Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Ivacaftor 25 mg/75 mg
* Drug: Ivacaftor 75 mg/150 mg
* Drug: Ivacaftor 150 mg or 250 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Weighing at least 40 kg Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height Willing to remain on stable medication regimen for the duration of study participation No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study History of alcohol, medication or illicit drug abuse within one year prior to Day 1 Abnormal liver function ≥ 3x the upper limit of normal History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) History of solid organ or hematological transplantation Pregnant or breast-feeding (for women) Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ivacaftor Group A<br>Subjects in Part 1 who first received 25 mg or 75 mg of ivacaftor every 12 hours (q12h) for 14 days, then crossed over to receive the alternate dose for another 14 days. | Drug: Ivacaftor 25 mg/75 mg<br>* 25 mg or 75 mg q12h for a total of 28 days (Part 1)<br>* Other names: VX-770;|
| Experimental: Ivacaftor Group B<br>Subjects in Part 1 who first received 75 mg or 150 mg of ivacaftor q12h for 14 days then crossed over to receive the alternate dose for another 14 days. | Drug: Ivacaftor 75 mg/150 mg<br>* 75 mg or 150 mg q12h for a total of 28 days (Part 1)<br>* Other names: VX-770;|
| Experimental: Ivacaftor Group C<br>Subjects in Part 2 who received 150 mg or 250 mg of ivacaftor q12h for 28 days. | Drug: Ivacaftor 150 mg or 250 mg<br>* 150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2)<br>* Other names: VX-770;|
| Placebo Comparator: Placebo<br>Subjects who received placebo in Part 1 and subjects who received placebo in Part 2. | Drug: Placebo<br>* Given q12h for 28 days each in Part 1 and Part 2 of the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline to Follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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). | 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. | 14 days and 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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G551D mutation, Fibrosis, Pancreatic Diseases, Digestive System Diseases, Lung Diseases, Respiratory Tract Diseases, Genetic Diseases, Inborn, Infant, Newborn, Diseases, Pathologic Processes