The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis

Abstract

Background: Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients' functional outcome.

Methods/design: The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2-15 days after stroke onset. Patients are randomised centrally via each trials' web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months.

Discussion: Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020.

Trial registration: FOCUS: ISRCTN , ISRCTN83290762 . Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012.

Affinity: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921 . Registered on 22 July 2011.

Effects: ISRCTN , ISRCTN13020412 . Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213 . Registered on 2 February 2016. EudraCT, 2011-006130-16 . Registered on 8 August 2014.

Keywords: Antidepressants; Depression; Fluoxetine; Haemorrhagic stroke; Ischaemic stroke; Recovery; SSRI.

Conflict of interest statement

Ethics approval and consent to participate

Each trial has received approval for its protocol and trial materials from the relevant local ethics committees and regulatory authorities in their respective countries (FOCUS: Scotland A Research Ethics Committee (for UK) Ref 11/SS/0100 (21/12/2011), AFFINITY: Western Australia, Royal Perth Hospital Human Research Ethics Committee Ref 2011-131 (24/02/2012), St John of God Healthcare HREC for St John of God Hospital Midland, Western Australia Ref 894, (16/02/2016), New South Wales, Victoria & Queensland, Western Sydney Local Health District Ref HREC/13/WMEAD/165 (30/04/2013), South Adelaide Clinical HREC Ref 275.14 -HREC/14/SAC/284 (01/09/2014), The Alfred HREC for Caulfield Hospital Victoria Ref 248/16 (19/08/2016). Calvary Health Care Bruce HREC Ref 29-2014 (07/04/2015). New Zealand, Central Health and Disability Ethics Committee Ref 14/CEN/39 (17/04/2014)). EFFECTS: Stockholm Ethics Committee Ref 2013/1265-31/2 (30/09/2013). No centre can start recruitment until it has received relevant ethics and regulatory approvals. Informed consent is obtained before the patient is enrolled except where it has been waived. Consent procedures had to comply with national requirements, so that in FOCUS and AFFINITY approval was obtained for consent by either patient or proxy, AFFINITY also has approval for waiver of consent, while in EFFECTS patients have to be capable of consenting for themselves.

Consent for publication

Not applicable.

Competing interests

None of the authors declare any financial competing interests relating to this research other than the chief investigators of these three trials having received grant funding to support the trials (see below). None of the authors have any non-financial competing interests.

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