https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413691/
This article has been cited by other articles in PMC.
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
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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