Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial

Background Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. We assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation. Methods We did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV,) of at least 40. We randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11,12-17, and.18 years) and % predicted FEV, (<70, to -90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV, through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis. Findings After 24 weeks, the treatment difference in mean absolute change in % predicted FEV, between ivacaftor (n=34) and placebo (n=35) was 2.1 percentage points (95% CI 1.13 to 5.35; p=0.20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24.0 mmol/L, 95% CI 28.01 to 19.93; p<0.0001) and CFQ-R respiratory domain (8.4, 2.17 to 14.61; p=0.009). In prespecified subgroup analyses, % predicted FEV, significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5.0 percentage points, 95% CI 1.15 to 8.78; p=0.01), but not in patients aged 6-11 years (-6.3 percentage points, 11.96 to 0.71; p=0.03). In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV, improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5.0 percentage points [p=0.0005]; ivacaftor-to-ivacaftor, 6.0 percentage points [p=0.006]). We did not identify any new safety concerns. The studies are registered with ClinicalTrials.gov (the randomised, placebo-controlled study, number NCT01614457; the open-label extension study, number NCT01707290). Interpretation Although this study did not show a significant improvement in % predicted FEV ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease.