Clinical trial NCT02683213: Efficacy of Fluoxetine - a Trial in Stroke
Official title: Establishing the Effect(s) and Safety of Fluoxetine Initiated in the Acute Phase of Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stroke
Keywords: fluoxetine
outcome
depression
plasticity
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: The Swedish Research Council
name: Swedish Heart Lung Foundation
name: Stroke-Riksförbundet
name: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
name: Hjärnfonden (The Swedish Brain foundation)
name: The Swedish Medical Association
First posted: 2016-02-17
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Functional status, measured with the modified Rankin scale.
timeFrame: 6 months
Secondary outcomes:
measure: Survival
timeFrame: This will be determined by following patients up for 12 months.
measure: Functional status, measured with the modified Rankin scale.
timeFrame: 12 months
measure: Health status measured with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Arm, hand, leg and foot strength assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Hand function assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Mobility assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Communication and understanding assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Memory and thinking assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Mood and emotions assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Daily activities assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Participation in work, leisure and social activities assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Overall rating of recovery assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Adverse events/outcomes
timeFrame: At 6 and 12 months
measure: Depression using the Montgomery-Åsberg Depression Rating Scale (MADRS)
timeFrame: At 6 and 12 months
measure: Number of participants with a recurrent stroke including ischaemic and hemorrhagic strokes
timeFrame: At 6 and 12 months
measure: Number of participants with an acute coronary syndromes
timeFrame: At 6 and 12 months
measure: Number of participants with an Epileptic seizures
timeFrame: At 6 and 12 months
measure: Number of participants with an episodes of Hyponatraemia
timeFrame: At 6 and 12 months
measure: Number of participants with an upper gastrointestinal bleeding
timeFrame: At 6 and 12 months
measure: Number of participants with other major bleeds
timeFrame: At 6 and 12 months
measure: Number of participants with poorly controlled diabetes
timeFrame: At 6 and 12 months
measure: Number of participants with falls resulting in injury
timeFrame: At 6 and 12 months
measure: Number of participants with new fractures
timeFrame: At 6 and 12 months
measure: Fatigue measured with the vitality subscale of the Health Questionnaire
timeFrame: At 6 and 12 months
measure: Cognition assessed with the Stroke Impact Scale
timeFrame: At 6 and 12 months
measure: Health-related quality of life measured with the five-level Euroqol 5D (EQ5D-5 L)
timeFrame: At 6 and 12 months
measure: Cost-effectiveness and cost-utility assessed by measuring costs, survival and health related quality of life (EQ5D)
timeFrame: At 6 and 12 months
measure: Physical activity
timeFrame: 1 week, 1 month, 3 months, and 6 months
Other outcomes:
Locations:
city: Stockholm
country: Sweden
facility: Karolinska Institutet
Study officials:
affiliation: Karolinska Institutet
name: Erik Lundström, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.