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Co-primary endpoints were 6-min walk test distance and serum TTR reduction.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Revusiran treatment was stopped after a median of 6.71\u00a0months; 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\u2009\u2265\u200975\u00a0years 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Clinical Trial Registration<\/jats:title>\n                <jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02319005\">NCT02319005<\/jats:ext-link>.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10557-019-06919-4","type":"journal-article","created":{"date-parts":[[2020,2,15]],"date-time":"2020-02-15T10:02:28Z","timestamp":1581760948000},"page":"357-370","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Phase 3 Multicenter Study of Revusiran in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Cardiomyopathy (ENDEAVOUR)"],"prefix":"10.1007","volume":"34","author":[{"given":"Daniel P.","family":"Judge","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnt V.","family":"Kristen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Grogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew S.","family":"Maurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney H.","family":"Falk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazen","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Gillmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pushkal","family":"Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay K.","family":"Vaishnaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Harrop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Karsten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne T.","family":"Sweetser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Vest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N.","family":"Hawkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,15]]},"reference":[{"key":"6919_CR1","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1007\/s11897-013-0182-4","volume":"11","author":"M Hanna","year":"2014","unstructured":"Hanna M. 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Corrections should also be noted for Tables 1 and 4: in the Table 1 legend <i>\ufffd\ufffd\ufffdLow risk \ufffd\ufffd\ufffd Neither above at baseline\ufffd\ufffd\ufffd<\/i> should read <i>\ufffd\ufffd\ufffdLow risk \ufffd\ufffd\ufffd Neither above threshold at baseline\ufffd\ufffd\ufffd<\/i>; in Table 4, the rows <i>\ufffd\ufffd\ufffdMild: eGFR > 60 to < 90 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>\ufffd\ufffd\ufffd and <i>\ufffd\ufffd\ufffdModerate: eGFR > 30 to < 60 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>\ufffd\ufffd\ufffd should read <i>\ufffd\ufffd\ufffdMild: eGFR \ufffd\ufffd\ufffd 60 to < 90 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>\ufffd\ufffd\ufffd and <i>\ufffd\ufffd\ufffdModerate: eGFR \ufffd\ufffd\ufffd 30 to < 60 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>\ufffd\ufffd\ufffd, respectively. The original article also contained a mistake in the text of the Pharmacokinetics sub-section of Results; <i>\ufffd\ufffd\ufffdThere were no apparent differences in revusiran C<\/i><sub><i>max<\/i><\/sub><i>between patients with mild (eGFR: 30 and < 60 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>) <i>or moderate (eGFR: 60 to < 90 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>) <i>renal impairment when compared with patients with normal (eGFR: \ufffd\ufffd\ufffd 90 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>) <i>renal function at Weeks 0, 26, and 52 (p > 0.20) (Supplementary Fig. 6)\ufffd\ufffd\ufffd<\/i> should read <i>\ufffd\ufffd\ufffdThere were no apparent differences in revusiran C<\/i><sub><i>max<\/i><\/sub><i>between patients with mild (eGFR: \ufffd\ufffd\ufffd 60 to < 90 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>) <i>or moderate (eGFR: \ufffd\ufffd\ufffd 30 and < 60 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>) <i>renal impairment when compared with patients with normal (eGFR: \ufffd\ufffd\ufffd 90 ml\/min\/1.73 m<\/i><sup><i>2<\/i><\/sup>) <i>renal function at Weeks 0, 26, and 52 (p > 0.20) (Supplementary Fig. 6)\ufffd\ufffd\ufffd<\/i>.","order":4,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"Daniel P. Judge received support for clinical trial participation, scientific consultation, and writing from Alnylam Pharmaceuticals, Inc. and support for scientific consultation from GlaxoSmithKline plc and Pfizer. Arnt V. Kristen received a research grant, support for scientific consultation, and symposia honoraria from Alnylam Pharmaceuticals, Inc. Martha Grogan received support for clinical trial participation from Alnylam Pharmaceuticals, Inc., Eidos Therapeutics, Inc., Pfizer, and Prothena Corporation plc. Matthew S. Maurer received support for clinical research from Alnylam Pharmaceuticals, Inc., Eidos Therapeutics, Inc., Pfizer, and Prothena Corporation plc; support for Data and Safety Monitoring Board participation from Prothena Corporation plc; and support for steering committee participation from Pfizer. Rodney H. Falk received support for consultancy and research from Akcea Therapeutics, Inc. Eidos Therapeutics, Inc., and Alnylam Pharmaceuticals, Inc. Mazen Hanna received support for advisory board participation from Alnylam Pharmaceuticals, Inc., Akcea Therapeutics, Inc, Eidos Therapeutics, Inc., and Pfizer. Julian Gillmore received support for clinical trial and advisory board participation from Alnylam Pharmaceuticals, Inc. Pushkal Garg, Akshay K. Vaishnaw, Jamie Harrop, Christine Powell, Verena Karsten, Marianne Sweetser, John Vest, and Xiaoping Zhang are employees of, and own stock in, Alnylam Pharmaceuticals, Inc.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure of Potential Conflicts of Interest"}},{"value":"This study was approved by central and local institutional review boards or ethics committees and performed in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. A DMC, comprising a cardiologist, hepatologist, and statistician, reviewed all pertinent benefit\u2013risk data and an independent clinical adjudication committee performed blinded adjudication of the causes of hospitalization and death.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research Involving Human Participants [Note this Information Is Also Contained in the Methods]"}},{"value":"All patients in this study gave their informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent [Note this Information Is Also Contained in the Methods]"}}]}}