Higher Doses of Intensive Upper Limb Rehabilitation for Moderate to Severe Impairment in Acute, Subacute Stroke: Phase I Dose Escalation Study

BACKGROUND: To determine the maximum time spent on upper limb rehabilitation in people with moderate to severe impairment in acute and early sub-acute stage of stroke, in a phase I dose-escalation study. METHODS: Participants were recruited using a 3+3 study design from 2 stroke units and rehabilitation centers in Belgium. Patients received standard care plus escalating doses of upper limb motor training at 4 dose time-on-task levels: 1 (40 minutes), 2 (67 minutes), 3 (100 minutes) and 4 (133 minutes). Treatment was provided for 3 daily sessions, starting with 3 participants at level 1 and if dose was completed based on dose-limiting toxicity criteria, it was escalated to the next level with 3 new participants. RESULTS: Eighteen participants were recruited (median days post-stroke: 7.5 [Q1:5; Q3: 23.3]) with a mean Fugl Meyer Assessment Upper Extremity score of 29.4 (SD: 11.2). The maximum tolerated time-on-task of upper limb rehabilitation was, 100 minutes per day, with an additional 35 minutes of routine upper limb therapy provided as part of standard care. Level of fatigue and rate of perceived exertion were highest at dose level 4, resulting in participants not completing the dose of 133 minutes. CONCLUSIONS: Confirmative with existing literature using a different intervention, individuals with moderate to severe impairment in the early-stage of stroke, can tolerate higher doses of upper limb rehabilitation than those typically administered in standard care. These findings support future investigation into phase I/IIa dose-finding clinical trials exploring long-duration, high-intensity upper limb rehabilitation programs in the early post-stroke period. REGISTRATION: NCT04973553 (July 22, 2021). https://classic. CLINICALTRIALS: gov/ct2/show/NCT04973553.