1. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation
- Author
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Harry G M Heijerman, Edward F McKone, Damian G Downey, Eva Van Braeckel, Steven M Rowe, Elizabeth Tullis, Marcus A Mall, John J Welter, Bonnie W Ramsey, Charlotte M McKee, Gautham Marigowda, Samuel M Moskowitz, David Waltz, Patrick R Sosnay, Christopher Simard, Neil Ahluwalia, Fengjuan Xuan, Yaohua Zhang, Jennifer L Taylor-Cousar, Karen S McCoy, Karen McCoy, Scott Donaldson, Seth Walker, James Chmiel, Ronald Rubenstein, Deborah K. Froh, Isabel Neuringer, Manu Jain, Kathryn Moffett, Jennifer L. Taylor-Cousar, Bruce Barnett, Gary Mueller, Patrick Flume, Floyd Livingston, Nighat Mehdi, Charlotte Teneback, John Welter, Raksha Jain, Dana Kissner, Kapilkumar Patel, Francisco J. Calimano, Jimmy Johannes, Cori Daines, Thomas Keens, Herschel Scher, Subramanyam Chittivelu, Sudhakar Reddivalam, Ross Carl Klingsberg, Larry G. Johnson, Stijn Verhulst, Patricia Macedo, Damien Downey, Gary Connett, Edward Nash, Nicholas Withers, Timothy Lee, Marleen Bakker, Harry Heijerman, Francois Vermeulen, Christiane Knoop, Elke De Wachter, Renske van der Meer, Petrus Merkus, Christof Majoor, Pulmonology, AII - Inflammatory diseases, Clinical sciences, Physiotherapy, Human Physiology and Anatomy, and Pediatrics
- Subjects
Male ,Indoles ,Pyrrolidines ,Cystic Fibrosis ,Pyridines ,Clinical Trial, Phase III ,Phases of clinical research ,Cystic Fibrosis Transmembrane Conductance Regulator ,030204 cardiovascular system & hematology ,Quinolones ,Aminophenols ,Cystic fibrosis ,law.invention ,Ivacaftor ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,law ,030212 general & internal medicine ,Pyridines/administration & dosage ,Non-U.S. Gov't ,Chloride Channel Agonists ,Sweat ,Child ,Chloride Channel Agonists/administration & dosage ,Medicine(all) ,biology ,Research Support, Non-U.S. Gov't ,Lumacaftor ,General Medicine ,Indoles/administration & dosage ,Clinical Trial ,Cystic fibrosis transmembrane conductance regulator ,Pyrrolidines/administration & dosage ,Quinolones/administration & dosage ,Randomized Controlled Trial ,Combination ,Drug Therapy, Combination ,Female ,medicine.drug ,medicine.medical_specialty ,Adolescent ,Research Support ,Article ,Benzodioxoles/administration & dosage ,Sweat/chemistry ,N.I.H ,03 medical and health sciences ,Phase III ,Research Support, N.I.H., Extramural ,Double-Blind Method ,Drug Therapy ,Internal medicine ,Journal Article ,medicine ,Aminophenols/administration & dosage ,Humans ,Benzodioxoles ,business.industry ,Extramural ,medicine.disease ,Pyrazoles/administration & dosage ,Clinical trial ,Regimen ,chemistry ,biology.protein ,Pyrazoles ,Cystic Fibrosis Transmembrane Conductance Regulator/genetics ,sense organs ,Cystic Fibrosis/drug therapy ,business - Abstract
BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], pINTERPRETATION: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.FUNDING: Vertex Pharmaceuticals.
- Published
- 2019
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