The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.
This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. Enrollment of 39 subjects occurred at 15 centers in the US, Canada, and Germany. The study was conducted in 2 parts: * Part 1 consisted of Group A and Group B. Subjects in Group A (10 subjects) were randomized to receive 25 mg of ivacaftor every 12 hours \[q12h\] (4 subjects), 75 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. Subjects in Group B (10 subjects) were randomized to receive 75 mg of ivacaftor q12h (4 subjects), 150 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, the subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. * Part 2 consisted of Group C; these subjects did not participate in Part 1. Subjects were randomized to receive 150 mg of ivacaftor q12h (7 subjects), 250 mg of ivacaftor q12h (7 subjects), or placebo (4 subjects) for a total of 28 days. Ivacaftor doses studied in Part 2 were selected following an interim pharmacokinetic/pharmacodynamic (PK/PD) and statistical analyses of data from Part 1. The 2 doses selected for Part 2 were anticipated to enable better definition of the optimal therapeutic dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
25 mg or 75 mg q12h for a total of 28 days (Part 1)
75 mg or 150 mg q12h for a total of 28 days (Part 1)
150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2)
University of Alabama Hospital
Birmingham, Alabama, United States
Stanford University Medical Center
Palo Alto, California, United States
Number of Subjects With Adverse Events (Combined Part 1 and Part 2)
Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
Time frame: Baseline to Follow-up
Number of Adverse Events (Combined Part 1 and Part 2)
Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
Time frame: Baseline to Follow-up
Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)
The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest.
Time frame: 14 days and 28 days
Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)
Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Relative change reflects the percent change from the baseline values \[100% \* (X-Y)/Y\], where X and Y are post-baseline and baseline values, respectively.
Time frame: 14 days and 28 days
Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)
The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID).
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Masking
QUADRUPLE
Enrollment
39
Given q12h for 28 days each in Part 1 and Part 2 of the study
The Children's Hospital
Aurora, Colorado, United States
Roy J. and Lucille A. Carver College of Medicine, The University of Iowa
Iowa City, Iowa, United States
Johns Hopkins Hospital
Baltimore, Maryland, United States
Pulmonary and Critical Care Medicine, Massachusetts General Hospital
Boston, Massachusetts, United States
Children's Hospital of Boston
Boston, Massachusetts, United States
Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota
Minneapolis, Minnesota, United States
Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States
...and 5 more locations
Time frame: 14 days and 28 days
Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)
The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.
Time frame: 14 days and 28 days