Critical periods after stroke study: translating animal stroke recovery experiments into a clinical trial

Alexander W Dromerick, Matthew A Edwardson, Dorothy F Edwards, Margot L Giannetti, Jessica Barth, Kathaleen P Brady, Evan Chan, Ming T Tan, Irfan Tamboli, Ruth Chia, Michael Orquiza, Robert M Padilla, Amrita K Cheema, Mark E Mapstone, Massimo S Fiandaca, Howard J Federoff, Elissa L Newport, Alexander W Dromerick, Matthew A Edwardson, Dorothy F Edwards, Margot L Giannetti, Jessica Barth, Kathaleen P Brady, Evan Chan, Ming T Tan, Irfan Tamboli, Ruth Chia, Michael Orquiza, Robert M Padilla, Amrita K Cheema, Mark E Mapstone, Massimo S Fiandaca, Howard J Federoff, Elissa L Newport

Abstract

Introduction: Seven hundred ninety-five thousand Americans will have a stroke this year, and half will have a chronic hemiparesis. Substantial animal literature suggests that the mammalian brain has much potential to recover from acute injury using mechanisms of neuroplasticity, and that these mechanisms can be accessed using training paradigms and neurotransmitter manipulation. However, most of these findings have not been tested or confirmed in the rehabilitation setting, in large part because of the challenges in translating a conceptually straightforward laboratory experiment into a meaningful and rigorous clinical trial in humans. Through presentation of methods for a Phase II trial, we discuss these issues and describe our approach.

Methods: In rodents there is compelling evidence for timing effects in rehabilitation; motor training delivered at certain times after stroke may be more effective than the same training delivered earlier or later, suggesting that there is a critical or sensitive period for strongest rehabilitation training effects. If analogous critical/sensitive periods can be identified after human stroke, then existing clinical resources can be better utilized to promote recovery. The Critical Periods after Stroke Study (CPASS) is a phase II randomized, controlled trial designed to explore whether such a sensitive period exists. We will randomize 64 persons to receive an additional 20 h of upper extremity therapy either immediately upon rehab admission, 2-3 months after stroke onset, 6 months after onset, or to an observation-only control group. The primary outcome measure will be the Action Research Arm Test (ARAT) at 1 year. Blood will be drawn at up to 3 time points for later biomarker studies.

Conclusion: CPASS is an example of the translation of rodent motor recovery experiments into the clinical setting; data obtained from this single site randomized controlled trial will be used to finalize the design of a Phase III trial.

Keywords: adaptive randomization; cerebrovascular disorders; critical period; motor recovery; multi-omics; stroke rehabilitation.

Figures

Figure 1
Figure 1
Study design. Baseline assessment (T1) occurs within the first month following stroke and subjects are randomized to one of four groups: early—additional 20 h of occupational therapy (OT) initiated <1 mo. from stroke onset, subacute—additional 20 h of OT initiated 2-3 mo. from stroke onset, chronic—additional 20 h of OT initiated 6-7 mo. from stroke onset, and control—no additional OT. All subjects are reassessed at 1 year (T2) to evaluate for durable change in study-related outcome measures.

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