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
Authors: Mayer Stephan A. , Bruder Nicolas , Citerio Giuseppe , Defreyne Luc , Dubois Cecile , Gupta Rajiv , Higashida Randall , Marr Angelina , Nguyen Thanh N. , Roux Sébastien , Smrčka Martin , Torné Ramon Torné , Aldrich E. François , _ _ , Thomé Claudius , Gruber Andreas , Wittebole Xavier , Defreyne Luc , Creteur Jacques , van Loon Johannes , Ledoux Didier , Darsaut Tim , Kelly Michael , Pickett Gwynedd , Kaufmann Anthony , Bradáč Ondřej , Smrcka Martin , Řehák Svatopluk , Hrbac Tomas , Sames Martin , Priban Vladimir , Nielsen Troels Halfeld , Birkeland Peter , Ronkainen Antti , Huhtakangas Justiina , Rinne Jaakko , Koivisto Timo , Dumont Jean-Claude , Simeone Pierre , Chabanne Russell , Lukaszewicz Anne-Claire , Ritzenthaler Thomas , Degos Vincent , Costalat Vincent , Seguin Philippe , Legros Vincent , Calviere Lionel , Gayat Etiénne , Rozec Bertrand , Westphal Manfred , Bele Sylvia , Unterberg Andreas W. , Wostrack Maria , Brandner Sebastian , Eyüpoglu Ilker , Konczalla Jürgen , Hecht Nils , Wolf Stefan , Dammann Philipp , Berlis Ansgar , Ehlert Angelika , Leppert Jan , König Ralph , Cornelius Jan , Petridis Athanasios , Gessler Florian , Lajgut Attila , Barzó Pál , Büki András , Tóth Péter , Szabó Sándor , Shoshann Yigal , Leon Levi , Attia Moshe , Harnof Sagi , Munari Marina , Citerio Giuseppe , Rossi Sandra , Caricato Anselmo , Słoniewski Paweł , Kunert Przemysław , Śniegocki Maciej , Jaskólski Dariusz , Juszkat Robert , Ibanez Javier , Lagares Alfonso , Alen Jose Fernandez , Abello Fuat Arikan , Canals Andreu Gabarros , Torné Ramon Torné , Molina Jesús Morera , Alonso Carlos Dominguez , Romero-Chala Fabián , Nilsson Ola , Ljungqvist Johan , Aneman Oscar , Eneling Johanna , Thomas Ajith , Ogilvy Christopher , Liu Jesse J , Woo Henry , Bambakidis Nicholas , Reavey-Cantwell John , Claassen Jan , Steinberg Gary , Sauvageau Eric , Cheema Ahmed , Ray Bappaditya , Garcia Jorge Ortiz , Desai Masoom , Nguyen Thanh , Alaraj Ali , Amin-Hanjani Sepideh , Erkmen Kadir , Zipfel Gregory , Powers Ciaran , Shoirah Hazem , Mocco J , Singh Paul , Aldrich Francois , Simard J. Marc , Froehler Michael , Cockroft Kevin , Freeman William , Romit Jia 
Published: August 2024

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)