A Phase 2a randomized trial of once- versus twice-daily remote ischemic conditioning in vascular cognitive impairment...

Cerebral small vessel disease.(CSVD) is a leading cause of vascular cognitive impairment.(VCI). Remote ischemic conditioning (RIC) is a promising strategy to prevent CSVD progression, but it is unclear what doses of daily RIC are tolerable/adherable for older patients with CSVD-associated VCI.

The Trial of Remote Ischemic Pre-conditioning in Vascular Cognitive Impairment (TRIC-VCI; ClinicalTrials.gov:NCT04109963) was a prospective, open-label, randomized controlled trial with blinded endpoint assessment. Participants completing 14-day run-in were randomized to once- or twice-daily RIC for 30 days. RIC consisted of four cycles of blood-pressure cuff inflation to 200 mmHg around an arm for 5 minutes followed by 5-minute deflation using automated devices. Inclusion criteria: ages 60 to 85, CSVD evidence on computed tomography/magnetic resonance imaging, Montreal Cognitive Assessment score 13 to 24, and preserved basic activities of daily living. Outcomes were assessed at 30 and 90 days. The primary outcome was adherence (completing ≥ 80% of sessions). Secondary outcomes included percentage of sessions completed, safety, and pain/discomfort ratings. Exploratory outcomes included changes in white matter hyperintensity (WMH) volume, cognitive tests, and blood biomarkers. We explored trial experiences in a focus group with five patient-caregiver dyads.

Twenty-two of 23 patients completed run-in and were randomized. Ten of 11.(90.9%) patients in each RIC-group completed ≥ 80% of sessions; median session completion was 96% (interquartile range [IQR]: 89%-100%) for once-daily and 98% (IQR: 93%-100%) for twice-daily RIC. Pain/discomfort ratings were numerically higher with twice-daily RIC (median rating/10: 4.23, IQR.0.98-4.95 vs. once-daily: 1.63, IQR:1.00-3.36, P = 0.60). No patients developed tissue/neurovascular injury or venous thrombosis. Cognitive tests neither changed nor differed significantly between groups; WMH volumes were stable (90-day change from randomization: -0.21.mL, 95% confidence interval:-0.54 to +0.13). Tumor-necrosis-factor alpha and interleukin-1b declined from baseline to 30 days, persisting at 90 days, in both groups. Focus group participants opined the device was easy to use but desired greater portability, generally favored once-daily RIC, and were open to longer treatment courses in future trials.

Patients with CSVD-associated VCI adhered well to once- and twice-daily RIC, with no significant differences in safety or tolerability outcomes. We will incorporate participant feedback into device design and future efficacy trials.