Study of VX-809 in Cystic Fibrosis Subjects With the ∆F508-CFTR Gene Mutation

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study was to evaluate the safety and tolerability of VX-809 in participants with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.

Detailed Description
-----------------
This was a Phase 2, randomized, double-blind, placebo-controlled, multiple-dose study of orally-administered VX-809 in participants with CF who are homozygous for the specific CFTR mutation known as ∆F508 or F508del. Enrollment was planned for 90 participants at approximately 20 centers. Participants were planned to be randomized in a 4:1 ratio to receive 1 of 4 doses of VX-809 or placebo once a day for 28 days in a parallel design. Participants were outpatients during the study, except for overnight stays on Day 1 and 28.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study of VX-809 to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of VX-809 in Cystic Fibrosis Subjects Homozygous for the ∆F508-CFTR Gene Mutation

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

Intervention / Treatment
-----------------
* Drug: VX-809
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of CF with ∆F508-CFTR mutation in both alleles Forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) of predicted normal for age, gender, and height Weight >=40 kilograms (kg) and body mass index greater than or equal to 18.5 kilogram per square meter (kg/m^2) Screening laboratory values, tests, and physical examination within acceptable ranges Negative pregnancy test (for women of child-bearing potential) Able and willing to follow contraceptive requirements Willing to remain on a stable medication regimen for the duration of study participation Exclusion Criteria: History of any illness, or any ongoing acute illness, that could impact the safety of the study participant or may confound results of study Pulmonary exacerbation or changes in therapy for pulmonary disease within 14 days before receiving the first dose of study drug Impaired hepatic or renal function History of organ or hematological transplant

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo matched to VX-809 capsule orally once daily for 28 days. | Drug: Placebo<br>* Placebo matched to VX-809 capsules.<br>|
| Experimental: VX-809, 25 mg<br>VX-809, 25 milligram (mg) capsule orally once daily for 28 days. | Drug: VX-809<br>* Capsules<br>|
| Experimental: VX-809, 50 mg<br>VX-809, 50 mg capsule orally once daily for 28 days. | Drug: VX-809<br>* Capsules<br>|
| Experimental: VX-809, 100 mg<br>VX-809, 100 mg capsule orally once daily for 28 days. | Drug: VX-809<br>* Capsules<br>|
| Experimental: VX-809, 200 mg<br>VX-809, 200 mg capsule orally once daily for 28 days. | Drug: VX-809<br>* Capsules<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability Based on Adverse Events (AEs) | AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Non-serious AEs. Serious adverse event (SAE) (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Number of participants with AEs and SAEs are reported. An AE that started at or after initial dosing of study drug, or increased in severity after initial dosing of study drug visit is considered treatment-emergent. | Up to 14 days after last dose (last dose = Day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Day 28 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Day 28 | 
| Change From Baseline in Percent Predicted FEV1 at Day 28 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. | Baseline, Day 28 | 
| Change From Baseline in Forced Vital Capacity (FVC) at Day 28 | FVC is the volume of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. | Baseline, Day 28 | 
| Change From Baseline in Forced Expiratory Flow Over the Middle Half of the FVC (FEF25-75) at Day 28 | FEF25-75 is total volume of air exhaled from the lungs over the middle half of the FVC test, expressed as liters per second (L/sec). | Baseline, Day 28 | 
| Change From Baseline in Sweat Chloride at Day 28 | Sweat samples were collected using an approved Macroduct (Wescor) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. | Baseline, Day 28 | 
| Change From Baseline in Nasal Potential Difference (NPD) of Zero Chloride Plus Isoproterenol Response at Day 28 | Nasal potential difference (NPD) provides a direct and sensitive evaluation of sodium and chloride transport in secretory epithelial cells via assessment of transepithelial bioelectric properties. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol is reported. NPDs were performed according to Cystic Fibrosis Foundation Therapeutics Development Network (CFFT TDN) Standard Operating Procedure (SOP) 528.00 Standardization of Measurement of Nasal Membrane Transepithelial Potential Difference (NPD) - electronic data capture (EDC) and Perfusion or Perfusion-Free Probe. | Baseline, Day 28 | 
| Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Domain Scores at Day 28 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. CFQ-R domains include: Body, Digestion, Eat, Emotion, Health Perceptions, Physical, Respiratory, Role, Social, Treatment Burden, Vitality, and Weight. Individual domain score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | Baseline, Day 28 | 
| Maximum Plasma Concentration (Cmax) of VX-809 | Only participants who received VX-809 were analyzed for this outcome measure. | Day 1 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, and 24 hours post-dose), Day 28 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, 24, and 30-60 hours post dose) | 
| Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of VX-809 | Only participants who received VX-809 were analyzed for this outcome measure. | Day 1 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, and 24 hours post-dose), Day 28 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, and 24 hours post dose) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
∆F508, F508del, Cystic Fibrosis Transmembrane Conductance Regulator, CFTR, Pancreatic diseases, Lung diseases, Genetic disease, inborn, Infant, newborn, diseases