학술논문
Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial
Document Type
Academic Journal
Author
Heijerman, Harry G M; McKone, Edward F; Downey, Damian G; Van Braeckel, Eva; Rowe, Steven M; Tullis, Elizabeth; Mall, Marcus A; Welter, John J; Ramsey, Bonnie W; McKee, Charlotte M; Marigowda, Gautham; Moskowitz, Samuel M; Waltz, David; Sosnay, Patrick R; Simard, Christopher; Ahluwalia, Neil; Xuan, Fengjuan; Zhang, Yaohua; Taylor-Cousar, Jennifer L; McCoy, Karen S; McCoy, Karen; Donaldson, Scott; Walker, Seth; Chmiel, James; Rubenstein, Ronald; Froh, Deborah K.; Neuringer, Isabel; Jain, Manu; Moffett, Kathryn; Taylor-Cousar, Jennifer L.; Barnett, Bruce; Mueller, Gary; Flume, Patrick; Livingston, Floyd; Mehdi, Nighat; Teneback, Charlotte; Welter, John; Jain, Raksha; Kissner, Dana; Patel, Kapilkumar; Calimano, Francisco J.; Johannes, Jimmy; Daines, Cori; Keens, Thomas; Scher, Herschel; Chittivelu, Subramanyam; Reddivalam, Sudhakar; Klingsberg, Ross Carl; Johnson, Larry G.; Verhulst, Stijn; Macedo, Patricia; Downey, Damien; Connett, Gary; Nash, Edward; Withers, Nicholas; Lee, Timothy; Bakker, Marleen; Heijerman, Harry; Vermeulen, Francois; Knoop, Christiane; De Wachter, Elke; van der Meer, Renske; Merkus, Petrus; Majoor, Christof
Source
The Lancet. Nov 23, 2019, Vol. 394 Issue 10212, 1940
Subject
Language
English
ISSN
0140-6736
Abstract
Summary 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 (ppFEV.sub.1) 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 ppFEV.sub.1 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 ppFEV.sub.1 (least squares mean [LSM] treatment difference of 10*0 percentage points [95% CI 7*4 to 12*6], p Interpretation 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.