EFFECTS 2020.

Study characteristics
Methods	Multicentre RCT Study type: interventional (clinical trial) Allocation: randomised Intervention model: parallel assignment Masking: quadruple (participant, care provider, investigator, outcomes assessor) Primary purpose: treatment
Participants	1500 participants Country: Sweden Setting: inpatient At randomisation number allocated: N = 1500: fluoxetine (n = 750 ); placebo (n = 750 ) % male: fluoxetine (62%); placebo (62%) Age: mean age: fluoxetine = 70.6 ± 11.3; placebo = 71.0± 10.5 Subtype of stroke Total anterior circulation infarct: fluoxetine (27%); placebo (29%) Partial anterior circulation infarct: fluoxetine (46%); placebo (44%) Lacunar infarct: fluoxetine (15%); placebo (16%) Posterior circulation infarct: fluoxetine (10%); placebo (9%) Uncertain: fluoxetine (x2%); placebo (2%) Inclusion criteria Age ≥ 18 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 got answers to their questions, wants to participate in the trial Brain imaging is compatible with intracerebral haemorrhage or ischaemic stroke Randomisation can be performed between 2 and 15 days after stroke onset and by the research group at the person's local/emergency hospital Persisting focal neurological deficit is present at the time of randomisation severe enough to warrant treatment from the physicians and the patient's and relative's perspective Exclusion criteria Subarachnoidal haemorrhage (except where secondary to a primary intracerebral haemorrhage) Unlikely to be available for follow‐up for the next 12 months e.g. no fixed home address Unable to speak Swedish and no close family member available to help with follow‐up forms Other life‐threatening illness (e.g. advanced cancer) that will make 12‐month survival unlikely History of epileptic seizures History of allergy or contraindications to fluoxetine Pregnant or breastfeeding Previous drug overdose or attempted suicide Already enrolled into a CTIMP Current or recent (within the last month) depression requiring treatment with an SSRI antidepressant Current use of medications which have serious interactions with fluoxetine Use of any MAOI during the last 5 weeks
Interventions	Fluoxetine (20 mg once daily) for 6 months with oral capsules
Outcomes	Outcomes collected at 6 months and 12 months Primary outcome mRS Secondary outcomes Death from all causes HRQoL (EQ5D‐5L) Depression and anxiety (MHI‐5) Level of fatigue (vitality subscale of the Health Questionnaire) Recovery from stroke (SIS) New diagnosis of depression since randomisation Adverse events (including participant‐completed diary) Health and social care utilisation Adherence to trial medication Motor function (NIHSS) Aphasia (NIHSS), aphasia (Norsk Grunntest for Afasi) Depression (MADRS + DSM‐IV/DSM‐V) Cognitive function (MoCA)
Funding source	The Swedish Research Council, the Swedish Heart‐Lung Foundation, the Swedish Brain Foundation, the Swedish Society of Medicine, King Gustav V and Queen Victoria’s Foundation of Freemasons, and the Swedish Stroke Association (STROKE‐Riksförbundet)
Notes	clinicaltrials.gov/ct2/show/NCT02683213. Recruitment between Oct 20, 2014, and June 28, 2019 BN has received honoraria for data monitoring committee work in the SOCRATES and THALES trials (AstraZeneca) and the NAVIGATE‐ESUS trial (Bayer). HW has received grants from the Swedish Medical Research Council (Vetenskapsrådet) during the conduct of the study; the grant was for the study that is presented inthe submitted manuscript. GJH has received grants from the National Health and Medical Research Council (NHMRC) of Australia, Vetenskapsrådet, and UK National Institute for Health Research Technology, during the conduct of the study; and personal fees from American Heart Association, outside of the submitted work. MD reports that the University of Edinburgh received some funding from the grants for EFFECTS (Vetenskapsrådet) in relation to its provision of a randomisation system. MLH has received grants from the NHMRC of Australia, outside of the submitted work. All other authors declare no competing interests
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A physician or nurse entered patients’ baseline data into a secure web‐based randomisation system. The system checked the data for completeness and consistency and allocated each patient an identification number and a treatment number. Patients were randomly assigned in a 1:1 ratio to either oral fluoxetine 20 mg once daily or placebo for 6 months."
Allocation concealment (selection bias)	Low risk	Quote: "secure web‐based randomisation system"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Patients, their families, health‐care personnel, investigators, outcomes assessors, and staff in the coordinating centre (Karolinska Institutet, Department of Clinical Sciences Danderyd Hospital, Stockholm, Sweden), and the pharmacy were masked to treatment allocation. The placebo capsules were visually identical to the fluoxetine capsules, even when broken open. The success of the masking procedure was not assessed. An emergency unmasking system was available but was designed so that the coordinating centre and staff doing follow‐up continued to be masked throughout the study."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Patients, their families, health‐care personnel, investigators, outcomes assessors, and staff in the coordinating centre (Karolinska Institutet, Department of Clinical Sciences Danderyd Hospital, Stockholm, Sweden), and the pharmacy were masked to treatment allocation"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 11 dropped out; 2 crossed over; the rest were included in the analysis
Selective reporting (reporting bias)	Low risk	All outcomes that were prespecified were reported
Other bias	Low risk	The study appears to be free of other sources of bias