Background Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may protect the brain from ischemic reperfusion injury. Methods and Results We performed a phase IIb blinded dose-escalation sham-controlled trial in patients with hyperacute stroke, randomized 1:1 to receive RIC (four 5-minute cycles) or sham to the nonparetic upper limb, in 3 blocks of increasing dose, starting within 6 hours of ictus. The primary outcome was trial feasibility (recruitment, attrition). Secondary outcomes included adherence, tolerability, safety (serious adverse events), plasma biomarkers at days 1 and 4 (S100-ß protein, matrix metalloproteinase-9, and neuron-specific enolase), and functional outcome. Sixty participants were recruited from 2 centers (3 per month) with no loss to follow-up: time to randomization 4 hours 5 minutes (SD 72 minutes), age 72 years (12), men 60%, blood pressure 154/80 mm Hg (25/12), National Institutes of Health Stroke Scale 8.4 (6.9), and 55% thrombolyzed. RIC was well tolerated with adherence not differing between RIC and sham, falling in both groups on day 3 (P=0.001, repeated measures ANOVA) because of discharge or transfer. S100ß increased in the sham group (mean rise 111 pg/mL [302], P=0.041, repeated measures ANCOVA) but not the RIC group. There were no differences in matrix metalloproteinase-9, neuron-specific enolase, number with serious adverse events (RIC 10 versus sham 10, P=0.81), deaths (2 versus 4, P=0.36), or modified Rankin Scale score (2 [interquartile range 1-4], 2 [interquartile range, 1-3]; P=0.85). Conclusions RIC in hyperacute stroke is feasible when given twice daily for 2 days and appears safe in a small population with hyperacute stroke. A larger phase III trial is warranted. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02779712.

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