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.

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 (LCI _2·5 ) 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 LCI _2·5 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.
Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: CAO, DC, EH, NA, PP, and RSH are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated. CSa: LCI over reading fees with Vertex Pharmaceuticals Incorporated during the conduct of the study. CW: Income on a per-patient basis derived from pharmaceutical studies (Vertex Pharmaceuticals Incorporated and Boehringer-Ingelheim); research grant from Novo Nordisk Pharmaceuticals for the P/L-CF-IDEA study; Vertex Pharmaceuticals P/L honorarium to attend the CF International Advisory Board Meeting in February 2014; Vertex Pharmaceuticals P/L honorarium to attend CF Medical Advisory Board Meeting in Adelaide in April 2014; Novartis Pharmaceuticals P/L honorarium to present a symposium at the National Pediatric Congress in Lebanon in May 2014; Vertex Pharmaceuticals P/L return travel and honorarium for lecture & discussions at the European CF Conference in Gothenburg in June 2014; DKBmed, LLC honorarium to present symposium at the North American CF Conference Georgia in October 2014; Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting series in Brisbane and Sydney in April 2015; Vertex Pharmaceuticals P/L honorarium to attend the Vertex Steering Committee Meetings on the VX15-770-123 study in 2014; Vertex Pharmaceuticals P/L honorarium for Vertex Medical Advisory Board-Innovative endpoints in CF in August 2015; University of Miami honorarium for meeting attendance in 2015; Thorax honorarium for associate editor duties in Q3/Q4 2015; BMJ honorarium for work as a reviewer; Vertex Pharmaceuticals 2015 Chicago return flight and accommodation for work as investigator in lumacaftor study; Vertex Pharmaceuticals 2015-2017 honorarium for being a speaker at Vertex-sponsored educational meeting series in Australia; Vertex Pharmaceuticals 2016 Phoenix return flight and accommodation as investigator in the Next Gen study; Vertex Pharmaceuticals December 2016 honoraria for work as a speaker at a Vertex-sponsored educational meeting in Liverpool, UK; DKBmed eCF review issue honoraria in January 2017; Vertex Pharmaceuticals March 2017 honoraria for being a speaker at TSANZ meeting; Vertex Pharmaceuticals Incorporated 2014-2018 honorarium for acting as a consultant on the Vertex Orkambi 6-11 HTA Advisory Board, the Global Pediatric Advisory Committee, the Global Medical Advisory Board, and the VIA Grants Committee; Gilead Sciences Ltd. honorarium for meeting attendance on CF imaging; honorarium for In Vivo Academy Limited for webcast meeting attendance at ECFC 2018; Vertex Pharmaceuticals P/L honorarium to present as a speaker in an educational meeting at ECFC in Belgrade 2018; Vertex Pharmaceuticals Incorporated honorarium to attend the Next Gen Early Lifecycle Management Plan in London in 2018; Vertex Pharmaceuticals P/L to act as consultant and to render such services in the form of documents, advice, meetings, and conferences from October 2018 to present; Vertex Pharmaceuticals (Australia) P/L to attend as a steering committee member at the Medical Symposium Event (SHIFT 2019) in Perth in 2019; Vertex Pharmaceuticals P/L to attend the EU Real World Evidence steering committee in Amsterdam in 2019; Current board positions: International Advisory Board, Vertex Pharmaceuticals P/L; Associate Editor, Thorax; Associate Editor, Respirology. ISG: Support for scientific project and PI of different clinical trials with Vertex Pharmaceuticals Incorporated during the conduct of this study. JCD: advisory board and clinical trial lead with Algipharma AS, UK lead investigator and advisory board with Bayer AG, advisory board with Boehringer Ingelheim Pharma GmbH & Co. KG, advisory board and clinical trial leadership with Galapagos NV, advisory and trial design assistance with ImevaX GmbH, advisory board with Nivalis Therapeutics Inc, advisory board and trial design advice with ProQR Therapeutics III B.V., advisory and clinical trial leadership with Proteostasis Therapeutics Inc, advisory with Raptor Pharmaceuticals Inc, advisory board and National Co-ord/Global Co-I with Vertex Pharmaceuticals (Europe) Limited, advisory board with Enterprise, Novartis, Pulmocide, and Flatley, grant from CF Trust, and educational activities with Teva outside the submitted work. CSh and LN had nothing further to disclose.
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