Pablo Garcia-Pavia, Jose Fernando Rodriguez Palomares, Gianfranco Sinagra, Roberto Barriales-Villa, Neal K Lakdawala, Robert L Gottlieb, Randal I Goldberg, Perry Elliott, Patrice Lee, Huihua Li, Franca S Angeli, Daniel P Judge, Calum A MacRae
{"title":"REALM-DCM：ARRY-371797 在症状性 LMNA 相关性扩张型心肌病患者中的 3 期多国随机安慰剂对照试验。","authors":"Pablo Garcia-Pavia, Jose Fernando Rodriguez Palomares, Gianfranco Sinagra, Roberto Barriales-Villa, Neal K Lakdawala, Robert L Gottlieb, Randal I Goldberg, Perry Elliott, Patrice Lee, Huihua Li, Franca S Angeli, Daniel P Judge, Calum A MacRae","doi":"10.1161/CIRCHEARTFAILURE.123.011548","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong><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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with <i>LMNA</i>-related dilated cardiomyopathy.</p><p><strong>Registration: </strong>URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e011548"},"PeriodicalIF":7.8000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11244753/pdf/","citationCount":"0","resultStr":"{\"title\":\"REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic <i>LMNA</i>-Related Dilated Cardiomyopathy.\",\"authors\":\"Pablo Garcia-Pavia, Jose Fernando Rodriguez Palomares, Gianfranco Sinagra, Roberto Barriales-Villa, Neal K Lakdawala, Robert L Gottlieb, Randal I Goldberg, Perry Elliott, Patrice Lee, Huihua Li, Franca S Angeli, Daniel P Judge, Calum A MacRae\",\"doi\":\"10.1161/CIRCHEARTFAILURE.123.011548\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong><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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with <i>LMNA</i>-related dilated cardiomyopathy.</p><p><strong>Registration: </strong>URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.</p>\",\"PeriodicalId\":10196,\"journal\":{\"name\":\"Circulation: Heart Failure\",\"volume\":\" \",\"pages\":\"e011548\"},\"PeriodicalIF\":7.8000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11244753/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Heart Failure\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCHEARTFAILURE.123.011548\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Heart Failure","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCHEARTFAILURE.123.011548","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy.
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.
期刊介绍：
Circulation: Heart Failure focuses on content related to heart failure, mechanical circulatory support, and heart transplant science and medicine. It considers studies conducted in humans or analyses of human data, as well as preclinical studies with direct clinical correlation or relevance. While primarily a clinical journal, it may publish novel basic and preclinical studies that significantly advance the field of heart failure.
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