Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC)

Abstract

Background: Basic science studies have reported remote ischemic conditioning (RIC) as neuroprotective in acute ischemic stroke, although clinical evidence remains conflicting. The TRICS BASIC study (Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke) investigated the efficacy and safety of RIC in experimental ischemic stroke using a rigorous clinical trial methodology.

Methods: Multicenter, multispecies, parallel group, randomized, controlled, preclinical trial of transient femoral artery clipping to induce RIC in female and male rats and mice subjected to transient endovascular occlusion of the middle cerebral artery. Animals were randomized to receive RIC, or sham surgery, after reperfusion. The primary end point was a good functional outcome at 48 hours, assessed using a composite functional neuroscore. Secondary end points were infarct volume at 48 hours and safety, assessed using a standardized health report at 24 and 48 hours. Preenrollment harmonization, centralized monitoring, allocation concealment, blinded outcome assessment, and intention-to-treat analysis were applied.

Results: The trial enrolled 164 rodents (82 mice and 82 rats) of both sexes (53% females), across 7 laboratories. A greater proportion of RIC-treated rodents achieved a favorable functional outcome compared with controls, at 48 hours postischemia (55% versus 36%; odds ratio, 2.2 [95% CI, 1.23-4.4]; P=0.009). RIC was associated with a small reduction in infarct volume (standardized mean difference, -0.38 [95% CI, -0.70 to -0.05]; P=0.024). Health monitoring indicated no major safety concerns, and postoperative analgesia requirements were lower in RIC-treated mice.

Conclusions: Surgically induced RIC provided a modest but evident neuroprotective effect in experimental ischemic stroke, underscoring the potential of this strategy as an adjunctive treatment in stroke care. The findings of the TRICS BASIC study highlighted the importance of multicenter preclinical trials in addressing variability and enhancing translational validity.

Registration: URL: https://www.preclinicaltrials.eu; Unique identifier: PCTE0000177.

Keywords: ischemic stroke; models, animal; multicenter study; neuroprotection.

Figure 1.

Flow diagram of the TRICS BASIC preclinical trial (Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke). MCAO− indicates sham carotid artery surgery; MCAO+, middle cerebral artery occlusion; RIC−, sham femoral artery surgery; and RIC+, remote ischemic conditioning.

Figure 2.

Functional neuroscore and infarct volume. Distribution of De Simoni neuroscore (A) and infarct volume (B) of individual animals enrolled in the TRICS BASIC trial (Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke; mice in blue; rats in red). The threshold of 20 for a good functional outcome is indicated with a dotted line. Data are expressed as box and whiskers plots (median [25%–75% quartiles]; minimum [25% quartile–1.5×interquartile range]; and maximum [75% quartile + 1.5×interquartile range], with outliers). RIC− indicates sham femoral artery surgery; and RIC+, remote ischemic conditioning.