Title: A Multicentre randomised trial to establish the effect (s) of routine administration of Fluoxetine in patients with a recent stroke (FOCUS)
Funder: Chief Scientist Office, Scotland

Abstract: Design: Multicentre randomised, parallel group, double-blind, placebo-controlled clinical trial. Setting: Patients with an acute stroke admitted to hospital or seen as outpatients, recruited by NHS hospitals in the UK. Target population: UK patients who had a stroke within the previous 2 to 15 days. Inclusion criteria: Age at least 18 years; clinical and brain imaging compatible with ischaemic stroke or intracerebral haemorrhage within 2-15 days; persisting focal deficit severe enough to warrant treatment (from the patient’s or carer’s perspective) with a once daily trial capsule for 6 months. Exclusions: Subarachnoid haemorrhage; unlikely to be available for 12 month follow-up; patient unable to understand spoken or written English AND no close relative to help with follow-up forms; other life threatening illnesses; pregnant; breast-feeding; child bearing age not taking contraception; previous epileptic seizures; previous self-harm; allergy or contraindication to fluoxetine; current or recent depression (within 1 month) requiring treatment with SSRI; currently taking an SSRI or other medication with serious interaction with fluoxetine. Health technology: Fluoxetine 20mg daily or matching placebo for 6 months, orally or via a feeding tube if the patient is unable to swallow. All patients will receive usual stroke care. We chose fluoxetine 20mg as this was the most commonly used drug and dose in our Cochrane review of Selective serotonin reuptake inhibitors (SSRI) for stroke recovery. It has a longer half life than other SSRIs so withdrawal syndrome is rare. Six months treatment is in the range of previous trials (4 weeks to 1 year) and is the period during which most neurological recovery occurs. Measurement of costs and outcomes: The primary outcome is dependency (modified Rankin scale (mRS)) at 6 months after randomisation. An NHS perspective will be used for measuring and valuing health service use. Several other patient-centred outcomes (including EuroQol (EQ5D-5L)) will be measured at 6 months and 12 months to determine whether any benefits persist to 12 months, and cost-effectiveness. Survival times will be adjusted using EQ5D-5L to calculate quality adjusted life years (QALYs). We will estimate one year cumulative costs of in-patient episodes and community care. Justification of outcomes: The modified Rankin Scale (mRS) at 6 months (our primary outcome) is a simple, time efficient measure to categorise functional outcome, is the most commonly used primary outcome in multicentre stroke trials and can be completed by postal questionnaire, telephone and by proxies. Its predictive validity and reliability have been well-studied. Our secondary outcomes are patient centred, have been used extensively in other stroke trials, and have acceptable validity and reliability in stroke. They are: Stroke Impact Scale (also tested for proxies), Mental Health Inventory 5 (anxiety and depression), vitality subscale of the Short-Form 36 (fatigue), EQ5D-5L (health related quality of life), new diagnosis of depression (by clinician responsible for patient’s care), adverse events, health and social care resource use. These outcomes are collected by post or telephone by the trial co-ordinating centre, thus avoiding expensive, time-consuming face-to-face follow-up. Our postal/telephone follow-up at 12 months (mRS and all secondary outcomes) will determine whether any benefits persist. Long-term follow-up for hospital admission and mortality will be by flagging patient records with GRO in Scotland and Medical Research Information in the rest of the UK. Our mechanism for reporting adverse events have been approved by MHRA. We have searched the COMET database using the term ‘stroke’ and found no relevant core outcomes to inform our decision. Sample size: Based on the distribution of mRS at 6 months in our start-up phase, and using an ordinal sample size method, we have 90% power (alpha=0.05) to detect a Commons Odds Ratio of 1.23 (equivalent to a 5.1% absolute increase in proportion of patients with a mRS of 0-2 (independent)) with 1494 patients per group. Thus FOCUS will detect an effect of fluoxetine which is modest in size, plausible but nonetheless clinically important to patients and the NHS, and detectable with a sample size which can be attained within the constraints of the NIHR budget and timescales. However, as fluoxetine is cheap and would be easy to implement into clinical practice should an effect be seen, it is important not to miss a smaller treatment effect. Thus, we have instigated collaborations with colleagues in Australasia and Sweden who will run the AFFINITY and EFFECTS trials respectively which together aim to double the overall sample size to 6000. If FOCUS, AFFINITY & EFFECTS combined enrol 6000, based on our current distribution of mRS in our start up phase we would have 90% power (alpha 5%) to detect a COR of 1.16, equivalent to a 3.6% absolute difference in percentage with mRS 0-2 (39.6% to 43.2%). Timetable: The start up phase (Stroke Association funded) was for 2 years. The start-up phase will move seamlessly into the main phase which is HTA funded. During the first year of the main phase, we will continue to recruit sites, aiming for up to 120 in total. We estimate that we will complete recruitment of patients by month 30. We then have one year to complete follow-ups and a further year to close out centres, analyse and report results. Expertise: One Co-Chief Investigator has extensive experience in leading non-commercial multicentre stroke trials and recently completed HTA-funded CLOTS-3 trial ahead of schedule. The other Co-Chief Investigator has led single centre stroke trials and will be mentored by the more experienced Co-Chief Investigator. The trial statistician has designed and analysed several multicentre stroke trials. We have a service user, stroke neurologists, health economist, psychiatrist, pharmacist, epidemiologist and two academic general practitioners. A Trial Steering Committee (TSC) and DMC have been convened.

Lay abstract: Stroke is a major cause of adult disability in the UK. A stroke is caused by sudden blockage or bursting of an artery in the brain. The immediate effects of stroke depend on what part of the brain is affected. Effects can include paralysis of an arm or leg, loss of vision, problems with co-ordination, slurred speech, difficulties with communication, swallowing problems and loss of control of the bladder and bowel. Although some of these problems improve over time, many patients are left disabled and dependent on others for care. Therefore, new treatments are urgently needed to reduce the burden of disability caused by stroke. Selective serotonin reuptake inhibitors (SSRIs) are a type of drug that has been used successfully, and widely, for many years to relieve depression and other mood problems after stroke. Accumulating research has suggested that SSRIs may also have other potentially beneficial effects on the brain e.g. development of new brain cells (neurogenesis) that may help patients make a better recovery from the physical effects of their stroke. For example, a small trial from France, published in 2011, suggested that fluoxetine (one of the SSRIs), might improve the strength of an arm affected by the stroke, and reduce dependency on others. A review of all previous trials of SSRIs in stroke (published in November 2012) combined data statistically from these trials. This review confirmed the promising effects on stroke recovery, even in people who were not depressed. However, the scientific quality of the trials was not sufficiently high to be confident enough to recommend routine use of SSRIs to improve recovery from stroke, most of the trials did not recruit patients with language or memory difficulties and most did not report side effects of treatment. This review attracted extensive media coverage (BBC online, Channel 4 online, the Daily Telegraph, the Scottish Daily Express, numerous regional papers and a live radio interview by BBC Scotland). The press coverage described the results as ‘promising’, but emphasised the need for further research. Therefore, a large, well-designed trial, recruiting a wide range of stroke patients, is now needed to settle the question about whether SSRIs improve recovery after stroke. The Fluoxetine Or Control Under Supervision trial (FOCUS, for short) is designed to settle the question about whether SSRIs improve recovery after stroke. It uses fluoxetine because it was the most commonly used SSRI in previous trials. FOCUS will recruit at least 3000 stroke survivors from hospitals throughout the UK, who are between 2 and 15 days after the onset of their stroke, and who have residual effects of the stroke e.g. a weak arm, weak leg or language problems. The main aim is to find out whether fluoxetine, given for 6 months, improves overall recovery at 6 months. We also want to find out whether fluoxetine improves mood, fatigue, quality of life, survival and specific problems caused by the stroke e.g. language and memory difficulties, whether any benefits persist to 12 months when the fluoxetine has been stopped and whether fluoxetine is associated with an excess of side effects. We will not include patients who are pregnant or breast feeding, those at high risk of side effects (e.g. previous seizures), and patients with depression who need an antidepressant of the same type as fluoxetine. We will explain the trial to the patients and/or carers, and will obtain informed consent. Then we will collect information about the type of stroke, its consequences and impact. We will enter the patients’ details into our secure computer system. The patients will be allocated at random to either fluoxetine or an identical ‘placebo’ capsule, to be taken for 6 months. The contents of the capsule can be given down a feeding tube if a patient cannot swallow. When the patients are discharged from hospital, we will collect data about any adverse effects that might be related to the trial capsule. We will telephone patients just after discharge to check that all is well. Patients and/or their carers will be contacted at 3 months after their stroke to give them the opportunity to tell us how they are getting on and report potential side effects. Then, at 6 months and at 12 months, patients and/or carers will be sent questionnaires to assess recovery, mood, fatigue, quality of life, use of health and social services and adverse events. These outcomes will be assessed by post and/or telephone (rather than face-to-face) in order to minimise the burden on patients and to maximise completeness of follow up. We will use these data to assess the cost-effectiveness of treatment. General practitioners will be contacted for information about medication, adverse events, mood and health service use. Patients and their GPs will be able to talk with a chief investigator about any problem via a 24 hour telephone helpline number. FOCUS is large enough to identify a modest-sized effect of fluoxetine on recovery after stroke, which would be of substantial importance to patients, carers, the health and social services. If the treatment is effective, it could become a widely used treatment for patients with stroke around the world within weeks of reporting the results. The cost of treatment would be less than £10 per patient for the six month course of capsules. Our trial team includes a stroke survivor, stroke physicians, epidemiologist, stroke neurologists, a psychiatrist, a psychologist, pharmacist, two academic general practitioners, a statistician and a health economist who together have many years of experience of running large trials in stroke patients. Previous trials run by team members have led to worldwide changes in the management of stroke patients

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE