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.
- Davies, J. C.
- Sermet-Gaudelus, I.
- Naehrlich, L.
- Harris, R. S.
- Campbell, D.
- Ahluwalia, N.
- Short, C.
- Haseltine, E.
- Panorchan, P.
- Saunders, C.
- Owen, C. A.
- Wainwright, C. E.
- V. X. Investigator Group
Keywords
- Clinical trial
- Cystic fibrosis
- F508del-CFTR mutation
- Ivacaftor
- Lung clearance index
- Residual function CFTR mutation
- Tezacaftor
- (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.
