Multi-center Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC)

Beretta, S.; Tettamanti, M.; Mariani, J.; Diamanti, S.; Valente, A.; Cuomo, O.; Di Santo, C.; Dettori, I.; Venturini, M.; Bulli, I.; Coppi, E.; Montano Castillo, M. A.; Butti, E.; Gullotta, G. S.; Vigano, M.; Santangelo, F.; Pedrazzini, F. A.; Perego, C.; Seminara, S.; Anzilotti, S.; Rzemieniec, J.; Castiglioni, L.; Mercuriali, B.; Muluhie, M.; Zoia, C. P.; Sala, G.; Sironi, L.; Bacigaluppi, M.; Martino, G.; Pedata, F.; Pugliese, A. M.; Amantea, D.; Bagetta, G.; Vinciguerra, A.; Pignataro, G.; Fumagalli, S.; De Simoni, M.-G.; Ferrarese, C.

doi:10.1101/2025.03.25.645373

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bioRxiv · 10.1101/2025.03.25.645373

Multi-center Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC)

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Abstract

BackgroundBasic science studies have reported remote ischemic conditioning (RIC) as neuroprotective in acute ischemic stroke, while clinical evidence remains conflicting. The TRICS BASIC study investigated the efficacy and safety of RIC in experimental ischemic stroke using a rigorous clinical trial methodology. MethodsMulti-center, multi-species, 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 endpoint was good functional outcome at 48 hours, assessed using a composite functional neuroscore. Secondary endpoints was infarct volume at 48 hours and safety, assessed using a standardized health report at 24 and 48 hours. Pre-enrollment harmonization, centralized monitoring, allocation concealment, blinded outcome assessment and intention-to-treat analysis were applied. ResultsThe trial enrolled 164 rodents (82 mice and 82 rats) of both sexes (53% females), across seven laboratories. A greater proportion of RIC-treated rodents achieved a favorable functional outcome compared to controls, at 48 hours post-ischemia (55% versus 36%; OR 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, -0.05], p=0.024). Health monitoring indicated no major safety concerns, and post-operative analgesia requirements were lower in RIC-treated mice. ConclusionsSurgically-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. Registrationregistered at preclinicaltrials.eu, identifier PCTE0000177.

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Beretta, S., Tettamanti, M., Mariani, J., Diamanti, S., Valente, A., Cuomo, O., Di Santo, C., Dettori, I., Venturini, M., Bulli, I., Coppi, E., Montano Castillo, M. A., Butti, E., Gullotta, G. S., Vigano, M., Santangelo, F., Pedrazzini, F. A., Perego, C., Seminara, S., Anzilotti, S., Rzemieniec, J., Castiglioni, L., Mercuriali, B., Muluhie, M., Zoia, C. P., Sala, G., Sironi, L., Bacigaluppi, M., Martino, G., Pedata, F., Pugliese, A. M., Amantea, D., Bagetta, G., Vinciguerra, A., Pignataro, G., Fumagalli, S., De Simoni, M.-G., Ferrarese, C.. 2025-03-26. Multi-center Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC). https://doi.org/10.1101/2025.03.25.645373

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