Efficacy of Fluoxetine - a Trial in Stroke (EFFECTS)

Establishing the Effect(s) and Safety of Fluoxetine Initiated in the Acute Phase of Stroke

The purpose of this study is to investigate whether routine administration of fluoxetine 20mg once daily in the 6 months initiated during the acute stroke improves the patient's functional outcome.

EFFECTS is an investigator lead Sweden-based, multicenter, parallel group, double blind placebo controlled trial with broad entry criteria and follow up at 6 and 12 months.

EFFECTS managed to recruit its anticipated numbers of 1,500 participants between 20th October 2014 and 28th June 2019. Data will be unblinded when the 6-months follow-up is completed, and the primary outcome is due to report on May 2020.

Study Overview

• Status: Completed
• Conditions: Stroke
• Intervention / Treatment: Drug: Placebo; Drug: Fluoxetine

Detailed Description

Stroke is a serious, life-threatening medical condition that happens when the blood supply to a part of the brain is cut off, usually due to a blood clot (ischemic) or hemorrhage. Symptoms vary according to how much of the brain is affected and where in the brain the stroke occurs but includes paralysis, muscle weakness and speech problems.

A stroke can also have an impact on the sufferers emotions and can lead to anxiety, depression and personality changes. Fluoxetine (otherwise known as Prozac) has been used for many years to treat depression. However, there is evidence to suggest that it may also have other effects of the brain and enhance brain plasticity (the reorganisation of neural pathways in the brain) in a number of different ways.

One small study, for example, has shown that, if taken soon after a stroke, fluoxetine might improve the recovery of arm strength and lead to greater restoration of movement of the limbs.

Adult participants (at least 18 years old) who have had a stroke (either ischemic or hemorrhagic) within the last 2-15 days and still have some residual problems caused by the stroke e.g. weakness, or problems with their speech (speech impairment).

Participants are randomly allocated into one of two groups. Those in group 1 are given fluoxetine capsules for 6 months. Those in group 2 are given a placebo capsules for 6 months.

The participants are contacted after one week of starting their treatment, and then again after one month, to check on their well-being and that they are still taking their allocated caplets. Each participant is asked about any side effects and how much training they have had with e.g. a physiotherapist, occupational- or speech-therapist.

The research team contacts each participant at 3 months to check whether they are still taking the capsules, ask about bad side effects, and about how they are feeling (mood). If all is well, the participant is given enough medication to cover the rest of the study period.

The participant is asked to stop the study medication after 6 months and repeat assessments that they did before they started the study at the local hospital. They are also asked to fill in questionnaires together with their next of kin or carer. These questionnaires are sent to the trial main centre. If needed, they can also be filled in with the help of a trial nurse over the telephone.

The participants are contacted again one month after they have stopped the medication to see how they have progressed.

At 12 months after recruitment, participants are asked to complete the same questionnaires again about how well they have recovered from their stroke and what problems they now have after the stroke e.g. weakness in limbs, memory problems, problems with speech, low mood. These questionnaires can again be completed on paper or by telephone. The researchers then collect data on long-term recovery through national statistics.

• Study Type: Interventional
• Enrollment (Actual): 1500
• Phase: Phase 3

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 171 76
    • Karolinska Institutet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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 intra cerebral hemorrhage or ischemic stroke.
• Randomization can be performed between 2 and 15 days after stroke onset and by the research group at the patient's local/emergency hospital.
• Persisting focal neurological deficit is present at the time of randomization severe enough to warrant treatment from the physicians and the patient's and relative's perspective.

Exclusion Criteria:

• Subarachnoidal hemorrhage except where secondary to a primary intracerebral hemorrhage.
• 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 including: Hepatic impairment (S-ASAT/ALAT > 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. An HCG-test is to be made prior randomization and after the end of trial medication.
• 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 mono-amino-oxidase inhibitor (MAOI) during the last 5 weeks. Co-administration of Fluoxetine and a mono-amino-oxidase inhibitor (MAOI) may result in life threatening interactions. Therefore, patients on MAOI are ineligible for the EFFECTS trial. Also, any patient in need of treatment with a MAOI must stop their trial treatment for at least 5 weeks before commencing the MAOI, or to be treated as in-patients by a psychiatrist.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Fluoxetine; One capsule Fluoxetine 20mg once daily for 6 months.	Drug: Fluoxetine; Fluoxetine 20mg once daily for 6 months.
PLACEBO_COMPARATOR: Placebo; One matching capsule placebo once daily for 6 months.	Drug: Placebo; Matching placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional status, measured with the modified Rankin scale.	The simple modified Rankin scale questionnaire delivered by postal questionnaire, or via interview over the telephone or face to face to determine the modified Rankin scale.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Survival will be analysed with the Cox proportional hazards model adjusting for the factors included in the minimisation algorithm	This will be determined by following patients up for 12 months.
Functional status, measured with the modified Rankin scale.	The simple modified Rankin scale questionnaire delivered by postal questionnaire, or via interview over the telephone or face to face to determine the modified Rankin scale. The study will also investigate if the benefits of Fluoxetine remains at 12 months.	12 months
Health status measured with the Stroke Impact Scale	Health status will be measured with the Stroke Impact Scale	At 6 and 12 months
Arm, hand, leg and foot strength assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum. The 8 domains in the Stroke Impact Scale will be used for secondary outcome measures 5 to 13.	At 6 and 12 months
Hand function assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Mobility assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Communication and understanding assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Memory and thinking assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Mood and emotions assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Daily activities assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Participation in work, leisure and social activities assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Overall rating of recovery assessed with the Stroke Impact Scale	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. The Stroke Impact Scale was developed with input from both patients and caregivers and includes 8 domains (strength, hand function, ADL/IADL, mobility, communication, emotion, memory and thinking, participation) from across the full impairment-participation continuum.	At 6 and 12 months
Adverse events/outcomes	We will specifically ask for adverse events at each follow-up time (1 week, 1 month, 3 months, 6 months and 12 months), see the outcome 16-24 below. The definition of the SAE is defined according to Good Clinical Practice. We will not register known side effects of fluoxetine, which are listed in the drug's Summary of Product Characteristics. We will not register known problems following stroke, such as pneumonia, deep vein thrombosis etc.	At 6 and 12 months
Depression using the Montgomery-Åsberg Depression Rating Scale (MADRS)	Depression using the Montgomery-Åsberg Depression Rating Scale (MADRS) and patients scoring high have a diagnosis of depression confirmed based on the DSM-IV criteria.	At 6 and 12 months
Number of participants with a recurrent stroke including ischaemic and hemorrhagic strokes	Number of participants with a recurrent stroke including ischaemic and hemorrhagic strokes	At 6 and 12 months
Number of participants with an acute coronary syndromes	Number of participants with an acute coronary syndromes	At 6 and 12 months
Number of participants with an Epileptic seizures	Number of participants with an epileptic seizures	At 6 and 12 months
Number of participants with an episodes of Hyponatraemia	Number of participants with an episodes of hyponatraemia (<125 mmol/l)	At 6 and 12 months
Number of participants with an upper gastrointestinal bleeding	Number of participants with an upper gastrointestinal bleeding	At 6 and 12 months
Number of participants with other major bleeds	Number of participants with an other major bleeds includes lower GI, extracranial, intracranial but extracerebral	At 6 and 12 months
Number of participants with poorly controlled diabetes	Number of participants with an poorly controlled diabetes including hyperglycaemia (>22 mmol/l) and hypoglycaemia	At 6 and 12 months
Number of participants with falls resulting in injury	Number of participants with falls resulting in injury	At 6 and 12 months
Number of participants with new fractures	Number of participants with new fractures	At 6 and 12 months
Fatigue measured with the vitality subscale of the Health Questionnaire	Fatigue will be measured with the vitality subscale of the Health Questionnaire, equivalent to SF 36.	At 6 and 12 months
Cognition assessed with the Stroke Impact Scale	Cognition-the Stroke Impact Scale, which incorporates an assessment of memory and thinking, is used in conjunction with with the Montreal Cognitive Assessment (MoCA)	At 6 and 12 months
Health-related quality of life measured with the five-level Euroqol 5D (EQ5D-5 L)	Health-related quality of life measured with the five-level Euroqol 5D (EQ5D-5 L).	At 6 and 12 months
Cost-effectiveness and cost-utility assessed by measuring costs, survival and health related quality of life (EQ5D)	Direct and indirect costs will be estimated at 3-month, 6- month and 1 year. Effects will be measured using survival and EuroQoL 5 Dimensions (EQ5D) scale, 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.	At 6 and 12 months
Physical activity	Physical activity will be measured using the Saltin-Grimby Physical Activity Level Scale	1 week, 1 month, 3 months, and 6 months

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: The Swedish Research Council; Swedish Heart Lung Foundation; Stroke-Riksförbundet; Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Hjärnfonden (The Swedish Brain foundation); The Swedish Medical Association
• Investigators: Principal Investigator: Erik Lundström, MD, PhD, Karolinska Institutet

Publications and helpful links

General Publications

• Mead G, Hackett ML, Lundstrom E, Murray V, Hankey GJ, Dennis M. The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: a study protocol for three multicentre randomised controlled trials. Trials. 2015 Aug 20;16:369. doi: 10.1186/s13063-015-0864-1.
• Mead GE, Hsieh CF, Lee R, Kutlubaev MA, Claxton A, Hankey GJ, Hackett ML. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev. 2012 Nov 14;11(11):CD009286. doi: 10.1002/14651858.CD009286.pub2.
• Graham C, Lewis S, Forbes J, Mead G, Hackett ML, Hankey GJ, Gommans J, Nguyen HT, Lundstrom E, Isaksson E, Nasman P, Rudberg AS, Dennis M. 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. Trials. 2017 Dec 28;18(1):627. doi: 10.1186/s13063-017-2385-6.
• Lundstrom E, Isaksson E, Wester P, Laska AC, Nasman P. Enhancing Recruitment Using Teleconference and Commitment Contract (ERUTECC): study protocol for a randomised, stepped-wedge cluster trial within the EFFECTS trial. Trials. 2018 Jan 8;19(1):14. doi: 10.1186/s13063-017-2367-8.
• Legg LA, Rudberg AS, Hua X, Wu S, Hackett ML, Tilney R, Lindgren L, Kutlubaev MA, Hsieh CF, Barugh AJ, Hankey GJ, Lundstrom E, Dennis M, Mead GE. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD009286. doi: 10.1002/14651858.CD009286.pub4.
• Lundstrom E, Isaksson E, Greilert Norin N, Nasman P, Wester P, Martensson B, Norrving B, Wallen H, Borg J, Hankey GJ, Hackett ML, Mead GE, Dennis MS, Sunnerhagen KS. Effects of Fluoxetine on Outcomes at 12 Months After Acute Stroke: Results From EFFECTS, a Randomized Controlled Trial. Stroke. 2021 Oct;52(10):3082-3087. doi: 10.1161/STROKEAHA.121.034705. Epub 2021 Aug 31.
• Mead GE, Graham C, Billot L, Nasman P, Lundstrom E, Lewis S, Hankey GJ, Hackett ML, Forbes J, Dennis M; FOCUS, AFFINITY and EFFECTS trialists. Update to the FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical analysis plan for the trials and for the individual patient data meta-analysis. Trials. 2020 Nov 25;21(1):971. doi: 10.1186/s13063-020-04875-1.
• EFFECTS Trial Collaboration. Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020 Aug;19(8):661-669. doi: 10.1016/S1474-4422(20)30219-2.
• Lundstrom E, Isaksson E, Nasman P, Wester P, Martensson B, Norrving B, Wallen H, Borg J, Dennis M, Mead G, Hankey GJ, Hackett ML, Sunnerhagen KS; EFFECTS Trial Collaboration. Update on the EFFECTS study of fluoxetine for stroke recovery: a randomised controlled trial in Sweden. Trials. 2020 Feb 28;21(1):233. doi: 10.1186/s13063-020-4124-7. Erratum In: Trials. 2020 May 7;21(1):388.
• Isaksson E, Wester P, Laska AC, Nasman P, Lundstrom E. Identifying important barriers to recruitment of patients in randomised clinical studies using a questionnaire for study personnel. Trials. 2019 Oct 30;20(1):618. doi: 10.1186/s13063-019-3737-1.

Helpful Links

• The EFFECTS study home page, for investigators, layman and participants in the study. Currently only available in Swedish.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 20, 2014
• Primary Completion (ACTUAL): June 1, 2020
• Study Completion (ACTUAL): June 1, 2020

Study Registration Dates

• First Submitted: February 2, 2016
• First Submitted That Met QC Criteria: February 16, 2016
• First Posted (ESTIMATE): February 17, 2016

Study Record Updates

• Last Update Posted (ACTUAL): September 2, 2020
• Last Update Submitted That Met QC Criteria: September 1, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: depression; outcome; fluoxetine; plasticity
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Fluoxetine
• Other Study ID Numbers: EFFECTS2012; 2011-006130-16 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Three trial investigator teams have collaboratively developed a core protocol for Fluoxetine after stroke. Minor variations have been tailored to the national setting in the UK (FOCUS), Australia and New Zealand (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 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.