Research in context
Evidence before this study
We searched PubMed on Feb 6, 2017, with the terms “ivacaftor” or “VX-770” and “lumacaftor” or “VX-809”, with no restrictions on publication date or language. We identified four relevant clinical studies: one combined report of two phase 3 trials in patients aged 12 years or older with cystic fibrosis and homozygous for F508del-CFTR (TRAFFIC and TRANSPORT); a phase 3 extension study of TRAFFIC and TRANSPORT (PROGRESS); and an open-label, phase 3 study in patients aged 6–11 years with cystic fibrosis and homozygous for F508del-CFTR. Lumacaftor and ivacaftor are modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Combination therapy with lumacaftor and ivacaftor for 24 weeks in patients aged 12 years and older improved lung function and nutritional status, and decreased rates of pulmonary exacerbation, with an acceptable safety profile in the TRAFFIC and TRANSPORT trials. In the 96-week extension study (PROGRESS), the safety profile remained consistent, with benefits of lumacaftor and ivacaftor therapy being observed up to 120 weeks of treatment. Lumacaftor and ivacaftor treatment was also well tolerated over 24 weeks in younger patients with cystic fibrosis (aged 6–11 years) and homozygous for F508del-CFTR in an open-label, phase 3 study.
Added value of this study
In this phase 3, randomised, placebo-controlled trial (VX14-809-109), the efficacy of lumacaftor and ivacaftor combination therapy in patients aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was further assessed. Lung function in this paediatric population was measured by lung clearance index (LCI2·5), a sensitive measure of ventilation inhomogeneity, and spirometry (percent predicted forced expiratory volume in 1 s [ppFEV1]). Pharmacodynamic effect on CFTR function was established by assessment of sweat chloride concentration. LCI2·5 and sweat chloride concentration improved significantly (ie, decreased) in the lumacaftor and ivacaftor group versus the placebo group. A significant treatment difference favouring lumacaftor and ivacaftor over placebo was also observed for ppFEV1. The safety findings were consistent with those reported previously in young patients with cystic fibrosis homozygous for the F508del-CFTR mutation.
Implications of all the available evidence
Significant improvements in lung function with lumacaftor and ivacaftor treatment were seen when measured by absolute change from baseline in LCI2·5 relative to placebo treatment. Sweat chloride concentration also improved significantly (ie, decreased), thus providing a mechanistic CFTR biomarker of modulator efficacy. This phase 3 trial provides rigorous evidence for efficacy with lumacaftor and ivacaftor in the paediatric population at the early stages of disease and is among the first to use LCI2·5 as a primary endpoint.