Adaptive trials in stroke: Current use & future directions

Inclusion of adaptive design features in a clinical trial provides pre-planned flexibility to dynamically modify a trial during its conduct, while preserving validity and integrity. Adaptive trials are needed to accelerate the conduct of more efficient, informative, and ethical clinical research in the field of neurology as compared to traditional fixed designs. Stroke is a natural candidate for adoption of these innovative approaches to trial design. This Research Methods in Neurology paper is informed by a scoping review that identified 45 completed and ongoing adaptive clinical trials in stroke that were appraised: 14 trials had published results with or without a published protocol, 15 trials had a published protocol, and 16 trials were registered only. Treatments spanned acute (n=28), rehabilitation (n=8), prevention (n=8), and rehabilitation and prevention (n=1) domains. A subsample of these trials were selected to illustrate the utility of adaptive design features and discuss why each adaptive feature(s) were incorporated in the design to best achieve the aim, whether each individual feature was used and if it resulted in expected efficiencies, and any learnings during preparation, conduct or reporting. We then discuss the operational, ethical, and regulatory considerations that warrant careful consideration during adaptive trial planning and reflect on the workforce readiness to deliver adaptive trials in practice. We conclude that adaptive trials can be designed, funded, conducted, and published for a wide range of research questions and offer future directions to support adoption of adaptive trial designs in stroke and neurological research more broadly. ### Competing Interest Statement KSH is supported by a NHMRC Emerging Leadership (#2016420) Fellowship, Heart Foundation Future Leader (#106607) Fellowship, and Award from the Victorian Health and Medical Research Workforce Project, The Victorian Government, The Victorian Department of Jobs, Precincts and Regions, AAMRI and Veski; has received a research grant from the Medical Research Future Fund (2007425); has received support to attend meetings of the World Stroke Congress and World Congress of NeuroRehabilitation; and is co-Chair of the third Stroke Recovery and Rehabilitation Roundtable. ED has received a PhD scholarship from Australian Government Research Training Program; and received support from University of Melbourne and Smart Strokes to attend conferences. BCVC holds a NHMRC Leadership (#1174514) Fellowship. KSH/BCCV/JB/LC are investigators of the NHMRC Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (#2015705). LC has received grants from the Medical Research Future Fund (#2007425, Frontiers Australian Stroke Alliance), and NHMRC (#2010766). PK has grants or contracts with NIH, Cerenovus/Johnson & Johnston (ENDOLOW trial PI), Bayer (PACIFIC-Stroke trial national leader contract), NIH; royalties from UpToDate, Inc (online publication); consulting fees from Basking Biosciences, Lumosa, Shionogi; NIH-appointed DSMB Chair of Nourish Trial; and has received drug and drug assays from Translational Sciences for NIH funded SISTER trial. VY holds a CIHR Fellowship Award (430288) and is supported by a Scholarship from the University of Melbourne. SW is a member of European Stroke Organisation executive committee. SS has held contracts with Novartis and Uriach; received consulting fees, payment or honoraria or support to attend meetings from Novartis, Allergan-Abbvie, Teva, Lilly, Lundbeck, Pfizer, NovoNordisk, Abbott, AstraZeneca, or Lundbeck; is President Elect of the European Stroke Organisation and Second Vice-President for the European Headache Federation; and has received materials from Allergan-Abbvie and NovoNordisk. JB is supported by a NHMRC fellowship (#1154904); an investigator on MRFF, NHMRC, Alfred Felton Bequest and University of Melbourne projects; DSMB Chair of iWHO, SCI-MT and ESTRELL trials; DSMB member of RESTORE trial; Steering Committee member of PISCES, PESTO, UPLIFT and ENABLE trials; member of scientific advisory board for academic institutions in Norway and India; Executive Chair of the International Stroke Recovery and Rehabilitation Alliance; received support to attend World Stroke Organisation, World Stroke Congress, Global Stroke Alliance, Lausanne University Hospital Switzerland, Dutch Society of NeuroRehabilitation meetings; received payment or honoraria from Japanese Association of Rehabilitation Medicine, Chinese Association of Rehabilitation Medicine, American Congress of Rehabilitation Medicine, Belgian Stroke Council, Department of Rehabilitation Medicine Asan Medical Centre Korea, University of Otago New Zealand, Kaiser Permanente USA, Moleac Pty Ltd, and University Hospital Bern. JLS reports consulting fees (for advising on rigorous and safe clinical trial design and conduct) from Abbott, Acticor, Aeromics, Amgen, Argenica, Astrocyte, Bayer, Biogen, Boehringer Ingelheim, BrainsGate, BrainQ, CSL Behring, Filterlex, Genentech, Johnson&Johnson, MindRhythm, Medtronic, NeuroMerit, Neuronics, Novo Nordisk, Occlutech, Phenox, Phillips, QuantalX, Rapid Medical, Roche, and Stream Biomedical. HJ, JP have no declarations of interest ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript