A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects With Cystic Fibrosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and efficacy of VX-121 combination therapy in subjects with cystic fibrosis (CF).

Official Title
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A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: VX-121
* Drug: TEZ
* Drug: VX-561
* Drug: TEZ/IVA
* Drug: IVA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Part 1: Heterozygous for F508del and an MF mutation (F/MF) Part 2: Homozygous for F508del (F/F) FEV1 value ≥40% and ≤90% of the predicted mean for age, sex, and height Key Exclusion Criteria: History of clinically significant cirrhosis with or without portal hypertension Lung infection with organisms associated with a more rapid decline in pulmonary status History of solid organ or hematological transplantation Other protocol-defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 1: Placebo<br>Participants received placebo matched to VX-121/TEZ/VX-561 triple combination (TC) for 4 weeks in the treatment period and placebo matched to TEZ/VX-561 for 18 days in the washout period. | Drug: Placebo<br>* Placebos matched to VX-121, TEZ, and VX-561 for oral administration.<br>|
| Experimental: Part 1: VX-121/TEZ/VX-561 TC - Low Dose<br>Participants received VX-121 5 milligram (mg) once daily (qd)/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period | Drug: VX-121<br>* Tablets for oral administration.<br>Drug: TEZ<br>* TEZ tablet for oral administration.<br>* Other names: Tezacaftor;Drug: VX-561<br>* Tablets for oral administration.<br>* Other names: Deutivacaftor (D-IVA);|
| Experimental: Part 1: VX-121/TEZ/VX-561 TC - Medium Dose<br>Participants received VX-121 10 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period. | Drug: VX-121<br>* Tablets for oral administration.<br>Drug: TEZ<br>* TEZ tablet for oral administration.<br>* Other names: Tezacaftor;Drug: VX-561<br>* Tablets for oral administration.<br>* Other names: Deutivacaftor (D-IVA);|
| Experimental: Part 1: VX-121/TEZ/VX-561 TC - High Dose<br>Participants received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period. | Drug: VX-121<br>* Tablets for oral administration.<br>Drug: TEZ<br>* TEZ tablet for oral administration.<br>* Other names: Tezacaftor;Drug: VX-561<br>* Tablets for oral administration.<br>* Other names: Deutivacaftor (D-IVA);|
| Active Comparator: Part 2: TEZ/IVA<br>Following run-in period with TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) for 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the treatment period and TEZ 100 mg/IVA 150 mg q12h for 4 weeks in the washout period. | Drug: TEZ/IVA<br>* Fixed-dose combination tablets for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablets for oral administration.<br>* Other names: Ivacaftor;|
| Experimental: Part 2: VX-121/TEZ/VX-561 TC - High Dose<br>Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period. | Drug: VX-121<br>* Tablets for oral administration.<br>Drug: TEZ<br>* TEZ tablet for oral administration.<br>* Other names: Tezacaftor;Drug: VX-561<br>* Tablets for oral administration.<br>* Other names: Deutivacaftor (D-IVA);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From Day 1 Through Safety Follow-up (up to Day 75 for Part 1 and up to Day 85 for Part 2) | 
| 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 Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Sweat Chloride (SwCl) Concentrations | Sweat samples were collected using an approved collection device. | From Baseline Through Day 29 | 
| 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 Day 29 | 
| Observed Pre-dose Plasma Concentration (Ctrough) of VX-121, TEZ and Its Metabolite (M1-TEZ) and, VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) |  | Pre-dose at Day 15 and Day 29 |