Chest
Original ResearchCystic FibrosisIvacaftor in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation
Section snippets
Study Design
This was a two-part, phase 2, multicenter, randomized (4:1), placebo-controlled, double-blind study of ivacaftor (Kalydeco, formerly known as VX-770; Vertex Pharmaceuticals Incorporated), 150 mg po administered every 12 h for 16 weeks (part A), followed by an open-label 96-week extension for subjects who met prespecified eligibility criteria (part B). The rationale for selecting subjects for the open-label extension was to determine whether the changes from baseline observed in part A of the
Subjects
The study was conducted between September 2009 and July 2010. Thirty-four study sites in the United States enrolled and randomized 140 subjects (ivacaftor, n = 112; placebo, n = 28). The groups were generally similar at baseline (Table 1).
A total of 104 subjects (92.9%) in the ivacaftor group and 26 (92.9%) in the placebo group completed dosing in part A (Fig 1). The most frequent reason for discontinuation was an adverse event (three subjects [2.7%] in the ivacaftor group and two subjects
Discussion
This randomized, double-blind, placebo-controlled, multicenter study evaluated the safety and efficacy of the CFTR potentiator, ivacaftor, in subjects with CF homozygous for the F508del-CFTR mutation. The safety profile of ivacaftor compared with placebo in this study supports further clinical evaluation in patients with CF. Treatment with ivacaftor was not associated with significant improvements in FEV1 or other clinical end points. There was a small reduction in sweat chloride concentration
Conclusions
This study augments the safety information for ivacaftor and supports the continued evaluation of ivacaftor in subjects with CF. The lack of an observed clinical effect suggests that CFTR potentiation with ivacaftor alone will not benefit patients with CF who are homozygous for the F508del-CFTR mutation. Although a proportion of subjects treated with ivacaftor showed a small change in the sweat chloride biomarker, this was not associated with clinical benefit. Additional studies are needed to
Acknowledgments
Author contributions: Dr Flume served as guarantor of the manuscript.
Dr Flume: contributed to the acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and approval of the final version.
Dr Liou: contributed to the acquisition of data and critical revision of the manuscript for important intellectual content and saw and approved the final version.
Dr Borowitz: contributed to the acquisition of
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Funding/Support: The DISCOVER study is sponsored by Vertex Pharmaceuticals Incorporated. This research was supported by the Cystic Fibrosis Foundation to the Women and Children's Hospital of Buffalo [Grant BOROWI03CS0] and to the Medical University of South Carolina [Grant C104-TDC10Y].
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.
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A complete list of study participants is located in e-Appendix 1.