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

Sorry, but this is just tweaking the 10% full recovery rate using standard rehab. We need something much more innovative like maybe solving the neuronal cascade of death by these 5 causes in the first week and preventing that damage that there would be much less dead and damaged neurons. A great stroke association president would make sure we are following the best stroke strategy that addresses the complete problems in stroke.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413691/

Alexander W. Dromerick,^1,2,* Matthew A. Edwardson,^1,2 Dorothy F. Edwards,³ Margot L. Giannetti,¹ Jessica Barth,¹ Kathaleen P. Brady,¹ Evan Chan,¹ Ming T. Tan,⁴ Irfan Tamboli,⁵ Ruth Chia,⁵ Michael Orquiza,⁵ Robert M. Padilla,⁵ Amrita K. Cheema,⁶ Mark E. Mapstone,⁷ Massimo S. Fiandaca,^2,5 Howard J. Federoff,^2,5 and Elissa L. Newport^1,2

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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: stroke rehabilitation, cerebrovascular disorders, critical period, motor recovery, multi-omics, adaptive randomization

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Background

Using animal models of stroke, substantial scientific progress has been made in the understanding of the neural substrates of recovery after brain injury. Experimental studies of motor training after injury show that motor function can be improved significantly when a number of recovery and training variables are controlled. The experiment of Biernaskie et al. (2004) has been particularly intriguing given the finding of a sensitive period after experimental stroke in which rodents are most responsive to motor training in a specific time window soon after stroke. This finding has provoked much discussion in the stoke rehabilitation research community, since of course one wants to rehabilitate stroke patients at the time after stroke when therapies can be most effective. In this paper, we discuss the challenges faced by clinical trialists in translating a conceptually straightforward rodent experiment into a stroke rehabilitation clinical trial. We present our methods for the Critical Periods after Stroke Study (CPASS) as one example of the choices that can be made in testing whether promising findings in rodents have relevance in rehabilitation of patients with stroke.

The CPASS trial is designed to translate important findings from the rodent motor recovery literature into the human clinical trial setting. Adapting the critical elements of the rodent studies to the stroke rehabilitation setting requires a series of decisions and accommodations. In this paper, we review and discuss these considerations and how we have addressed them. Where possible we have retained essential elements of the rodent studies, including manipulation of intervention timing, randomization, standardized motor training paradigm based on a highly salient reward, and the use of motor performance measures. Data obtained from this randomized controlled trial will be used to formulate more effective treatments to better focus on the needs of individuals with stroke.

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