Dissemin is shutting down on January 1st, 2025

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American Heart Association, Circulation: Heart Failure, 7(17), 2024

DOI: 10.1161/circheartfailure.123.011548

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REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA -Related Dilated Cardiomyopathy

Journal article published in 2024 by Pablo Garcia-Pavia ORCID, Jose Fernando Rodriguez Palomares, Gianfranco Sinagra ORCID, Roberto Barriales-Villa ORCID, Neal K. Lakdawala ORCID, Robert L. Gottlieb ORCID, Randal I. Goldberg ORCID, Perry Elliott ORCID, Patrice Lee, Huihua Li, Franca S. Angeli, Daniel P. Judge ORCID, Calum A. MacRae ORCID, Tomas V. Ripoll Vera, Thomas V. McDonald and other authors.
This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Data provided by SHERPA/RoMEO

Abstract

BACKGROUND: LMNA ( lamin A/C )-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. METHODS: REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA -related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23–72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences ( P >0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, −24.2 to 34.1]; P =0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, −6.4 to 11.2]; P =0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, −4.3 to 14.9]; P =0.48); and NT-proBNP concentration (−339.4 pg/mL [95% CI, −1131.6 to 452.7]; P =0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11–1.74]; P =0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23–6.02]; P =0.84) were similar between groups. No new safety findings were observed. CONCLUSIONS: Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA -related dilated cardiomyopathy. REGISTRATION: URL: https://classic.clinicaltrials.gov ; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.