A Phase 3 Study of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

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 heterozygous for F508del and a minimal function mutation (F/MF subjects).

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 Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

Conditions
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Cystic Fibrosis

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


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Heterozygous for the F508del mutation (F/MF) 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants who received placebo matched to VX-445/TEZ/IVA for 24 weeks in the TC treatment period. | Drug: Placebo<br>* Participants received placebo matched VX-445/TEZ/IVA orally once daily in the morning and placebo matched to IVA orally once daily in the evening.<br>|
| Experimental: VX-445/TEZ/IVA TC<br>Participants who received VX-445 200 mg/TEZ 100 mg/IVA150 mg as fixed-dose combination (FDC) tablets in the morning and IVA 150 mg as mono tablet in the evening for 24 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;|

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 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 through Week 24 | 
| Number of Pulmonary Exacerbations (PEx) | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. | From Baseline through Week 24 | 
| Absolute Change in Sweat Chloride (SwCl) | Sweat samples were collected using an approved collection device. | From Baseline through Week 24 | 
| 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 indicating fewer symptoms and better health-related quality of life. | From Baseline through Week 24 | 
| Absolute Change in Body Mass Index (BMI) | BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2). | From Baseline at Week 24 | 
| Absolute Change in Sweat Chloride | 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 indicating fewer symptoms and better health-related quality of life. | From Baseline at Week 4 | 
| Time-to-first Pulmonary Exacerbation (PEx) | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. | From Baseline through Week 24 | 
| Absolute Change in BMI Z-score for Participants <=20 Years of Age at Baseline | BMI was defined as weight in kg divided by height in m^2. Z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI. | From Baseline at Week 24 | 
| Absolute Change in Body Weight |  | From Baseline at Week 24 | 
| 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 28 weeks) | 
| Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA |  | Pre-dose on Week 4, 8, 12, and 16 |