دورية أكاديمية
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Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study.

التفاصيل البيبلوغرافية
العنوان: Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study.
المؤلفون: Mall MA; Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin and.; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.; German Center for Lung Research, Associated Partner, Berlin, Germany., Brugha R; Great Ormond Street Hospital for Children, London, United Kingdom., Gartner S; Hospital Universitari Vall d'Hebron, Barcelona, Spain., Legg J; Southampton Children's Hospital, Hampshire, United Kingdom., Moeller A; University Children's Hospital, Zurich, Switzerland., Mondejar-Lopez P; Hospital Clinico Universitario Virgen de la Arrixaca, Murcia, Spain., Prais D; Schneider Children's Medical Center of Israel, Petah Tikva, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Pressler T; Copenhagen University Hospital, Rigshospitalet, Denmark., Ratjen F; The Hospital for Sick Children, Toronto, Ontario, Canada., Reix P; Hôpital Femme Mère-Enfant, Hospices Civils de Lyon, Bron, France., Robinson PD; The Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, Australia., Selvadurai H; The Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, Australia., Stehling F; Universitätsklinikum Essen, Klinik für Kinderheilkunde III, Essen, Germany., Ahluwalia N; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Arteaga-Solis E; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Bruinsma BG; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Jennings M; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Moskowitz SM; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Noel S; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Tian S; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Weinstock TG; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Wu P; Vertex Pharmaceuticals Incorporated, Boston, Massachussetts., Wainwright CE; Queensland Children's Hospital, University of Queensland, Queensland, Australia., Davies JC; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Royal Brompton and Harefield Hospitals, part of Guy's and St Thomas' NHS Trust, London, United Kingdom; and.; European Cystic Fibrosis Society Lung Clearance Index Core Facility, London, United Kingdom.
المصدر: American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2022 Dec 01; Vol. 206 (11), pp. 1361-1369.
نوع المنشور: Randomized Controlled Trial; Clinical Trial, Phase III; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Thoracic Society Country of Publication: United States NLM ID: 9421642 Publication Model: Print Cited Medium: Internet ISSN: 1535-4970 (Electronic) Linking ISSN: 1073449X NLM ISO Abbreviation: Am J Respir Crit Care Med Subsets: MEDLINE
أسماء مطبوعة: Publication: 2000- : New York, NY : American Thoracic Society
Original Publication: New York, NY : American Lung Association, c1994-
مواضيع طبية MeSH: Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/genetics , Cystic Fibrosis Transmembrane Conductance Regulator*/genetics , Cystic Fibrosis Transmembrane Conductance Regulator*/therapeutic use, Child ; Humans ; Aminophenols/adverse effects ; Benzodioxoles/adverse effects ; Chloride Channel Agonists/adverse effects ; Forced Expiratory Volume ; Mutation
مستخلص: Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation ( F /MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA ( n  = 60) or placebo ( n  = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index 2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index 2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P  < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV 1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F /MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.
التعليقات: Comment in: Am J Respir Crit Care Med. 2022 Dec 1;206(11):1308-1310. (PMID: 35947636)
References: Thorax. 2010 May;65(5):379-83. (PMID: 20435858)
Am J Respir Crit Care Med. 2017 Jun 15;195(12):1567-1575. (PMID: 27911585)
Am J Respir Crit Care Med. 2020 May 15;201(10):1193-1208. (PMID: 31860331)
Lancet Respir Med. 2017 Jul;5(7):557-567. (PMID: 28606620)
Am J Respir Crit Care Med. 2021 Jun 15;203(12):1522-1532. (PMID: 33734030)
Expert Rev Respir Med. 2021 Jun;15(6):723-735. (PMID: 33249928)
Pediatr Pulmonol. 2021 May;56(5):1271-1273. (PMID: 33434352)
Lancet. 2019 Nov 23;394(10212):1940-1948. (PMID: 31679946)
Lancet Respir Med. 2020 Jan;8(1):65-124. (PMID: 31570318)
Front Pharmacol. 2020 Feb 21;10:1662. (PMID: 32153386)
Eur Respir J. 2011 Apr;37(4):806-12. (PMID: 20693248)
Am J Respir Crit Care Med. 2017 Apr 1;195(7):912-920. (PMID: 27805836)
Respiration. 2009;78(3):339-55. (PMID: 19521061)
Am J Respir Crit Care Med. 2019 May 15;199(10):1238-1248. (PMID: 30409023)
Am J Respir Crit Care Med. 2017 Feb 1;195(3):349-359. (PMID: 27575911)
N Engl J Med. 2019 Nov 7;381(19):1809-1819. (PMID: 31697873)
Am J Respir Crit Care Med. 2021 Oct 15;204(8):943-953. (PMID: 34283704)
Science. 1989 Sep 8;245(4922):1066-73. (PMID: 2475911)
Lancet Respir Med. 2022 Mar;10(3):267-277. (PMID: 34942085)
J Cyst Fibros. 2021 Jan;20(1):68-77. (PMID: 32967799)
Lancet. 2016 Nov 19;388(10059):2519-2531. (PMID: 27140670)
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30. (PMID: 19846789)
Am J Respir Crit Care Med. 2005 Feb 15;171(4):371-8. (PMID: 15531750)
Pediatrics. 2001 Jan;107(1):1-13. (PMID: 11134427)
Pediatr Pulmonol. 2021 Jun;56(6):1496-1503. (PMID: 33470563)
Am J Respir Crit Care Med. 2022 Mar 1;205(5):540-549. (PMID: 34936849)
Science. 1991 Jul 12;253(5016):202-5. (PMID: 1712984)
Curr Probl Cardiol. 2019 May;44(5):148-172. (PMID: 30545650)
J Appl Physiol (1985). 2021 Sep 1;131(3):1148-1156. (PMID: 34351818)
Chest. 2009 Jun;135(6):1610-1618. (PMID: 19447923)
J Cyst Fibros. 2022 May;21(3):e204-e207. (PMID: 34526221)
Nat Rev Dis Primers. 2015 May 14;1:15010. (PMID: 27189798)
Eur Respir J. 2021 Jul 8;58(1):. (PMID: 33361098)
Ital J Pediatr. 2019 May 2;45(1):56. (PMID: 31046783)
Annu Rev Biochem. 2008;77:701-26. (PMID: 18304008)
Respir Res. 2017 May 17;18(1):96. (PMID: 28514950)
Thorax. 2008 Feb;63(2):129-34. (PMID: 17675316)
فهرسة مساهمة: Keywords: children; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor
المشرفين على المادة: 0 (Aminophenols)
0 (Benzodioxoles)
0 (Chloride Channel Agonists)
126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RRN67GMB0V (elexacaftor)
1Y740ILL1Z (ivacaftor)
0 (tezacaftor)
تواريخ الأحداث: Date Created: 20220711 Date Completed: 20221209 Latest Revision: 20221222
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9746869
DOI: 10.1164/rccm.202202-0392OC
PMID: 35816621
قاعدة البيانات: MEDLINE
الوصف
تدمد:1535-4970
DOI:10.1164/rccm.202202-0392OC