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Trial registered on ANZCTR


Registration number
ACTRN12619000573156
Ethics application status
Approved
Date submitted
8/04/2019
Date registered
11/04/2019
Date last updated
14/07/2020
Date data sharing statement initially provided
11/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
FRAMBOISE: Fluoxetine, Recovery and Motor BiOmarkers in StrokE.
Scientific title
FRAMBOISE: Fluoxetine, Recovery and And Motor BiOmarkers in StrokE. A single-site, randomised, triple-blinded, placebo-controlled phase IIa trial of the effect of fluoxetine treatment for 90 days on paretic upper limb impairment at the sub-acute stage of stroke.
Secondary ID [1] 297850 0
Nil
Universal Trial Number (UTN)
Trial acronym
FRAMBOISE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 312224 0
Condition category
Condition code
Stroke 310769 310769 0 0
Haemorrhagic
Stroke 310770 310770 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be instructed to orally ingest fluoxetine in the form of 1 x 20 mg capsule, daily for 90 days, starting within 10 days of stroke symptom onset.
Intervention code [1] 314088 0
Treatment: Drugs
Comparator / control treatment
Participants will be instructed to orally ingest a placebo (inert calcium lactate) in the form of 1 x 20 mg capsule, daily for 90 days, starting within 10 days of stroke symptom onset.

Participants will be blinded to which treatment they receive. Overcapsulation will be use to ensure that participants remain blinded to which treatment they receive. Compliance will be measured through capsule counting. Treatment will be initiated while in hospital and maintained at home after leaving hospital.
Control group
Placebo

Outcomes
Primary outcome [1] 319619 0
Change in upper limb motor impairment assessed by the change the Upper Extremity Fugl-Meyer score (UE-FM)
Timepoint [1] 319619 0
Difference in UE FM score at baseline (within the first 7 days after stroke) and after 90 days of treatment.
Secondary outcome [1] 368875 0
Presence (or absence) of motor-evoked potentials elicited by transcranial magnetic stimulation (TMS) in the affected upper limb. Surface electromyography (EMG) will be recorded from the first dorsal interosseous and extensor carpi radialis muscles of the paretic upper limb, to enable the detection of motor evoked potentials in response to TMS.
Timepoint [1] 368875 0
After 30 and 90 days of treatment.
Secondary outcome [2] 368882 0
Tendon vibration reflex amplitude recorded from the affected biceps brachii muscle using surface electromyography. A vibration stimulus will be applied to the tendon of the affected biceps brachii muscle and any resulting reflex muscle activity will be recorded by the surface EMG.
Timepoint [2] 368882 0
At baseline (<10 days after stroke), after 30 and 90 days of treatment (initiated after 10 days following the stroke).
Secondary outcome [3] 368893 0
Depression status, assessed using the Montgomery-Asberg Depression Rating Scale.
Timepoint [3] 368893 0
During the first week following stroke, and after 30 and 90 days of treatment.

Eligibility
Key inclusion criteria
At least 18 years old
Monohemispheric cerebral ischaemic or haemorrhagic stroke
Stroke symptom onset in the previous 10 days
Moderate to severe upper limb motor impairment on day 3 post-stroke, defined as a Shoulder Abduction, Finger extension (SAFE) score <5 out of 10 and upper limb Fugl-Meyer (UE-FM) score <20.
Patients must not have motor evoked potentials (be MEP-) when tested with transcranial magnetic stimulation (TMS) between 3 and 7 days after stroke.
Patients treated with intravenous thrombolysis and/or intra-arterial thrombectomy are eligible.
Patients with previous ischaemic or haemorrhagic stroke are eligible.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Contraindications to fluoxetine, including: hepatic impairment, renal impairment, and hyponatraemia, as assessed by the study physician.
Contraindications to TMS and evaluated using a safety screening checklist, including biomedical implant devices, history of seizures or medications increasing seizure risk, and pregnancy
Unable to safely swallow capsules, as determined by the patient’s clinical team
Cognition and/or communication impairment precluding informed consent or compliance with the research procedures, as determined by the patient’s clinical team
Life expectancy less than 12 months, as determined by the patient’s clinical team
Upper limb motor performance limited by pre-existing conditions, such as musculoskeletal disease
Concurrent diagnosis of depression
Any anti-depressant usage in the month prior to stroke
Residing out of region precluding follow-up.
Need for an interpreter

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The Pharmacy Department at Auckland City Hospital will randomly allocate participants to the treatment or control group, using custom software to minimise between-group differences in age and stroke severity. This central randomisation will conceal allocation from the researchers involved in recruiting participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The Pharmacy Department at Auckland City Hospital will randomly allocate participants to the treatment or control group, using custom software to minimise between-group differences in age and stroke severity.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The planned sample size is up to 54 patients. Allowing for an estimated 25% loss to follow up, the sample size available for evaluating FRAMBOISE will be 40 participants (20 per treatment group).

The primary outcome is the change in UE-FM score after 90 days of treatment. This will be analysed with a two-tailed independent samples t-test. Based on a database of previously identified MEP- stroke patients from Professor Stinear’s work, on average, MEP- patients demonstrate an increase in UE-FM score of 8.33 points (95% CI 5.55 – 11.32) between baseline and 12-week post-stroke, with a standard deviation of 9.36 (95% CI 7.45 – 11.04). We consider a between-group difference of 10 points in the increase in UE-FM score to be clinically meaningful. The sample size is therefore calculated assuming that the mean increase in UE-FM will be 8.33 points for the control group and 18.33 points for the treatment group. Taking a conservative approach, we assume that the standard deviation of the mean increase in UE-FM for the control and treatment groups will match the upper confidence limit (11.04 points) of the database group. Assuming alpha = 0.05, a sample size of 40 participants (20 per treatment group), will allow us to detect a treatment effect size of 1.07 with 90% power. A total of 54 patients will be recruited to allow for a 25% loss to follow up.

Secondary outcomes analyses:
A two-tailed independent samples t-test will be completed to examine differences in tendon vibration reflex amplitude between treatment groups.
A Pearson’s chi-squared test will be completed to compare the proportion of MEP- patients who convert to MEP+ during treatment between treatment groups.
Secondary analyses will also explore differences in the incidence of any adverse events reported throughout the 90-day treatment period by the control and treatment groups.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Participant recruitment difficulties
Other reasons/comments
Other reasons
The COVID-19 pandemic has prompted re-prioritisation of resources.
Date of first participant enrolment
Anticipated
17/06/2019
Actual
Date of last participant enrolment
Anticipated
1/10/2021
Actual
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
54
Accrual to date
Final
Recruitment outside Australia
Country [1] 21381 0
New Zealand
State/province [1] 21381 0

Funding & Sponsors
Funding source category [1] 302373 0
Charities/Societies/Foundations
Name [1] 302373 0
Neurological Foundation of New Zealand
Country [1] 302373 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
The University of Auckland
Private Bag 92019
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 302261 0
None
Name [1] 302261 0
Address [1] 302261 0
Country [1] 302261 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303048 0
Health and Disabilities Ethics Committee
Ethics committee address [1] 303048 0
Ethics committee country [1] 303048 0
New Zealand
Date submitted for ethics approval [1] 303048 0
26/04/2019
Approval date [1] 303048 0
05/06/2019
Ethics approval number [1] 303048 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92282 0
Prof Cathy Stinear
Address 92282 0
Department of Medicine
The University of Auckland
Private Bag 92019
Auckland 1142
Country 92282 0
New Zealand
Phone 92282 0
+64 9 92 33 779
Fax 92282 0
Email 92282 0
[email protected]
Contact person for public queries
Name 92283 0
Cathy Stinear
Address 92283 0
Department of Medicine
The University of Auckland
Private Bag 92019
Auckland 1142
Country 92283 0
New Zealand
Phone 92283 0
+64 9 92 33 779
Fax 92283 0
Email 92283 0
[email protected]
Contact person for scientific queries
Name 92284 0
Cathy Stinear
Address 92284 0
Department of Medicine
The University of Auckland
Private Bag 92019
Auckland 1142
Country 92284 0
New Zealand
Phone 92284 0
+64 9 92 33 779
Fax 92284 0
Email 92284 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Anonymised individual participant data that form the basis of reports of this trial.
When will data be available (start and end dates)?
Anonymised data will be made available from 3 months after publication of the study's main results, for a period of 5 years.
Available to whom?
Anonymised data will be made available to researchers who make a reasonable request for access with a sound research proposal, at the discretion of the principal investigator.
Available for what types of analyses?
Any analyses.
How or where can data be obtained?
Access will be subject to approval by the principal investigator, with a signed data access agreement in place.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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