Title: Randomised placebo controlled trial of Pramipexole addition to mood stabilisers for treatment resistant bipolar depression (the PAX-BD study)
Funder: Department of Health and Social Care

Abstract: DESIGN: Multi-centre, randomised, double-blind, placebo-controlled. Pre-randomisation phase to withdraw antipsychotics and commence mood stabilisers if needed. Remote (on-line and phone) collection of outcome measures to facilitate UK wide recruitment SETTING: Secondary care mental health Trusts PLANNED INTERVENTIONS: 1:1 allocation to pramipexole (fixed dose to 12 weeks then flexible) or placebo, added to existing mood stabilisers (lithium, valproate, carbamazepine, lamotrigine). POPULATION: Patients with TRBD (failure of 2 NICE recommended medications). INCLUSION: Bipolar (type I or II); currently depressed (DSM-5 criteria) with consistent QIDS-SR score greater than 10; TRBD; aged over 18; able to provide informed consent. EXCLUSION: DSM-5 severe substance use disorder; current psychotic symptoms; contraindication to pramipexole; history of eye, cardiovascular or renal disease; on antipsychotics at randomisation; currently, planning or at risk of pregnancy; breast feeding; starting specific psychotherapy from 4 weeks before randomisation through to week 12. OUTCOMES: Primary: QIDS-SR at 12 weeks. Secondary: Weekly QIDS-SR and hypomanic symptoms (Altman Self Rating Scale of Mania – ASRM(5)) through to week 52. Anxiety (Genralised Anxiety Disorder 7 – GAD-7(6)), functioning (Work and Social Adjustment Scale – WSAS ), quality of life (EQ-5D-5L) & side effect burden (Treatment satisfaction Questionnaire for Medication – TSQM(7)) at weeks 0, 6, 12, 26 and 52. Health economics questionnaire including information on health and social services utilisation, broader societal costs (e.g. lost productivity, informal care) and broader well-being (using the ICECAP-A(1;2), OxCAP-MH(3) instruments) collected pre-randomisation, and at 12, 26, 40 and 52 weeks. Safety measures: Adverse effects monthly. Suicidality (Columbia–Suicide Severity Rating Scale – C-SSRS(4)), impulse control disorders (QUIP-RS(8)), pulse and blood pressure at 1, 6, 12, 26 and 52 weeks. Adherence via pill counts reported by participants and confirmed by Clinical Research Network (CRN) staff. ANALYSIS: INTERNAL PILOT – quantitative and qualitative data to refine study methodology. MAIN STUDY - Effect of pramipexole on QIDS-SR at 12 weeks compared with placebo using ANCOVA with baseline score among covariates. Clinical & cost-effectiveness over 1 year. Costs, QALYs/capabilities and incremental cost per QALY calculated. No planned interim analyses. SAMPLE SIZE: 290 participants gives 90% power to detect a 3 point difference in QIDS-SR between drug & placebo at 12 weeks and 80% at 52 weeks, based on the standard deviation (7.0) and dropout rates from CEQUEL study at 12 and 52 weeks (20% and 50% respectively)(1). Three QIDS-SR points equates to Cohen’s d=0.4 (considered clinically meaningful(9)). We estimate a 30% drop out during the pre-randomisation period based on the BALANCE study in bipolar disorder (BD)(10), giving a target initial population of 414. All participants followed up to 52 weeks. RECRUITMENT & TIMETABLE: Recruitment led from 5 academic sites, which link with 40 NHS Trusts, each facilitated by CRN support with additional recruitment from the other local clinical research networks. Internal pilot with stop/go criteria with contingency of expanding recruitment sites. Trial setup 0-6; recruitment 6-30; Internal pilot 6-18; follow up 32-43; analysis/reporting 44-48 months.

Lay abstract: BACKGROUND: Over a lifetime, 2.5% of people will suffer from bipolar disorder (BD). Sufferers can have great difficulty in leading a normal life and BD is associated with a 10 year reduction in life expectancy. NICE recommends ‘mood stabiliser’ treatments, such as lithium and valproate, to make episodes of elevated and depressed mood less likely. If, despite such treatment, depression occurs, a second (additional) medication is recommended: quetiapine, olanzapine or lamotrigine. Unfortunately, bipolar depression often does not respond to these treatments and can become chronic and disabling. In addition, many of these drugs have side effects, such as sedation and weight gain. Pramipexole is currently used as a treatment for Parkinson’s disease and its safety and side effects are well known. Notably it is less likely to cause weight gain than current NICE recommended treatments. Two studies suggest that it helps to treat bipolar depression but these studies were small and only lasted 6 weeks. AIM: To determine whether pramipexole, added on to mood stabilisers, is a cost effective treatment for patients with BD whose depression has not responded to NICE recommended treatment. We will examine this drug compared to placebo (dummy tablets) over 12 months. PARTICIPANTS: People with BD whose depression has not responded to at least two NICE recommended treatments. STUDY DESIGN: Prior to starting the study proper, if patients are on an antipsychotic it will be gradually withdrawn since it may block the effect of pramipexole. Additionally, if patients are not on a ‘mood stabiliser’, one will also be started. Once this is done, 290 patients will receive either pramipexole or placebo, chosen at random, in addition to an on-going mood stabiliser. The study team, participants and their treating mental health team will not know whether they receive pramipexole or placebo. We will check how effective pramipexole is after 12 weeks and patients will continue to be monitored by trial researchers for 12 months even if they discontinue the initial treatment, as it is important to know what happens in real life when this treatment is used. We will measure the effect on depressive symptoms, quality of life, side effects and whether any other treatments were needed. These assessments will be done using an on-line system that participants can fill in themselves supported by email or text prompts. These methods have worked well in our previous studies and patients report that they like them. It allows more frequent (weekly) self-ratings of BD symptoms and thus gives a more complete picture of long-term symptom control. Where necessary, internet access will be provided or paper versions used. We will telephone patients monthly to see if medication has changed and ask about symptoms and any side effects. PATIENT AND PUBLIC INVOLVEMENT (PPI): Patients and carers, including from a Bipolar Support Group, have contributed to the selection of the outcome measures used in the study and to the study plan. We will invite two PPI representatives to be on the Trial Steering Committee. DISSEMINATION: Academic presentations and publications, as well as dissemination in the wider press and direct to patient BD groups eg via Bipolar UK. Fully anonymised data made available to other researchers.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH