register based and opportunistic strategies. Carers will be approached for consent and recruitment following prior written consent from the trial participant to do so. The internal pilot incorporates a nested qualitative study to explore acceptability and to understand and optimise recruitment strategies. There are clear progression criteria for the trial based on a combination of site opening, recruitment rates, and protocol adherence (fidelity). The primary analysis will use intention to treat principles and will use mixed effects linear regression to account for the repeated measurements. The analysis will compare the weekly repeated 12-16-week QIDS-SR scores in the two arms adjusted for baseline QIDS-SR score and all stratification factors. The statistical analysis will use all weekly measurements available between 12 and 16 weeks. Secondary analyses will allow examination of trajectories of symptom change, the pattern and cause of drug discontinuation, cost-effectiveness and carer outcomes over 24 weeks. There is no planned interim analysis. Power analysis reveals that 270 participants randomised will provide 90% power using 5% two-sided significance testing. The study will run