Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Issue 7 (July 2015)

• Record Type: Journal Article
• Authors: Moss, Richard B; Flume, Patrick A; Elborn, J Stuart; Cooke, Jon; Rowe, Steven M; McColley, Susanna A; Rubenstein, Ronald C; Higgins, Mark; VX11-770-110 (KONDUCT) Study Group
• Is Part Of: Lancet. Volume 3:Issue 7(2015)
• Page Start: 524
• Page End: 533
• Publication Date: 2015-07
• Subjects: Respiratory organs -- Diseases -- Periodicals; 616.2005
• DOI: 10.1016/S2213-2600(15)00201-5
• Languages: English
• ISSNs: 2213-2600

Abstract

<abstract abstract-type="author" id="ceab10"> <title id="cestitle10">Summary</title> <sec> <title id="cestitle20">Background</title> <p id="spara170">Ivacaftor has been previously assessed in patients with cystic fibrosis with <italic>Gly551Asp-CFTR</italic> or other gating mutations. We assessed ivacaftor in patients with <italic>Arg117His-CFTR</italic>, a residual function mutation.</p> </sec> <sec> <title id="cestitle30">Methods</title> <p id="spara180">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 <italic>Arg117His-CFTR</italic> and percentage of predicted forced expiratory volume in 1 s (% predicted FEV<sub>1</sub>) 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<sub>1</sub> (<70, ≥70 to ≤90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV<sub>1</sub> 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.</p> </sec> <sec> <title id="cestitle40">Findings</title> <p id="spara190">After 24 weeks, the treatment difference in mean absolute change in % predicted FEV<sub>1</sub> 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<sub>1</sub> significantly improved with ivacaftor in patients aged 18 years or older (treatment difference <italic>vs</italic> 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<sub>1</sub> 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 <ext-link ext-link-type="unknown" id="interrefs10" xlink:type="simple" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link> (the randomised, placebo-controlled study, number <ext-link ext-link-type="unknown" id="interrefs20" xlink:type="simple" xlink:href="ctgov:NCT01614457" xmlns:xlink="http://www.w3.org/1999/xlink">NCT01614457</ext-link>; the open-label extension study, number <ext-link ext-link-type="unknown" id="interrefs30" xlink:type="simple" xlink:href="ctgov:NCT01707290" xmlns:xlink="http://www.w3.org/1999/xlink">NCT01707290</ext-link>).</p> </sec> <sec> <title id="cestitle50">Interpretation</title> <p id="spara200">Although this study did not show a significant improvement in % predicted FEV<sub>1</sub>, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with <italic>Arg117His-CFTR</italic>, indicating that ivacaftor might benefit patients with <italic>Arg117His-CFTR</italic> who have established disease.</p> </sec> <sec> <title id="cestitle60">Funding</title> <p id="spara210">Vertex Pharmaceuticals Incorporated.</p> </sec> </abstract>