دورية أكاديمية
IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.
| العنوان: | IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. |
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| المؤلفون: | Ridker PM; Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: pridker@bwh.harvard.edu., Devalaraja M; Corvidia Therapeutics, Waltham, MA, USA., Baeres FMM; Novo Nordisk, Bagsvaerd, Denmark., Engelmann MDM; Novo Nordisk, Bagsvaerd, Denmark., Hovingh GK; Novo Nordisk, Bagsvaerd, Denmark., Ivkovic M; Novo Nordisk, Bagsvaerd, Denmark., Lo L; Corvidia Therapeutics, Waltham, MA, USA., Kling D; Corvidia Therapeutics, Waltham, MA, USA., Pergola P; Renal Associates, San Antonio, TX, USA., Raj D; Division of Kidney Diseases and Hypertension, George Washington University, Washington, DC, USA., Libby P; the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Davidson M; Corvidia Therapeutics, Waltham, MA, USA. |
| مؤلفون مشاركون: | RESCUE Investigators |
| المصدر: | Lancet (London, England) [Lancet] 2021 May 29; Vol. 397 (10289), pp. 2060-2069. Date of Electronic Publication: 2021 May 17. |
| نوع المنشور: | Clinical Trial, Phase II; Journal Article; Multicenter Study; Randomized Controlled Trial |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: England NLM ID: 2985213R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-547X (Electronic) Linking ISSN: 01406736 NLM ISO Abbreviation: Lancet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2004- : London : Elsevier Original Publication: London : J. Onwhyn |
| مواضيع طبية MeSH: | Antibodies, Monoclonal, Humanized/*administration & dosage , C-Reactive Protein/*drug effects , Interleukin-6/*antagonists & inhibitors , Renal Insufficiency, Chronic/*drug therapy, Aged ; Atherosclerosis ; Biomarkers/blood ; Double-Blind Method ; Female ; Humans ; Inflammation/complications ; Inflammation/drug therapy ; Injections, Subcutaneous ; Male ; Middle Aged ; Renal Insufficiency, Chronic/complications ; Thrombosis/complications ; Treatment Outcome |
| مستخلص: | Background: IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. Methods: RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. Findings: Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were -66·2% for the 7·5 mg group, -77·7% for the 15 mg group, and -87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. Interpretation: Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. Funding: Novo Nordisk. Competing Interests: Declaration of interests During the course of this trial, PMR received research grant support from Novartis, Kowa, Amarin, Pfizer, and the National Heart, Lung, and Blood Institute; served as a consultant to Corvidia, Novartis, Novo Nordisk, Flame, Agepha, Inflazome, AstraZeneca, Jannsen, Civi Biopharm, SOCAR, and Omeicos; and has a financial interest in Uptton, a company developing unrelated anti-inflammatory therapy. MDe, LL, DK, and MDa were employees of and held equity in Corvidia Therapeutics. FMMB, MDME, GKH, and MI are employees of and hold equity in Novo Nordisk. PP has served as a consultant to Corvidia and was a trial investigator whose employer received trial funds. DR is supported by National Institutes of Health grants 1 R01 DK125256-01, U01DK099914, and U01DK099924. PL is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion, Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Merck, Novartis, Pfizer, and Sanofi-Regeneron; is a member of scientific advisory boards for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, a company developing therapeutic human antibodies; has received laboratory research funding in the past 2 years from Novartis; is on the Board of Directors of XBiotech; has a financial interest in Xbiotech, a company developing therapeutic human antibodies; and receives research funding support from the National Heart, Lung, and Blood Institute (1R01HL134892), the American Heart Association (18CSA34080399), the RRM Charitable Fund, and the Simard Fund. (Copyright © 2021 Elsevier Ltd. All rights reserved.) |
| التعليقات: | Comment in: Lancet. 2021 May 29;397(10289):2025-2027. (PMID: 34015339) Comment in: Nat Rev Cardiol. 2021 Aug;18(8):544. (PMID: 34040184) Comment in: Kidney Int. 2021 Dec;100(6):1152-1154. (PMID: 34302849) |
| سلسلة جزيئية: | ClinicalTrials.gov NCT03926117 |
| المشرفين على المادة: | 0 (Antibodies, Monoclonal, Humanized) 0 (Biomarkers) 0 (Interleukin-6) 0 (ziltivekimab) 9007-41-4 (C-Reactive Protein) |
| تواريخ الأحداث: | Date Created: 20210520 Date Completed: 20220110 Latest Revision: 20220113 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/S0140-6736(21)00520-1 |
| PMID: | 34015342 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1474-547X |
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| DOI: | 10.1016/S0140-6736(21)00520-1 |