Jane C Davies1, Isabelle Sermet-Gaudelus2, Lutz Naehrlich3, R Scott Harris4, Daniel Campbell4, Neil Ahluwalia4, Christopher Short5, Eric Haseltine4, Paul Panorchan4, Clare Saunders5, Caroline A Owen4, Claire E Wainwright6. 1. National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom. Electronic address: j.c.davies@imperial.ac.uk. 2. INSERM U1151, Institut Necker Enfants Malades, Université Paris Sorbonne, Paris, France, Hôpital Necker-Enfants malades, Paris, France. 3. Department of Pediatrics, Justus Liebig University Giessen, Giessen, Germany; Universities of Giessen and Marburg Lung Center, The German Center for Lung Research, Giessen, Germany. 4. Vertex Pharmaceuticals Incorporated, Boston, MA, United States. 5. National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom. 6. The University of Queensland, Brisbane, QLD, Australia.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Edith T Zemanick; Jennifer L Taylor-Cousar; Jane Davies; Ronald L Gibson; Marcus A Mall; Edward F McKone; Paul McNally; Bonnie W Ramsey; Jonathan H Rayment; Steven M Rowe; Elizabeth Tullis; Neil Ahluwalia; Chenghao Chu; Thang Ho; Samuel M Moskowitz; Sabrina Noel; Simon Tian; David Waltz; Tanya G Weinstock; Fengjuan Xuan; Claire E Wainwright; Susanna A McColley Journal: Am J Respir Crit Care Med Date: 2021-06-15 Impact factor: 21.405
Authors: Christopher H Goss; Isabelle Fajac; Raksha Jain; Wolfgang Seibold; Abhya Gupta; Ming-Chi Hsu; Sivagurunathan Sutharsan; Jane C Davies; Marcus A Mall Journal: Eur Respir J Date: 2022-02-17 Impact factor: 16.671
Authors: Alex R Horsley; John Belcher; Katie Bayfield; Brooke Bianco; Steve Cunningham; Catherine Fullwood; Andrew Jones; Anna Shawcross; Jaclyn A Smith; Anirban Maitra; Francis J Gilchrist Journal: Thorax Date: 2021-07-22 Impact factor: 9.139