Fluoxetine Opens Window to Improve Motor Recovery After Stroke

Study Overview
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Brief Summary
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The FLOW trial is a randomized placebo-controlled trial analyzing the effect of coupling an anti-depressant, fluoxetine (Prozac), and exercise to improve motor recovery following a stroke.

Detailed Description
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FLOW Trial is a randomized, placebo-controlled, blinded phase II trial evaluating the efficacy of coupling antidepressant therapy (e.g., selective serotonin reuptake inhibitor - fluoxetine) with exercise rehabilitation across multiple Canadian sites in 176 stroke patients. 88 patients will be enrolled in each arm of the study. Both groups will receive an exercise program in addition to standard of care rehabilitation, but only one group (the intervention group) will receive the active drug fluoxetine. Study participants will be evaluated at baseline, post-exercise program and 6-months post-exercise program. While enrolled in the study, participants will be required to take part in a 12 week, 3 times per week exercise program. Evaluators and patients will be blind to the treatment administered. The trial is constructed with randomization to remove selection and allocation biases and to ensure greater validity in observed differences in the outcome measures. The Applied Health Research Centre (AHRC) in Toronto will act as the coordinating and analysis center.

Official Title
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FLOW Trial: Fluoxetine to Open the Critical Period Time Window to Improve Motor Recovery After Stroke

Conditions
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Stroke, Cerebrovascular Accident, Cerebral Infarction, Brain Infarction, Brain Ischemia, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Vascular Diseases

Intervention / Treatment
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* Drug: Fluoxetine Hydrochloride
* Other: Placebo
* Behavioral: Exercise Program


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 25 years of age or older Days post stroke must be between 2 to 12 months when enrolled (i.e. day of consent) Patient-reported hemiparesis of the lower extremity Exclusion Criteria: Patients with subarachnoid hemorrhage Pre-morbid modified Rankin score > 2 Substantial premorbid disability or pre-existing deficit or language comprehension deficit that could interfere with assessments Diagnosis of major depressive disorder/anxiety disorder requiring antidepressant use within 6 weeks of enrolment Taking neuroleptic drugs, benzodiazepines, monoamine oxidase inhibitors within 30 days of enrolment Unstable serious medical condition (e.g., terminal cancer, renal or liver failure, congestive heart failure) Resting blood pressure exceeding 180/100mmHg Requires more than a one person assist for transfer Planned surgery that would affect participation in the trial Participating in another formal lower limbs exercise program more than one day per week History of QT prolongation or concomitant use of clearly identified potential QT prolonging drugs, at the investigators discretion (e.g. amiodarone, bepridil, dysopyramide, dofetilide, flecainide, ibutilide, procainamide, propafenone, quinidine, sotalol, phenothiazines, pimozide, ziprasidone, TCAs, halofantrine, cisapride, and probucol) History of glaucoma Patients with a history of thrombocytopenia or clinically significant bleeding disorder or use of NSAID, ASA or other anticoagulants, at the investigators' discretion History of convulsive disorders Potential pregnancy (per screening algorithm) Patients with an ongoing history of illicit drug use and/or alcohol abuse Patient unwilling or unable to comply with trial requirements Patient unable to understand English or communicate with the study team with staff support or translation services

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm 1: Intervention group (will receive the trial drug, fluoxetine, as well as an exercise intervention) Arm 2: Placebo group (will receive a placebo as well as an exercise intervention
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluoxetine Hydrochloride<br>Fluoxetine (Prozac) will be administered to this group. A ramp up period of 3-5 weeks will take place where the patient takes 10mg of Prozac per day. After that, the participant will take the regular dose of 20mg for the duration of the exercise intervention (12 weeks). | Drug: Fluoxetine Hydrochloride<br>* Half of the participants will take fluoxetine for a period of 15-17 weeks (depending on ramp-up period).<br>* Other names: Prozac;Behavioral: Exercise Program<br>* All participants will take part in a 12-week exercise program. The program will run 3 times/week, 1 hour/class.<br>|
| Placebo Comparator: Placebo<br>An over-encapsulated placebo, or sugar pill (so it appears identical to the trial drug) will be administered to this group. During the 3-5 week ramp up period for the experimental group, these participants will take a placebo identical to the 10mg Prozac capsule. After that, the participant will take a placebo identical to the 20mg Prozac capsule for the duration of the exercise intervention (12 weeks). | Other: Placebo<br>* Half of the participants will take the a placebo for a period of 15-17 weeks (depending on ramp-up period).<br>* Other names: Sugar Pill;Behavioral: Exercise Program<br>* All participants will take part in a 12-week exercise program. The program will run 3 times/week, 1 hour/class.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fugl-Meyer Lower Extremity Score | Fugl-Meyer Lower Extremity Assessment assesses motor and sensorimotor impairment in the lower extremities. Total score is between 0 and 34. Sub-scales include: proximal (0-18), knee/ankle (0-10) and coordination/speed (0-6). Higher scores indicate better performance. Sub-scale scores are summed to calculate total score. | Following completion of the 12-week exercise intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Minute Walk Test / 10 Meter Walk Test | Physical Measurement - Ambulatory Function | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Knee Strength | Physical Measurement- Lower Limb Strength | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Berg Balance Assessment | Physical Measurement - Balance Function | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Grip Strength | Physical Measurement - Grip Strength | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Waist-to-Hip Ratio | Physical Measurement - Health Measurement | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Body Mass Index | Physical Measurement - Health Measurement | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Stroke Impact Scale | Stroke-specific, self-report, health status measure. Assesses multiple domains on a 5-point Likert scale. Domains include: strength (4-20), hand function (5-25), activities of daily living/instrumental activities of daily living (10-50), mobility (9-45), communication (7-35), emotion (9-45), memory and thinking (7-35), and participation (8-40). An extra question asks that the patient rate on a scale from 0 - 100 how much they feel that he/she has recovered from his/her stroke. The 4 physical domains (strength, hand function, mobility and activities of daily living) can be summed together to create a single, physical dimension score (28-140) while all other domains should remain separate. Higher scores indicate better function. | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Fugl-Meyer Lower Extremity Score | Impairment Measurement (see description above) | 6-months post-exercise intervention | 
| Fugl-Meyer Upper Extremity Score | Fugl-Meyer Upper Extremity Assessment assesses motor and sensorimotor impairment in the upper extremities. There is no total score for this measure. Sub-scales include: upper extremity (0-36), wrist (0-10), hand (0-14), coordination/speed (0-6) (which can be combined to form a total motor function score out of 66), and sensation (0-4). Higher scores indicate better performance. | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Patient Health Questionnaire (PHQ)-9 | Depression Measurement | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Simple and Choice Reaction Time Test | Cognitive Measurement | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Trail Making Test - A & B | Cognitive Measurement | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Montreal Cognitive Assessment (including 5 word recall and clock test) | Cognitive Measurement | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 
| Fasting Blood Draws | Biological Biomarker | Following completion of the 12-week exercise intervention and 6-months post-exercise intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Exercise, Fluoxetine, Randomized Control Trial, Rehabilitation