Ahmad Masri, Francesco Cappelli, Margot K. Davis, Marianna Fontana, Pablo Garcia-Pavia, Julian D. Gillmore, Mazen Hanna, Laura Obici, Scott D. Solomon, Brett W. Sperry, Nobuhiro Tahara, Márcia Waddington-Cruz, Arnt V. Kristen, Rodney H. Falk, Sanjiv J. Shah, Jose Nativi-Nicolau, Nicholas J. Viney, Qingqing Yang, Jersey Chen, Sotirios Tsimikas, Mathew S. Maurer
BACKGROUND: messenger RNA to reduce the production of circulating TTR. METHODS: CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I-III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS: CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu; Unique identifier: EudraCT number 2019-002835-27.