A Phase 3 Study of Tezacaftor (VX-661) in Combination With Ivacaftor (VX-770) in Subjects Aged 12 Years and Older With Cystic Fibrosis (CF), Who Have One F508del-CFTR Mutation and a Second Mutation That Has Been Demonstrated to be Clinically Responsive to Ivacaftor

Study Overview
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Brief Summary
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This is a Phase 3, randomized, double-blind, ivacaftor-controlled, parallel-group, multicenter study of tezacaftor in combination with ivacaftor in subjects aged 12 years and older with CF who are heterozygous for the F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive.

Official Title
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A Phase 3, Randomized, Double-Blind, Ivacaftor-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation and a Second CFTR Allele With a Gating Defect That Is Clinically Demonstrated to be Ivacaftor Responsive

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Ivacaftor
* Drug: Tezacaftor/Ivacaftor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heterozygous for F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height during screening Stable CF disease as judged by the investigator. Exclusion Criteria: History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. Pregnant and nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Week -4 Visits). Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements

Ages Eligible for Study
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Minimum Age: 12 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 |
| --- | --- |
| Experimental: Ivacaftor (Run-in Period)<br>Ivacaftor 150 milligram (mg) tablet orally every 12 hours for 4 weeks. | Drug: Ivacaftor<br> <br> * Other names: VX-770;|
| Experimental: VX-661 + Ivacaftor (Active comparator period)<br>VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks. | Drug: Ivacaftor<br> <br> * Other names: VX-770;Drug: Tezacaftor/Ivacaftor<br> <br> * Other names: VX-661/VX-770;|
| Active Comparator: Ivacaftor monotherapy (Active comparator period)<br>Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks. | 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 Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Through Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Through Week 8 | 
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline Through Week 8 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | Baseline, Through Week 8 | 
| Absolute Change From Baseline in Sweat Chloride Through Week 8 | Sweat samples were collected using an approved collection device. | Baseline, Through Week 8 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Baseline up to Week 16 | 
| Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) |  | Predose on Week -2 for Run-in period; Pre-dose on Week 2 for Active comparator period |