A Phase 3 Study to Evaluate the Efficacy and Safety of Ivacaftor and VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of VX-661 in combination with ivacaftor (IVA, VX-770) and IVA monotherapy in participants with Cystic Fibrosis (CF) who are heterozygous for F508del-CFTR allele and a second allele with a CFTR mutation predicted to have residual function.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy and Safety of Ivacaftor and 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 Allele With a CFTR Mutation Predicted to Have Residual Function

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: VX-661/Ivacaftor
* Drug: Ivacaftor
* Drug: Placebo matched to VX-661/ ivacaftor
* Drug: Placebo matched to Ivacaftor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to have residual function Forced Expiratory Volume in 1 Second (FEV1) greater than or equal to (≥) 40 percent (%) and less than or equal to (≤) 90% of predicted normal for age, sex, and height during screening Sweat chloride value ≥60 millimole per liter (mmol/L) during screening OR as documented in the participant's medical record 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 participant An acute upper or lower respiratory infection, pulmonary exacerbation History of solid organ or hematological transplantation Ongoing or prior participation in an investigational drug study (including studies investigating VX-661, lumacaftor [VX-809], and/or ivacaftor) within 30 days of screening Pregnant and nursing females Sexually active participants 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VX-661/Ivacaftor combination<br> | Drug: VX-661/Ivacaftor<br>* Fixed dose combination tablet, oral use<br>* Other names: VX-661+VX-770;Drug: Ivacaftor<br>* Tablet, oral use<br>* Other names: IVA, VX-770;Drug: Placebo matched to Ivacaftor<br>* Tablet, oral use<br>|
| Experimental: Ivacaftor monotherapy<br> | Drug: Ivacaftor<br>* Tablet, oral use<br>* Other names: IVA, VX-770;Drug: Placebo matched to VX-661/ ivacaftor<br>* Fixed dose combination tablet, oral use<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo matched to VX-661/ ivacaftor<br>* Fixed dose combination tablet, oral use<br>Drug: Placebo matched to Ivacaftor<br>* Tablet, oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Week 4 and Week 8 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8 | The CFQ-R assessed respiratory symptoms on a scale with scores ranging from 0 to 100; where higher scores indicated fewer symptoms and better health-related quality of life. | Baseline, Week 4 and Week 8 of each treatment period | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Day 1 up to Week 28 | 
| Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Week 4 and Week 8 of each treatment period | 
| Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8 |  | Baseline, Week 4 and Week 8 of each treatment period | 
| Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy |  | Pre-morning dose on Week 8 of each treatment period | 
| Ctrough of IVA and IVA Metabolite (M1 IVA) After Administration of IVA Monotherapy |  | Pre-morning dose on Week 8 of each treatment period |