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

Abstract

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 FEV1) 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 FEV1 (<70, ≥70 to ≤90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV1 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 FEV1 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 FEV1 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 FEV1 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 FEV1, 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.

Funding: Vertex Pharmaceuticals Incorporated.

Conflict of interest statement

Declaration of interests

This study was sponsored by Vertex Pharmaceuticals Incorporated. This research publication was also supported by the National Center for Research Resources of the National Institutes of Health (NIH) grant 1UL1 RR025744 to Stanford University; Northwestern University Clinical and Translational Research Institute NIH grant number UL1TR000150; the South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, through NIH grant number UL1TR000062; University of Alabama Center for Clinical and Translational Science grant number UL1 TR000165; The University of Pennsylvania/Children’s Hospital of Philadelphia CTSA grant numbers UL1RR024134 (NCRR) and UL1TR000003 (NCATS); and by the NICRN (Respiratory Health) in Belfast Health and Social Care Trust. Medical writing and editorial support were funded by Vertex Pharmaceuticals Incorporated. No author received an honorarium or other form of financial support related to the development of this manuscript.

RBM has served as an investigator on Vertex Pharmaceuticals Incorporated, PTC, and N30 clinical studies; has participated in advisory boards or as a consultant for Celtaxys, GSK, Gilead, Novartis, ProQR, Asubio, Proteostasis Therapeutics, and Vertex Pharmaceuticals Incorporated; has received research funding from Genentech, CFF Therapeutics, Inc. PAF has served as an investigator on Vertex Pharmaceuticals Incorporated clinical studies; has participated in advisory boards or as a consultant for Aptalis, Enanta, Gilead, Insmed, Vertex Pharmaceuticals Incorporated, Novartis, Pharmaxis Limited; has received grant support from Aptalis, Gilead, Bayer Healthcare AG, Insmed, Novartis, Vertex Pharmaceuticals Incorporated, Pharmaxis Limited, Boehringer Ingelheim, Savara Pharmaceuticals, KaloBios, CFF. JSE has served as an investigator in Vertex Pharmaceuticals Incorporated clinical studies; has participated in advisory boards or as a consultant for Vertex Pharmaceuticals Incorporated, Novartis, Bayer, Actavis, and Boehringer Ingelheim and has received grant support from Gilead and Novartis. JC is an employee of Vertex Pharmaceuticals (Europe) Limited and may own stock or options in Vertex Pharmaceuticals Incorporated. SMR has served as an investigator on Vertex Pharmaceuticals Incorporated, Novartis, PTC Therapeutics, and Bayer clinical studies; has received grant funding from the National Institutes of Health, Forest Research Institute, CFF, CFF Therapeutics Inc, Bayer Healthcare, Novartis Research Institute, Galapagos and the American Lung Association. SAM has served as an investigator on Vertex Pharmaceuticals Incorporated, PTC Therapeutics, Novartis, SavaraInc, AbbVie Inc., Aptalis Pharma US, Inc. and Janssen Research & Development, LLC studies; served as a consultant for Vertex Pharmaceuticals Incorporated; and has received grant funding from CFF, CFF Therapeutics Inc., and the National Institutes of Health. RCR has served as an investigator on Vertex Pharmaceuticals Incorporated, KaloBios, and N30 clinical studies. MH is an employee of Vertex Pharmaceuticals (Europe) Limited and may own stock or options in Vertex Pharmaceuticals Incorporated.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Subject disposition.

Figure 2. Absolute change from baseline over 24 weeks in KONDUCT and over 12 weeks in KONTINUE in (A) percent predicted FEV1 and (B) CFR-R respiratory domain score (overall population)

aAtweek 0 of KONTINUE, data presented are mean change (±SE) from KONDUCT baseline at KONDUCT follow-up visit. Line graphs plot summary statistics (mean change ±SE) from KONDUCT baseline at each time point for KONDUCT and KONTINUE CFQ-R, Cystic Fibrosis Questionnaire-Revised; ppFEV1, percent predicted forced expiratory volume in 1 second; SE, standard error.

Figure 3. Absolute change from baseline through week 24 by MMRM (FAS) in (A) sweat chloride and (B) percent predicted FEV1 in KONDUCT by subject baseline parameters

MMRM, mixed-effects model for repeated measures; ppFEV1, percent predicted forced expiratory volume in 1 second.

Figure 4. Absolute change from baseline over 24 weeks in KONDUCT and over 12 weeks in KONTINUE in (A) percent predicted FEV1 and (B) CFQ-R respiratory domain score (adult subjects)

aAtweek 0 of KONTINUE, data presented are mean change (± standard error [SE]) from KONDUCT baseline at KONDUCT follow-up visit. Line graphs plot summary statistics (mean change ±SE) from KONDUCT baseline at each time point for KONDUCT and KONTINUE. CFQ-R, Cystic Fibrosis Questionnaire-Revised; ppFEV1, percent predicted forced expiratory volume in 1 second; SE, standard error.

Figure 5. Absolute change from baseline over 24 weeks in KONDUCT and over 12 weeks in KONTINUE in percent predicted FEV1 (children aged 6–11 years)

aAtweek 0 of KONTINUE, data presented are mean change (±SE) from KONDUCT baseline at KONDUCT follow-up visit. Line graphs plot summary statistics (mean change ±SE) from KONDUCT baseline at each time point for KONDUCT and KONTINUE. ppFEV1, percent predicted forced expiratory volume in 1 second; SE, standard error.