Year: 2019
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
Abstract: BACKGROUNDCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation.In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimalfunction mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODSWe conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes.Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks.The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV 1 ) at week 4. RESULTSA total of 403 patients underwent randomization and received at least one dose of active treatment or placebo.Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV 1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001for all comparisons).Elexacaftortezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile.Most patients had adverse events that were mild or moderate.Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONSElexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective.(Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.govnumber, NCT03525444.
Source: New England Journal of Medicine
Authors: Peter G. Middleton, Marcus A. Mall, Pavel Dřevínek, Larry C. Lands, Edward F. McKone, Deepika Polineni, Bonnie W. Ramsey, Jennifer L. Taylor-Cousar, Elizabeth Tullis, François Vermeulen, Gautham Marigowda, Charlotte M. McKee, Samuel M. Moskowitz, Nitin Nair, Jessica Savage, Christopher Simard, Simon Tian, David Waltz, Fengjuan Xuan, Steven M. Rowe, Raksha Jain
Institutions: The University of Sydney, Westmead Hospital, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Westmead Institute for Medical Research, Charité - Universitätsmedizin Berlin, German Center for Lung Research, Charles University, University Hospital in Motol, McGill University Health Centre, University College Dublin, St. Vincent's University Hospital, University of Kansas Medical Center, University of Washington, Seattle Children's Research Institute, National Jewish Health, St. Michael's Hospital, University of Toronto, KU Leuven, Vertex Pharmaceuticals (United States), University of Alabama at Birmingham, UAB Medicine, The University of Texas Southwestern Medical Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Cystic Fibrosis Foundation Therapeutics, Seattle Children's Research Institute, Vertex Pharmaceuticals, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
OpenAlex ID: W2985405196