Study of Ivacaftor in Cystic Fibrosis Subjects Aged 6 to 11 Years With the G551D Mutation

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective 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 adenosine monophosphate (AMP)-dependent protein kinase A (PKA) activation.

Detailed Description
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This is a Phase 3, 2-part, randomized, double-blind, placebo-controlled, parallel group multicenter study of orally administered ivacaftor in subjects with cystic fibrosis (CF) 6 to 11 years of age who have the G551D-CFTR mutation and a forced expiratory volume in 1 second (FEV1) between 90% and 105% predicted (using Knudson standards). Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, ivacaftor was selected for clinical development as a possible treatment for patients with CF. Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating effect of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation. This study was conducted in 2 parts. Part A was conducted to analyze the PK properties of ivacaftor and to determine the most appropriate dose to administer to subjects in Part B of this study. Part B explored the safety and efficacy of ivacaftor over long-term treatment in subjects 6 to 11 years of age.

Official Title
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A Phase 3, 2-Part, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Pharmacokinetics, Efficacy and Safety of VX-770 in Subjects Aged 6 to 11 Years With Cystic Fibrosis and the G551D Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Ivacaftor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Weighing at least 15 kg Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening Able to swallow tablets As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject Willing to use at least 1 highly effective birth control method during 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 Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study Abnormal liver function ≥ 3x the upper limit of normal Abnormal renal function at Screening History of solid organ or hematological transplantation Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening Use of inhaled hypertonic saline treatment Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4)

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 11 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects who received placebo every 12 hours (q12h) for up to 48 weeks. | Drug: Placebo<br>* Tablet given orally q12h for up to 48 weeks<br>|
| Experimental: 150 mg Ivacaftor q12h<br>Subjects who received 150 mg of ivacaftor q12h for up to 48 weeks. | Drug: Ivacaftor<br>* 150-mg tablet given orally q12h for up to 48 weeks<br>* Other names: VX-770;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. | baseline through 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 48 | Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. | baseline through 48 weeks | 
| Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children) | 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). | baseline through 24 weeks and 48 weeks | 
| Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | 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. | baseline through 24 weeks and 48 weeks | 
| Absolute Change From Baseline in Weight at Week 24 and Week 48 | As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status. | baseline to 24 weeks and 48 weeks | 

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