A Study of VX-445 Combination Therapy in CF Subjects Homozygous for F508del (F/F)

Study Overview
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Brief Summary
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This study will evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation (F/F)

Official Title
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A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation (F/F)

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: VX-445/TEZ/IVA
* Drug: TEZ/IVA
* Drug: IVA
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Homozygous for the F508del mutation (F/F) Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for age, sex, and height Key Exclusion Criteria: Clinically significant cirrhosis with or without portal hypertension Lung infection with organisms associated with a more rapid decline in pulmonary status Solid organ or hematological transplantation Other protocol defined Inclusion/Exclusion criteria may apply

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 |
| --- | --- |
| Active Comparator: TEZ/IVA<br>Following a run-in period of 4 weeks with Tezacaftor (TEZ)/Ivacaftor (IVA), participants received TEZ 100 milligram (mg)/IVA 150 mg as fixed-dose combination (FDC) tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the triple combination (TC) treatment period. | Drug: TEZ/IVA<br>* Participants received TEZ/IVA orally once daily in the morning.<br>* Other names: tezacaftor/ivacaftor;Drug: IVA<br>* Participants received IVA orally once daily in the evening.<br>* Other names: ivacaftor;Drug: Placebo<br>* Participants received placebo matched to VX-445/TEZ/IVA orally once daily in the morning.<br>|
| Experimental: VX-445/TEZ/IVA TC<br>Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-445 200 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period. | Drug: VX-445/TEZ/IVA<br>* Participants received VX-445/TEZ/IVA orally once daily in the morning.<br>* Other names: VX-445/tezacaftor/ivacaftor;Drug: IVA<br>* Participants received IVA orally once daily in the evening.<br>* Other names: ivacaftor;Drug: Placebo<br>* Participants received placebo matched TEZ/IVA orally once daily in the morning.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Sweat Chloride (SwCl) | Sweat samples were collected using an approved collection device. | From Baseline at Week 4 | 
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 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 indicate fewer symptoms and better health-related quality of life. | From Baseline at Week 4 | 
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to Week 8) | 
| Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA |  | Day 1 and Week 4 |