A Study Evaluating the Safety and Efficacy of VX-659 Combination Therapy in Subjects With Cystic Fibrosis

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, randomized, double-blind, placebo- and tezacaftor/ivacaftor (TEZ/IVA)-controlled, parallel-group, 3-part, multicenter study designed to evaluate the safety and efficacy of VX-659 in triple combination (TC) with TEZ and IVA in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).

Official Title
-----------------
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-659 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis

Conditions
-----------------
Cystic Fibrosis

Intervention / Treatment
-----------------
* Drug: VX-659
* Drug: TEZ/IVA
* Drug: IVA
* Drug: Placebo (matched to VX-659/TEZ/IVA)
* Drug: TEZ
* Drug: VX-561
* Drug: Placebo (matched to VX-659/TEZ/VX-561)


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Body weight ≥35 kg. Subjects must have an eligibleCFTR genotype. Part 1 and Part 3: Heterozygous for F508del and an MF mutation (F/MF) Part 2: Homozygous for F508del (F/F) FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height Key Exclusion Criteria: History of clinically significant cirrhosis with or without portal hypertension. Glucose-6-phosphate dehydrogenase (G6PD) deficiency 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 1: Placebo<br>Participants received placebo matched to VX-659/TEZ/IVA in TC treatment period for 4 weeks and placebo matched TEZ/IVA in washout period for 4 days. | Drug: Placebo (matched to VX-659/TEZ/IVA)<br>* Placebo matched to VX-659 and TEZ/IVA.<br>|
| Experimental: Part 1: VX-659/TEZ/IVA TC - Low Dose<br>Participants received VX-659 80 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days. | Drug: VX-659<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Experimental: Part 1: VX-659/TEZ/IVA TC - Medium Dose<br>Participants received VX-659 240 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days. | Drug: VX-659<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Experimental: Part 1: VX-659/TEZ/IVA TC - High Dose<br>Participants received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days. | Drug: VX-659<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Active Comparator: Part 2: TEZ/IVA<br>Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks. | Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Experimental: Part 2: VX-659/TEZ/IVA TC<br>Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks. | Drug: VX-659<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Placebo Comparator: Part 3: Placebo<br>Participants received placebo matched to VX-659/TEZ/VX-561 in TC treatment period for 4 weeks. | Drug: Placebo (matched to VX-659/TEZ/VX-561)<br>* Placebo matched to VX-659, TEZ and VX-561.<br>|
| Experimental: Part 3: VX-659/TEZ/VX-561 TC<br>Participants received VX-659 400 mg qd/TEZ 100 mg qd/VX-561 200 mg qd in TC treatment period for 4 weeks. | Drug: VX-659<br>* Tablet for oral administration.<br>Drug: TEZ<br>* Tablet for oral administration.<br>* Other names: Tezacaftor;Drug: VX-561<br>* Tablet for oral administration.<br>* Other names: CTP-656;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Day 1 Through Safety Follow-up (up to Day 61 for Part 1, Day 85 for Part 2 and Day 57 for Part 3) | 
| 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 Concentrations | Sweat samples were collected using an approved collection device. | From Baseline Through Day 29 | 
| Relative Change in ppFEV1 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | 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 Concentration (Ctrough) of VX-659, TEZ, M1-TEZ, IVA, M1-IVA, and VX-561 |  | Pre-dose at Day 15 and Day 29 |