A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor

Study Overview
=================
Brief Summary
-----------------
This is a Phase 3, randomized, double blind, placebo controlled, parallel group, multicenter study in people with cystic fibrosis (CF) who are homozygous for the F508del CF transmembrane conductance regulator (CFTR) gene mutation.

Detailed Description
-----------------
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in people with CF who are homozygous for the F508del-CFTR mutation. This study is designed to evaluate the efficacy and safety of VX-661 in combination with Ivacaftor (IVA, VX-770). The active treatment regimen comprised of a morning dose of a fixed-dose combination (FDC) tablet of 100 milligram (mg) VX-661/150 mg IVA once daily (qd) and an evening dose of IVA 150 mg to be taken approximately 12 hours after the morning dose. The placebo regimen was visually matched tablets to be taken with the same schedule as the active treatment.

Official Title
-----------------
A Phase 3, Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del CFTR Mutation

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

Intervention / Treatment
-----------------
* Drug: VX-661 Plus Ivacaftor Combination
* Drug: Ivacaftor
* Drug: VX-661 Plus Ivacaftor Combination Placebo
* Drug: Ivacaftor placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Homozygous for the F508del CFTR mutation, genotype to be confirmed at the Screening Visit Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis Forced expiratory volume at one second (FEV1) ≥40% and ≤90% of predicted normal for age, sex, and height during screening Stable CF disease as judged by the investigator Willing to remain on a stable CF medication regimen through Week 24 or, if applicable, the Safety Follow up Visit Exclusion Criteria: History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug) Pregnant or nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Day 1) Sexually active participants of reproductive potential who are not willing to follow the contraception requirements

Ages Eligible for Study
-----------------
Minimum Age: 12 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-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24. | Drug: VX-661 Plus Ivacaftor Combination Placebo<br>* FDC tablet, oral use<br>Drug: Ivacaftor placebo<br>* Tablet, oral use<br>|
| Experimental: VX-661/IVA<br>VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24. | Drug: VX-661 Plus Ivacaftor Combination<br>* FDC tablet, oral use<br>Drug: Ivacaftor<br>* Tablet, oral use<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline (Day 1) in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Day 1, Through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline (Day 1) in ppFEV1 Through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Day 1, Through Week 24 | 
| Number of Pulmonary Exacerbations Per Year | Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Pulmonary exacerbation events per year (48 weeks) were reported. | Day 1 through Week 24 | 
| Absolute Change From Baseline (Day 1) Body Mass Index (BMI) at Week 24 | BMI was defined as weight in kilograms (kg) divided by height in square meter (m^2). | Day 1, Week 24 | 
| Absolute Change From Baseline (Day 1) in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 | 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. | Day 1, Through Week 24 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. 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, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or newly developed at or after initial dosing of study drug to Week 28 was considered treatment-emergent. | Day 1 up to Week 28 | 
| Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24 | Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Time to event data was not collected and instead, Number of Subjects with first event were collected and are reported. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported. | Day 1 through Week 24 | 
| Absolute Change From Baseline (Day 1) in Sweat Chloride Through Week 24 | Sweat samples were collected using an approved collection device. | Day 1, Through Week 24 | 
| Absolute Change From Baseline (Day 1) in BMI Z-score at Week 24 in Participants Less Than (<) 20 Years Old at the Time of Screening) | 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 (BMI z-score). | Day 1, Week 24 | 
| Absolute Change From Baseline (Day 1) in Body Weight at Week 24 |  | Day 1, Week 24 | 
| Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | This outcome was not planned to be assessed in Placebo arm. | Pre-morning dose on Week 16 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Homozygous for the F508del CFTR Mutation