REACT: a randomized trial to assess the efficacy and safety of clazosentan for preventing clinical deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage
Stephan A. Mayer, Nicolas Bruder, Giuseppe Citerio, Luc Defreyne, Cécile Dubois, Rajiv Gupta, Randall T. Higashida, Angelina Marr, Thanh N. Nguyen, Sébastiên Roux, Martin Smrčka, Ramón Torné, E. François Aldrich, _ _, Claudius Thomé, Andreas Gruber, Xavier Wittebole, Luc Defreyne, Jacques Créteur, J. van Loon, Didier Ledoux, Tim E. Darsaut, Michael Kelly, Gwynedd E. Pickett, Anthony M. Kaufmann, Ondřej Bradáč, Martin Smrčka, S Rehák, Tomas Hrbac, Martin Sameš, Vladimír Přibáň, Troels Halfeld Nielsen, Peter Birkeland, Antti Ronkainen, Justiina Huhtakangas, Jaakko Rinne, Timo Koivisto, J.C. Dumont, Pierre Simeone, Russell Chabanne, Anne‐Claire Lukaszewicz, Thomas Ritzenthaler, Vincent Degos, Vincent Costalat, Philippe Séguin, Vincent Legros, Lionel Calviere, Étienne Gayat, Bertrand Rozec, Manfred Westphal, Sylvia Bele, Andreas Unterberg, Maria Wostrack, Sebastian Brandner, Ilker Y. Eyüpoglu, Juergen Konczalla, Nils Hecht, Stefan Wolf, Philipp Dammann, Ansgar Berlis, Angelika Ehlert, Jan Leppert, Ralph König, Jan F. Cornelius, A. Petridis, Florian Geßler, Attila Lajgut, Pál Barzó, András Büki, Péter Tóth, S. Szabó, Yigal Shoshann, Leon Levi, Moshe Attia, Sagi Harnof, Marina Munari, Giuseppe Citerio, Sandra Rossi, Anselmo Caricato, Paweł Słoniewski, Przemysław Kunert, Maciej Śniegocki, Dariusz J. Jaskólski, Robert Juszkat, Javier Ibáñez, Alfonso Lagares, J.F. Alén, Fuat Arikan Abello, Andreu Gabarrós Canals, Ramón Torné, Jesús Morera Molina, Carlos Dominguez Alonso, Fabián Romero-Chala, Ola Nilsson, Johan Ljungqvist, Oscar Åneman, Johanna Eneling, Ajith J. Thomas, Christopher S. Ogilvy, Jesse Liu
Abstract
OBJECTIVE: Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. METHODS: REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. RESULTS: A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. CONCLUSIONS: Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).