Early-phase dose articulation trials are underutilized for post-stroke motor recovery: A systematic scoping review

Dalton, Emily; Чурилов, Леонид; Lannin, Natasha A.; Corbett, Dale; Campbell, Bruce C.V.; Hayward, Kathryn S

doi:10.1016/j.rehab.2021.101487

Cited by 9 publications

(16 citation statements)

References 56 publications

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“…The majority of studies from the review progress straight to a phase IIA/B trial without building on appropriate preclinical evidence or completing a phase I trial. 6 The best example of a program of upper limb research that adopts some principles from the discovery pipeline 5 will inform the following discussion. We will explore the design and dose justification process for the 4 trials within the program of research (Figure 3).…”

Section: Systematic Discovery Pipelinementioning

confidence: 99%

“…We have established that there is a lack of published phase I dose ranging trials in early-phase nonpharmaceutical stroke recovery research. 6 To understand whether phase I trials are consistently neglected across all stroke research (pharmaceutical and nonpharmaceutical), a search of peak national government funding agencies (between calendar years 2017-2019) in Australia 41 and the United States 42 can demonstrate the number of funded phase I trials. Supplement File 2 outlines the search process for each funding body and the results.…”

Section: Systematic Discovery Pipelinementioning

confidence: 99%

“…Early-phase research, particularly the appropriate design and implementation of multidimensional phase I nonpharmaceutical stroke recovery trials, is in its infancy. 6 The proposed solution serves to increase knowledge and, thus, application in this field.…”

Section: Multidimensional Dose Articulation Has Not Been Adequately Considered In Stroke Recovery Interventionsmentioning

confidence: 99%

“…Here, we address phase I trial design only as it forms the first clinical phase in the discovery pipeline and is the least common early-phase design approach completed. 6 Acquired knowledge from the pharmaceutical field and the 2 published phase I stroke recovery trials 34,52 will be used to guide the solution. We present the desirable properties, each followed by a hypothetical worked example, to guide the design of multidimensional phase I dose ranging trials for stroke recovery interventions.…”

Section: Solutionmentioning

confidence: 99%

“…In stroke recovery, the completion of early-phase trials to articulate the dose of a nonpharmaceutical intervention is limited. 6 Increasing the uptake of early-phase trials may help address the neutral findings in stroke recovery. [7][8][9] There are 2 important concepts that guide the adoption of early-phase dose articulation research: a systematic discovery pipeline 5,10 that informs the dose articulation process and a multidimensional dose framework 11 that conceptualizes the dimensions of dose.…”

Section: Introductionmentioning

confidence: 99%

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Multidimensional Phase I Dose Ranging Trials for Stroke Recovery Interventions: Key Challenges and How to Address Them

Dalton

Чурилов

Lannin

et al. 2021

Neurorehabil Neural Repair

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Despite an increase in the amount of published stroke recovery research, interventions have failed to markedly affect the trajectory of recovery poststroke. We argue that early-phase research to systematically investigate dose is an important contributor to advance the science underpinning stroke recovery. In this article, we aim to ( a) define the problem of insufficient use of a systematic approach to early-phase, multidimensional dose articulation research and ( b) propose a solution that applies this approach to design a multidimensional phase I trial to identify the maximum tolerated dose (MTD). We put forward a design template as a decision support tool to increase knowledge of how to develop a phase I dose-ranging trial for nonpharmaceutical stroke recovery interventions. This solution has the potential to advance the development of efficacious stroke recovery interventions, which include activity-based rehabilitation interventions.

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Section: Systematic Discovery Pipelinementioning

confidence: 99%

Section: Systematic Discovery Pipelinementioning

confidence: 99%

Section: Multidimensional Dose Articulation Has Not Been Adequately Considered In Stroke Recovery Interventionsmentioning

confidence: 99%

Section: Solutionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multidimensional Phase I Dose Ranging Trials for Stroke Recovery Interventions: Key Challenges and How to Address Them

Dalton

Чурилов

Lannin

et al. 2021

Neurorehabil Neural Repair

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Timing and Dose of Upper Limb Motor Intervention After Stroke: A Systematic Review

Hayward

Kramer

Dalton

et al. 2021

Stroke

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This systematic review aimed to investigate timing, dose, and efficacy of upper limb intervention during the first 6 months poststroke. Three online databases were searched up to July 2020. Titles/abstracts/full-text were reviewed independently by 2 authors. Randomized and nonrandomized studies that enrolled people within the first 6 months poststroke, aimed to improve upper limb recovery, and completed preintervention and postintervention assessments were included. Risk of bias was assessed using Cochrane reporting tools. Studies were examined by timing (recovery epoch), dose, and intervention type. Two hundred and sixty-one studies were included, representing 228 (n=9704 participants) unique data sets. The number of studies completed increased from one (n=37 participants) between 1980 and 1984 to 91 (n=4417 participants) between 2015 and 2019. Timing of intervention start has not changed (median 38 days, interquartile range [IQR], 22–66) and study sample size remains small (median n=30, IQR 20–48). Most studies were rated high risk of bias (62%). Study participants were enrolled at different recovery epochs: 1 hyperacute (<24 hours), 13 acute (1–7 days), 176 early subacute (8–90 days), 34 late subacute (91–180 days), and 4 were unable to be classified to an epoch. For both the intervention and control groups, the median dose was 45 (IQR, 600–1430) min/session, 1 (IQR, 1–1) session/d, 5 (IQR, 5–5) d/wk for 4 (IQR, 3–5) weeks. The most common interventions tested were electromechanical (n=55 studies), electrical stimulation (n=38 studies), and constraint-induced movement (n=28 studies) therapies. Despite a large and growing body of research, intervention dose and sample size of included studies were often too small to detect clinically important effects. Furthermore, interventions remain focused on subacute stroke recovery with little change in recent decades. A united research agenda that establishes a clear biological understanding of timing, dose, and intervention type is needed to progress stroke recovery research. Prospective Register of Systematic Reviews ID: CRD42018019367/CRD42018111629.

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What Is Next After This Well-Conducted, but Neutral, Multisite Trial Testing Self-Rehabilitation Approaches?

Bernhardt

Hayward

2021

Stroke

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Early-phase dose articulation trials are underutilized for post-stroke motor recovery: A systematic scoping review

Cited by 9 publications

References 56 publications

Multidimensional Phase I Dose Ranging Trials for Stroke Recovery Interventions: Key Challenges and How to Address Them

Multidimensional Phase I Dose Ranging Trials for Stroke Recovery Interventions: Key Challenges and How to Address Them

Timing and Dose of Upper Limb Motor Intervention After Stroke: A Systematic Review

What Is Next After This Well-Conducted, but Neutral, Multisite Trial Testing Self-Rehabilitation Approaches?

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