biostudies-literatureUnknown17(7)Garcia-Pavia P<h4>Background</h4><i>LMNA</i> (<i>lamin A/C</i>)-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.<h4>Methods</h4>REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic <i>LMNA</i>-related dilated cardiomyopathy. Patients with confirmed <i>LMNA</i> 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.<h4>Results</h4>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 (<i>P</i>>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]; <i>P</i>=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; <i>P</i>=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; <i>P</i>=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; <i>P</i>=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; <i>P</i>=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; <i>P</i>=0.84) were similar between groups. No new safety findings were observed.<h4>Conclusions</h4>Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with <i>LMNA</i>-related dilated cardiomyopathy.<h4>Registration</h4>URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.Circulation. Heart failuree011548https://www.ebi.ac.uk/biostudies/studies/S-EPMC11244753biostudies-literatureREALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic <i>LMNA</i>-Related Dilated Cardiomyopathy.PMC11244753Garcia Alvarez AGarcia-Pavia PTang WHWWare JCarlos Castillo Dominguez JAndersen KWilliams JKlapholz MHershson ARPineda JRElliott PPinto YAlfonso Jimenez Diaz VLepage SCoats CBarriales-Villa RGoldberg RIBeatrice Musumeci MDavis DMcGrew FALeDoux JJudge DPMaurizio Parato VDib NMHershberger RLi HLakdawala NKVan Cleemput JGimeno Blanes JRREALM-DCM InvestigatorsSinagra GJones AEOwens ATCastillo AGTaylor MRGVanderheyden MOlivotto IPellicori PHofmeyer MAvaca HAHartleib MCForleo CAmbrosio GSheikh FLee PHaugaa KHMcDonald TVBotta CEEwald GAMacRae CARipoll Vera TVTallaj JACadrin-Tourigny JArbustini EPalomares JFRKatz SDGottlieb RLGupta DKWheeler MTPriori SGMoses JPan SKapoor SStempien-Otero ACGardner MMetra MHinchman DATrevino MELatif FAfshar KLoureyro JBurke MAToma MSamuel Montes Cruz EAngeli FSMartindale JfalseREALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic <i>LMNA</i>-Related Dilated Cardiomyopathy.<h4>Background</h4><i>LMNA</i> (<i>lamin A/C</i>)-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.<h4>Methods</h4>REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic <i>LMNA</i>-related dilated cardiomyopathy. Patients with confirmed <i>LMNA</i> 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.<h4>Results</h4>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 (<i>P</i>>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]; <i>P</i>=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; <i>P</i>=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; <i>P</i>=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; <i>P</i>=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; <i>P</i>=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; <i>P</i>=0.84) were similar between groups. No new safety findings were observed.<h4>Conclusions</h4>Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with <i>LMNA</i>-related dilated cardiomyopathy.<h4>Registration</h4>URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.2024-01-01T00:00:00Z2024 Jul2024-12-04T03:18:09.912Z2024-12-04T03:18:09.912ZS-EPMC112447533897960810.1161/CIRCHEARTFAILURE.123.011548