A Study to Evaluate Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation

Study Overview
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Brief Summary
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To evaluate the efficacy of ivacaftor treatment, as measured by lung clearance index (LCI), in subjects with cystic fibrosis (CF) who have a specified CF transmembrane conductance regulator (CFTR) gating mutation

Official Title
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A Phase 3b, 2-part, Randomized, Double-blind, Placebo-controlled Crossover Study With a Long-term Open-label Period to Investigate Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating 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: Male or female with confirmed diagnosis of CF. Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. Hematology, serum chemistry, and coagulation at Screening with no clinically significant abnormalities or concomitant diagnosis that would interfere with the LCI and CT scan study assessments, as judged by the investigator. Exclusion Criteria: An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (in the opinion of the investigator) Abnormal liver function, at Screening, defined as ≥3 × upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), and total bilirubin History of solid organ or hematological transplantation Any clinically significant non-CF-related illness within 2 weeks before Day 1 Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1 Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer or as determined by the local requirements) before Screening

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 5 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1-Sequence 1<br>ivacaftor in Treatment Period 1 →washout→placebo in Treatment Period 2 | Drug: ivacaftor<br> <br> * Other names: VX-770;Drug: Placebo<br> <br> |
| Experimental: Part 1 - Sequence 2<br>placebo in Treatment Period 1→washout→ivacaftor in Treatment Period 2 | Drug: ivacaftor<br> <br> * Other names: VX-770;Drug: Placebo<br> <br> |
| Experimental: Part 2: ivacaftor<br>open label period | Drug: ivacaftor<br> <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 Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5) | LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. | Baseline Through Week 8 for each treatment period, Up to 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8 | Serum samples were collected for evaluation of change in immunoreactive trypsinogen levels at Week 8. | Baseline and Week 8 of each treatment period, Up to 24 Weeks | 
| Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8 | Fecal elastase-1 was used clinically to diagnose pancreatic exocrine insufficiency in participants with cystic fibrosis. | Baseline and Week 8 of each treatment period, Up to 24 Weeks | 
| Absolute Change From Baseline in Weight at Week 8 |  | Baseline and Week 8 of each treatment period, Up to 24 Weeks | 
| Absolute Change From Baseline in Body Mass Index (BMI) at Week 8 | BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2). | Baseline and Week 8 of each treatment period, Up to 24 Weeks | 
| Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Baseline up to Month 15 |