Adaptive Trials in Stroke: Current Use and Future Directions.

Kathryn S Hayward, Emily J Dalton, Bruce C V Campbell, Pooja Khatri, Sean P Dukelow, Hannah Johns, Silke Walter, Vignan Yogendrakumar, Jeyaraj D Pandian, Simona Sacco, Julie Bernhardt, Mark W Parsons, Jeffrey L Saver, Leonid Churilov
Author Information
  1. Kathryn S Hayward: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  2. Emily J Dalton: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia.
  3. Bruce C V Campbell: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  4. Pooja Khatri: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  5. Sean P Dukelow: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  6. Hannah Johns: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  7. Silke Walter: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  8. Vignan Yogendrakumar: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  9. Jeyaraj D Pandian: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  10. Simona Sacco: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  11. Julie Bernhardt: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  12. Mark W Parsons: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  13. Jeffrey L Saver: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID
  14. Leonid Churilov: From the Melbourne School of Health Sciences (K.S.H., E.J.D.), and Melbourne Medical School (K.S.H., H.J., L.C.), University of Melbourne, Parkville; Stroke Theme (K.S.H., B.C.V.C., J.B., L.C.), The Florey Institute, University of Melbourne, Heidelberg; National Health and Medical Research Council Centre of Research Excellence to Accelerate Stroke Trial Innovation and Translation (K.S.H., B.C.V.C., L.C., J.B., H.J.), University of Melbourne, Parkville; Department of Medicine and Neurology (B.C.V.C., V.Y.), Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia; Department of Neurology and Rehabilitation Medicine (P.K.), University of Cincinnati, OH; Department of Clinical Neuroscience (S.P.D.), and Hotchkiss Brain Institute (S.P.D.), University of Calgary, Alberta, Canada; Department of Neurology (S.W.), Saarland University, Saarbrücken; Department of Neurology (S.W.), Martin-Luther-University, Halle, Germany; Department of Neurology (V.Y.), University of Ottawa, Ontario, Canada; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab, India; Department of Biotechnological and Applied Clinical Sciences (S.S.), University of L'Aquila, Italy; Department of Neurology (M.W.P.), Liverpool Hospital, UNSW South Western Sydney Clinical School, Warwick Farm, Australia; Comprehensive Stroke Center and Department of Neurology (J.L.S.), University of California Los Angeles; and Australian Stroke Alliance (L.C.), University of Melbourne, Parkville, Victoria, Australia. ORCID

Abstract

Inclusion of adaptive design features in a clinical trial provides preplanned 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. Stroke is a natural candidate for adoption of these innovative approaches to trial design. This Research Methods in Neurology article is informed by a scoping review that identified 45 completed or ongoing adaptive clinical trials in stroke that were appraised: 15 trials had published results with or without a published protocol and 30 ongoing trials (14 trials had a published protocol, and 16 trials were registered only). Interventions spanned acute (n = 28), rehabilitation (n = 8), prevention (n = 8), and rehabilitation and prevention (n = 1). A subsample of these trials was selected to illustrate the utility of adaptive design features and discuss why each adaptive feature was incorporated in the design to best achieve the aim; whether each individual feature was used and whether 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 neurologic research more broadly.

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MeSH Term

Humans
Adaptive Clinical Trials as Topic
Research Design
Stroke

Word Cloud

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