Dosage Matters: A Randomized Controlled Trial of Rehabilitation Dose in the Chronic Phase after Stroke

Abstract

Background and Purpose: For stroke rehabilitation, task-specific training in animal models and human rehabilitation trials is considered important to trigger inherent neuroplasticity, promote motor learning, and functional recovery. Little is known, however, about what constitutes an effective dosage of therapy. Methods: This is a parallel group, four arm, single blind, phase I, randomized control trial of four dosages of upper extremity therapy delivered in an outpatient setting during the chronic phase after stroke. Participants were randomized into groups that varied in total dosage of therapy (i.e., 0, 15, 30, or 60 hours). Seven hundred and four participants were assessed for eligibility, 50 were eligible to enroll, 45 were randomized, 44 participated and 41 completed the study. Planned primary analyses used linear mixed effects regression to model baseline to post-intervention changes in the Motor Activity Log-Quality of Movement rating (MALQ) and the Wolf Motor Function Test (WMFT) time score as a function of therapy dosage. A series of hierarchical models were constructed using the MALQ and WMFT. Results: We observed a significant dose response curve: the greater the dosage of training, the greater the change in MALQ, with the dose by week slope parameter of 0.0045 (ΔMAL/hour/week; p = 0.0011; 95% CI = [0.0019; 0.0071]). Over the 3 weeks of therapy, this corresponds to a gain of 0.81 in MALQ for the 60 hour dose. Conclusions: For mild-tomoderately impaired stroke survivors, the dosage of a patient-centered, task specific motor therapy was shown to systematically influence the gain in quality of arm use in the natural environment, but not functional capacity as measured in the laboratory. We highlight the importance of recovery outcomes that capture arm use vs. functional capacity.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT 01749358

The Efficiency, Efficacy, and Retention of Motor Training in Chronic Stroke

“…Detailed inclusion and exclusion criteria of the DOSE trial are described in 9 . Briefly, participants were included if they were older than 21 years, their score on the impairment UE Fugl-Meyer motor (UEFM) test at baseline was in the 19-60 range out of 66, their cognitive function sufficiently preserved to provide informed consent, and they presented little to no upper extremity sensory impairment or neglect.…”

“…It has been used extensively, including in the EXCITE trial, and has good validity and reliability 31 . Here, we analyzed the changes in the MAL Quality of Movement sub-scale, because we previously showed a robust and highly significant dose response for the MAL 9 .…”

“…First, the effect of increasing the amount of training on clinical outcomes is controversial. While both our recent Dose Optimization for Stroke Evaluation (DOSE) trial and meta-analyses 7,8 suggest that higher doses lead to greater gains 9 , a recent phase II clinical trial showed no effect of dose on arm function 10 . Second, although studies of motor training after stroke show that most gains in movement performance are achieved in the initial sessions 11,12 , the changes of efficiency of training with both additional doses and additional bouts of training on clinical outcomes are unknown.…”

“…Whereas some studies have shown decay of the gains post-training, as least for subgroups of patients 13 , others have shown that the gains can be maintained after training 11,14 , yet others have shown that the gains can even further increase following training, possibly through "self-training" if arm use is sufficient 13,[15][16][17] Here, we analyzed the changes in the Quality of Movement sub-scale of the Motor Activity Log (henceforth, the MAL) in the DOSE trial 9 , in which participants with chronic stroke were randomized into four dose groups. The total doses (0, 15, 30 and 60 hours) were equally distributed over the three bouts of training, as shown in Figure 1B.…”

“…Using linear models, we previously showed that the changes in MAL due to training in DOSE was dose-dependent 9 . While such "fixed" regression models can predict response to interventions or recovery 9,10,12 , they cannot simultaneously account for both the changes in outcomes during training (when an increase in performance is expected) and outside of training for individual patients (where either a decrease in performance due to forgetting or an increase in performance due to self-training is expected). Parsing the repeated measure data to test changes during specific periods (i.e.…”