A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation

• Published in: Journal of cystic fibrosis 2021-01, Vol.20 (1), p.68-77
• Main Authors: Davies, Jane C., Sermet-Gaudelus, Isabelle, Naehrlich, Lutz, Harris, R. Scott, Campbell, Daniel, Ahluwalia, Neil, Short, Christopher, Haseltine, Eric, Panorchan, Paul, Saunders, Clare, Owen, Caroline A., Wainwright, Claire E.
• Format: Article
• Language: English
• Subjects: Clinical trial; Cystic fibrosis; F508del-CFTR mutation; Ivacaftor; Lung clearance index; Residual function CFTR mutation; Tezacaftor
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2020.07.023

•In study participants 6 through 11 years of age with CF with F/F or F/RF genotypes:○TEZ/IVA significantly improved lung function as assessed by LCI2.5○TEZ/IVA improved sweat chloride concentrations○TEZ/IVA was safe and well tolerated; there were no new safety concerns○These findings support TEZ/IVA for F/F or F/RF pwCF 6 through 11 years of age The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F/RF respectively). We evaluated tezacaftor/ivacaftor's efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations. Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F, ivacaftor for F/RF). The primary endpoint was within-group change from baseline in the lung clearance index 2·5 (LCI2·5) through Week 8. Secondary endpoints were change from baseline in sweat chloride (SwCl), cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score, and safety. Sixty-seven participants received at least one study drug dose. Of those, 54 received tezacaftor/ivacaftor (F/F, 42; F/RF, 12), 10 placebo, and 3 ivacaftor; 66 completed the study. The within-group change in LCI2·5 was significantly reduced (improved) by −0·51 (95% CI: −0·74, −0·29). SwCl concentration decreased (improved) by −12·3 mmol/L and CFQ-R respiratory domain score increased (improved, nonsignificantly) by 2·3 points. There were no serious adverse events (AEs) or AEs leading to tezacaftor/ivacaftor discontinuation or interruption. The most common AEs (≥10%) in participants receiving tezacaftor/ivacaftor were cough, headache, and productive cough. Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F/RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.