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

Gillian Elizabeth Mead; Catriona Graham; Laurent Billot; Per Näsman; Erik Lundström; Steff Lewis; Graeme J Hankey; Maree L Hackett; John Forbes; Martin Dennis; FOCUS, AFFINITY and EFFECTS trialists

doi:10.1186/s13063-020-04875-1

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.

Affiliations

¹ Usher Institute, University of Edinburgh, , Room S1642, Royal Infirmary, Little France Crescent, Edinburgh, EH16 4SA, UK. gillian.e.mead@ed.ac.uk.
² Welcome Trust Clinical Research Facility, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
³ The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia.
⁴ Center for Safety Research, KTH Royal Institute of Technology, Stockholm, Sweden.
⁵ Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
⁶ University of Edinburgh, Level 2, NINE Edinburgh BioQuarter, 9 Little France Road, Edinburgh, EH16 4UX, UK.
⁷ Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, WA, Australia.
⁸ Health Research Institute, University of Limerick, Limerick, Ireland.
⁹ Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, Little France Crescent, Edinburgh, EH16 4SA, UK.

Abstract

Background: Three large trials of fluoxetine for stroke recovery (FOCUS (fluoxetine or control under supervision), AFFINITY (the Assessment oF FluoxetINe In sTroke recovery) and EFFECTS (Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke)) have been collaboratively designed with the same basic protocol to facilitate an individual patient data analysis (IPDM). The statistical analysis plan for the three individual trials has already been reported in Trials, including a brief description of the IPDM. In this protocol, we describe in detail how we will perform the IPDM.

Methods/design: Data from EFFECTS and AFFINITY will be transferred securely to the FOCUS statistician, who will perform a one-stage IPDM and a two-stage IPDM. For the one-stage IPDM, data will be combined into a single data set and the same analyses performed as described for the individual trials. For the two-stage IPDM, the results for the three individual trials will be combined using fixed effects meta-analyses. The primary and secondary outcome domains for the IPDM are the same as for individual trials. We will also perform analyses according to several subgroups including country of recruitment, ethnicity and trial. We will also explore the effects of fluoxetine on our primary and secondary outcomes in subgroups defined by combinations of characteristics. We also describe additional research questions that will be addressed using the combined data set, and published subsequently, including predictors of important post-stroke problems such as seizures, low mood and bone fractures.

Discussion: An IPDM of our three large trials of fluoxetine for stroke recovery will allow us to provide the most precise estimates of any risks and benefits of fluoxetine vs placebo, to detect reliably a smaller overall effect size than those detectable by the individual trials, to better determine the effects of fluoxetine vs placebo in subgroups of patients and outcomes and to broaden the generalisability of the results. Also, we may identify differences in treatment effects between studies.

Trial registration: FOCUS: ISRCTN ISRCTN83290762 . Registered on 23 May 2012. EudraCT 2011-005616-29 . Registered on 3 February 2012.

Affinity: Australian New Zealand Clinical Trials Registry ACTRN12611000774921 . Registered on 22 July 2011.

Effects: ISRCTN ISRCTN13020412 . Registered on 19 December 2014. ClinicalTrials.gov NCT02683213 . Registered on 2 February 2016. EudraCT 2011-006130-16 . Registered on 8 August 2014.

Keywords: AFFINITY; EFFECTS; FOCUS; Individual patient data meta-analysis; Recovery; Stroke.

MeSH terms

Aged
Brain Ischemia* / drug therapy
Data Interpretation, Statistical*
Female
Fluoxetine / therapeutic use*
Humans
Male
Meta-Analysis as Topic
Randomized Controlled Trials as Topic
Recovery of Function
Research Design
Stroke* / drug therapy
Treatment Outcome

Substances

Fluoxetine

Associated data

ClinicalTrials.gov/NCT02683213