Phase 3 Multicenter Study of Revusiran in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Cardiomyopathy (ENDEAVOUR)
| العنوان: | Phase 3 Multicenter Study of Revusiran in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Cardiomyopathy (ENDEAVOUR) |
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| المؤلفون: | Daniel P. Judge, Arnt V. Kristen, Martha Grogan, Mathew S. Maurer, Rodney H. Falk, Mazen Hanna, Julian Gillmore, Pushkal Garg, Akshay K. Vaishnaw, Jamie Harrop, Christine Powell, Verena Karsten, Xiaoping Zhang, Marianne T. Sweetser, John Vest, Philip N. Hawkins |
| المصدر: | Cardiovascular Drugs and Therapy Cardiovasc Drugs Ther |
| بيانات النشر: | Springer US, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Male, Canada, Time Factors, Cardiomyopathy, 030204 cardiovascular system & hematology, Revusiran, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Cause of Death, Humans, Prealbumin, ATTR amyloidosis, Pharmacology (medical), Genetic Predisposition to Disease, RNA, Small Interfering, Aged, Pharmacology, Aged, 80 and over, Amyloid Neuropathies, Familial, Exercise Tolerance, Correction, General Medicine, Recovery of Function, Middle Aged, United States, Europe, Phenotype, RNAi Therapeutics, Treatment Outcome, Early Termination of Clinical Trials, Mutation, Disease Progression, Female, Original Article, Cardiology and Cardiovascular Medicine, Cardiomyopathies, 030217 neurology & neurosurgery |
| الوصف: | Purpose The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. Methods Patients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction. Results Revusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events. Conclusions Causes for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded. Clinical Trial Registration NCT02319005. |
| اللغة: | English |
| تدمد: | 1573-7241 0920-3206 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::45887ee13b195341e5d70adae8db7d93Test http://europepmc.org/articles/PMC7242280Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....45887ee13b195341e5d70adae8db7d93 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15737241 09203206 |
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