This is an compressed and adapted research plan of EFFECTS (date 12/NOV/2017), the full protocol and amendments are available here.
Purpose of the project
The purpose of our study is to find a new treatment for stroke recovery. The aim is to test an established drug against depression (fluoxetine) to see whether it can improve recovery and quality of life after stroke as smaller studies indicate.
Expected results and benefits for individuals and society
The expected results are better functioning and improved quality of life.
Fluoxetine is inexpensive (only 300 SEK for 6 months’ treatment), simple to administer and generally well tolerated. If it proves effective, it can be implemented when the study is completed, in 2020. It could be available to a wide range of stroke patients, both ischemic and haemorrhagic stroke, and even in low to middle income countries.
The project’s originality and novelty
- We are studying a new mechanism for stroke, selective serotonin re-uptake inhibitors (SSRI), for stroke recovery. We want to test whether routine administration of fluoxetine (20 mg once daily) in the 6 months after an acute stroke improves the patient’s functional outcome.
- An academic-initiated, investigator-led, randomised controlled study (RCT).
- We aim to include 1,500 patients in Sweden, making EFFECTS the largest RCT study of stroke in Sweden.
- A collaboration with FOCUS and AFFINITY, two other international, investigator-led studies, with the same inclusion and exclusion criteria. A meta-analysis of individual patient data is planned.
- It has a pragmatic design, i.e. we investigate if the interventions work in normal practice, with fewer selected patients and a flexible intervention applied as it would be in normal practice, and finally, outcomes that are relevant to patients and society.
- The study includes both ischemic and haemorrhagic stroke.
- Fluoxetine is inexpensive (only 300 SEK for 6 months’ treatment), simple to administer, and generally well tolerated. If it proves effective, it can be implemented quickly in the healthcare system.
- Good track record regarding data quality and inclusion. Reassuringly, we randomise 30 pat/month. We have included 883 patients. The EFFECTS study will succeed with its objective to include all patients.
Each year, stroke affects 16 million people for the first time and causes about 6 million deaths worldwide(1). In Sweden, about 23,000 people suffer stroke annually(2) and 80% are over 65 years old. About half of survivors will have long-term residual disability and impaired quality of life .
Whereas major advances have been made in the acute treatment of stroke, there is an urgent need to identify new treatments that might reduce neurological impairments and enhance quality of life.
One promising intervention is fluoxetine, a selective serotonin re-uptake inhibitor (SSRI). SSRIs have been used since 1988 and several hundred million people have been treated for mood disorders, particularly depression.
Fluoxetine is inexpensive (only 300 SEK for 6 months’ treatment), simple to administer, and generally well tolerated. If it proves effective, it can be implemented quickly in the healthcare system.
A systematic review of SSRIs in animal models of stroke showed that neurobehavioural scores improved by 41%, but there was insufficient evidence to determine the likely underlying mechanisms(3). In functional magnetic resonance imaging studies of stroke patients with motor deficits, studies have indicated that fluoxetine can cause hyperactivation in the ipsi-lesional primary motor cortex during a motor task(4) and a decrease in motor excitability over the unaffected hemisphere(5).
What really ignited interest in fluoxetine was the FLAME trial(6). In this double-blind, placebo-controlled, multicentre trial, 118 patients with ischaemic stroke were randomised to fluoxetine 20 mg daily or placebo for 3 months. At day 90, the proportion of independent patients, defined as patients with a modified Rankin scale(7) of 0–2, was significantly higher in the fluoxetine group (26% versus 9%, p = 0.015).
A Cochrane systematic review of SSRIs for stroke recovery identified 52 randomised controlled trials of SSRI versus control (n=4059), given within the first year after ischaemic or haemorrhagic stroke(8). Only two trials (n=223) reported the modified Rankin Scale (mRS) – the most widely accepted outcome measure in stroke trials – as an outcome. The proportion of independent patients, defined as an mRS 0–2, at the end of treatment was 62.5% in the SSRI group and 55% in the control group (absolute difference 7.5%, 95% CI −5.3 to 20.4). Among 22 trials (n=1,310) that reported disability as an outcome measure, meta-analysis demonstrated a large effect size of SSRI (standardised mean difference 0.92, 95% CI 0.62 to 1.23).
The Cochrane review identified several weaknesses with the studies: Multiple biases in trial design, substantial statistical heterogeneity, wide confidence intervals for effect estimates and limited data on adverse effects. Only seven trials followed up patients after treatment had ended; of these, only two (n=155) provided data on disability. Fluoxetine was the most commonly used drug. However, only 12 fluoxetine trials (n=682) were placebo controlled.
Although promising, the data are not sufficient to prove that fluoxetine improves functional recovery after stroke and that any possible benefits are not offset by serious adverse effects.
What are the potential risks of fluoxetine in stroke?
There are potential risks associated with giving fluoxetine to a wide range of stroke patients. The Cochrane review(8) indicated that SSRIs, compared with placebo or usual care, were associated with a non-significant excess of seizures [relative risk (RR) 2.7; 95% CI 0.6-11.6], gastrointestinal adverse effects (RR 1.9; CI 0.9-3.8) and bleeding (RR 1.6; CI 0.2-13). Its interaction with antiplatelet and anticoagulant medication might increase bleeding risk. Reassuringly, fluoxetine has been very commonly prescribed to patients with stroke to treat depression and emotionalism without major problems emerging.
The need to identify the patients who might particularly benefit from treatment
Whilst fluoxetine may improve outcome for the whole range of stroke patients, it is also plausible given its diverse pharmacological effects that the balance of risk and benefit may vary in patients with different types of stroke. For instance, pre-clinical work has suggested that motor recovery may be specifically enhanced. Also, fluoxetine influences bleeding risk, particularly in those taking antithrombotic medication, so there could be differences in effectiveness between patients with ischaemic stroke (who are taking antithrombotics) and haemorrhagic stroke.
Does routine administration of fluoxetine 20 mg once daily in the 6 months after an acute stroke improve the patient’s functional outcome?
The primary outcome is functional status, measured with the modified Rankin scale (mRS)(7) at the 6-month follow-up. We use the simple modified Rankin scale questionnaire smRSq (10) delivered by postal questionnaire, via interview, over the telephone or face-to-face to determine the mRS.
- Survival until the end of the trial, analysed with the Cox proportional hazards model adjusting for the factors included in the minimisation algorithm.
- Functional status at 12 months, measured with the smRSq(10).
- Health status measured with the Stroke Impact Scale(11) at 6 and 12 months.
The Stroke Impact Scale will provide an overall assessment of patient outcome as well as allowing us to assess the effect of treatment on specific outcomes of importance to the patients.
- Adverse events/serious adverse events
At each follow-up (1 week, 1 month, 3 months, 6 months and 12 months) we will specifically ask for: a) Recurrent ischaemic and haemorrhagic strokes, b) Acute coronary syndromes, c) Epileptic seizures, d) Episodes of hyponatraemia (<125 mmol/l, e) Upper gastrointestinal bleeding, f) Other major bleeds, g) Poorly controlled diabetes including hyperglycaemia (>22 mmol/l) and hypoglycaemia, h) Falls resulting in injury, and i) New fractures.
- Depression based on the DSM-IV criteria plus using the Montgomery-Åsberg Depression Rating Scale(12) at 6 and 12 months.
- Fatigue measured with the vitality subscale of the Health Questionnaire.
- Cognition measured with the Montreal Cognitive Assessment(13).
- Health-related quality of life measured with five-level EuroQoL5D(14).
- Cost-effectiveness and cost-utility. Direct and indirect costs will be estimated at 3, 6 and 12 months. Effects will be measured using survival and EuroQoL5D, which will be estimated into a utility score. The effectiveness measure that will be used for comparison purposes, the quality adjusted life years (QALYs), will be estimated by multiplying the relevant time parameter of the comparison with the estimated utility scores. A societal perspective will be adapted for the analysis, and comparison of costs and effects (QALYs) will be conducted for the period of the clinical trial, as well as by adopting a lifetime perspective, where costs and QALYs will be extrapolated beyond the duration of the trial over the expected lifetime of patients. Standard statistical regressions will be used in order to calculate the expected lifetime costs and QALYs.
International collaboration with two other studies
EFFECTS collaborates with two other investigator-led, multicentre, parallel group, randomised, placebo-controlled trials that aim to determine whether routine administration of fluoxetine for 6 months after acute stroke improves patients’ functional outcome: FOCUS (in the UK) and AFFINITY (Australia, New Zealand and probably Vietnam). The three trial investigator teams have collaboratively developed a core protocol. Minor variations have been tailored to the national setting. 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 subsequently provide the most precise estimate of the overall effect of fluoxetine after stroke and establish whether any effects differ between trials and subgroups of patients.
EFFECTS is a Swedish multicentre, parallel-group, double-blind, placebo-controlled trial with broad entry criteria and follow-up to ascertain the primary and secondary outcomes at 6 and 12 months.
Eligible subjects are identified from acute stroke and rehabilitation units.
- Informed consent can only be obtained from a patient who, according to the trial investigator, is mentally capable of decision-making and who, after having received information and answers to their questions, wants to participate in the trial.
- Brain imaging is compatible with intra cerebral haemorrhage or ischemic stroke.
- Randomisation between 2 and 15 days after stroke onset.
- Persisting focal neurological deficit is present at the time of randomisation and is severe enough to warrant treatment from the physician’s and the patient’s and relative’s perspective.
- Primary subarachnoid haemorrhage.
- Unlikely to be available for follow-up for the next 12 months.
- Unable to speak Swedish and no close family member available to help with follow-up forms.
- Other life threatening illness that will make 12-month survival unlikely.
- History of epileptic seizures.
- History of allergy or contraindications to fluoxetine including hepatic impairment (S-ASAT> 3 upper normal limit) and renal impairment (S-Creatinine levels > 180 micromol/L).
- Pregnant or breastfeeding, women of childbearing age not taking contraception. Minimum contraception is an oral contraceptive. A pregnancy test (S-hCG) is to be taken prior to randomisation and after the end of trial medication.
- Previous drug overdose or attempted suicide.
- Already enrolled in a clinical trial of an investigational medical product study.
- Current use of medications which have serious interactions with fluoxetine.
Randomisation and blinding
After obtaining consent, the randomising physician enters data into a trial-specific computerised central randomisation service with a secure 24/7 web interface. The system checks baseline data for completeness and consistency, and allocates the patient a unique study identification number and a treatment pack number that corresponds to either fluoxetine or placebo. The trial-specific system applies a common minimisation programme to achieve a balance of four factors:
- Delay since stroke onset (2–8 versus 9–15 days)
- Predicted 6-month outcome, based on the six simple variable model(15)
- Presence of a motor deficit, based on the NIHSS
- Presence of aphasia, based on NIHSS
The patients, their families, the healthcare team including the pharmacist and anyone involved in outpatient assessments are blinded to the treatment allocation. Emergency unblinding systems are available. The chief investigators will decide on a case-by-case basis whether unblinding is required to ensure patient safety.
The minimisation algorithm randomly allocates the first patient to a treatment, but allocates each subsequent patient in a ratio of 1:1 to the treatment that leads to the least difference between the treatment groups with respect to the prognostic factors(15). To ensure that we retain a random element to treatment allocation, patients are allocated to the group that minimises differences between groups with a probability of 0.8. The systems contain a list of treatment codes for each centre.
|Study assessment schedule||Days||Weeks/month(s)|
|Assessment, interval (w=week, m=month)||2-15||1 W||1 M||3 M||6 M||7 M||12 M|
|+/- D (numbers of days)||3 D||7 D||7 D||14 D||7 D||14 D|
|Baseline data: NIHSS, MADRS and DSM-IV (depression), MoCA (cognition), NGTA (short aphasia test), EQ5D-5L||
|Dispense study medication for 3 months||X|
|E-mail notification of allocation||X|
|Letter informing GP of participation||X|
|Telephone, check AE/SAE adherence to medications and depression||X||X||X|
|Face-to-face or telephone at 3 months
Rule out depression, NGTA, EQ5D-5L, AE/SAE, returning first 3 months’ trial medication and dispensing for last 3 months
|Check survival and resource use||X||X||X||X|
|Face-to-face at 6 months
Retrieve residual capsules. NIHSS, MADRS, DSM-IV, MoCA,NGTA, EQ5D-5L
|Mail questionnaires, including modified Rankin scale, Stroke Impact Scale, Mental Health Inventory 5, EQ5D-5L, Health Questionnaire vitality subscale||
Statistical analysis plan
A statistical analysis plan for EFFECTS, and for an individual patient data meta-analysis including patients from FOCUS and AFFINITY, has been developed by the chief investigators and an independent statistician prior to the database being locked at the end of follow-up, and will be submitted to the journal Trials. The primary analyses will retain patients in their original assigned treatment groups. We will use ordinal regression to compare functional status (mRS) at the 6-month follow-up, adjusted for those factors included in our minimisation algorithm.
The functional status (mRS) at 6 months will be compared with ordinal regression in the following subgroups:
- Age (≤70, > 70 years).
- Baseline probability of a good outcome on mRS calculated with the six simple variable model – to see whether effects remain constant across the range of stroke severities(15) (<0.15 vs. 0.15-1 probability of being alive and independent at 6 months).
- Ischaemic versus haemorrhagic stroke.
- For FOCUS and AFFINITY: Patients who were unable give consent themselves, since this subgroup will allow us to answer the question of whether routine use of fluoxetine is likely to benefit patients for whom a formal assessment of mood is impossible because of communication and cognitive problems.
Sample size and power calculations
FOCUS, AFFINITY and EFFECTS are planning to enrol at least 3000, 1600 and 1500 patients respectively. The table below shows the effect sizes, expressed as a common odds ratio.
|Trial||Sample size||Common odds ratio||Percent mRS 0–2 fluoxetine||Percent mRS 0–2 placebo||Absolute percent improvement in mRS 0-2|
If FOCUS, AFFINITY and EFFECTS combined enrol 6000 patients, we would have 90% power (alpha 5%) to detect a common odds ratio of 1.16, equivalent to a 3.7% absolute difference in percentage with mRS 0–2 (44.0% to 47.7%).
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