Study to Evaluate Safety and Efficacy of VX-661 in Combination With Ivacaftor in Subjects With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation With an Open-Label Expansion

Study Overview
=================
Brief Summary
-----------------
The objective of this study was to evaluate the safety and efficacy of VX-661in combination with ivacaftor in participants with cystic fibrosis (CF) who are homozygous for F508del cystic fibrosis transmembrane conductance regulator (CFTR) mutation

Official Title
-----------------
A Phase 2, Randomized, Multicenter, Double Blind, Placebo Controlled Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-661 in Combination With Ivacaftor for 12 Weeks in Subjects With Cystic Fibrosis, Homozygous for the F508del CFTR Mutation With an Open-Label Extension

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

Intervention / Treatment
-----------------
* Drug: VX-661
* Drug: Ivacaftor
* Drug: Placebo matched to VX-661
* Drug: Placebo matched to Ivacaftor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Homozygous for the F508del CFTR mutation FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height Stable CF disease as judged by the investigator 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 Pregnant and nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1 of the PC Phase and Day -7 or Day 1 of the OLE Phase (whichever was applicable) Sexually active participants of reproductive potential who are not willing to follow the contraception requirements The participant or a close relative of the participant is the investigator or sub investigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study.

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 |
| --- | --- |
| Experimental: PC Phase: VX-661 50 mg q12h + IVA 150 mg q12h<br>Participants received VX-661 50 milligram (mg) tablet plus Ivacaftor (IVA) 150 mg tablet every 12 hours (q12h) for 12 weeks. | Drug: VX-661<br>* Tablet, oral use<br>Drug: Ivacaftor<br>* Film coated tablet, oral use<br>|
| Placebo Comparator: PC Phase: VX 661 placebo q12h + IVA placebo q12h<br>Participants received placebo matched to VX-661 tablet plus placebo matched to IVA tablet q12h for 12 weeks. | Drug: Placebo matched to VX-661<br>* Tablet, oral use<br>Drug: Placebo matched to Ivacaftor<br>* Film coated tablet, oral use<br>|
| Experimental: PC Phase: VX-661 100 mg qd + IVA 150 mg q12h<br>Participants received two VX-661 50 mg tablets once daily (qd) plus IVA 150 mg tablet q12h for 12 weeks. | Drug: VX-661<br>* Tablet, oral use<br>Drug: Ivacaftor<br>* Film coated tablet, oral use<br>|
| Placebo Comparator: PC Phase: VX -661 placebo qd + IVA placebo q12h<br>Participants received two placebo matched to VX-661 tablets qd plus placebo matched to IVA tablet q12h for 12 weeks. | Drug: Placebo matched to VX-661<br>* Tablet, oral use<br>Drug: Placebo matched to Ivacaftor<br>* Film coated tablet, oral use<br>|
| Experimental: OLE Phase: VX-661 100 mg qd + IVA 150 mg q12h<br>Participants who completed 12 week PC phase underwent a washout period of at least 4 weeks before entering the OLE phase and received two VX-661 50 mg tablets qd plus IVA 150 mg tablet q12h for 48 weeks in OLE phase. | Drug: VX-661<br>* Tablet, oral use<br>Drug: Ivacaftor<br>* Film coated tablet, oral use<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OLE Phase: Number of Participants With Treatment-Emergent AEs and 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. AEs with start date or increased severity on or after the first dose of study drug through the end of study participation considered treatment-emergent. Baseline was defined as Day 1 of the OLE Phase. | Baseline (OLE Phase) up to 364 days | 
| PC Phase: 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. AEs with start date or increased severity on or after the first dose of study drug through the end of study participation considered treatment-emergent. Baseline was defined as Day 1 of PC Phase. | Baseline (PC Phase) up to 112 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PC Phase: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Baseline was defined as Day 1 of PC Phase. | Baseline (PC Phase), Through Week 12 | 
| OLE Phase: Absolute Change From Baseline in Percent Predicted FEV1 Through Week 40 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Baseline was defined as Day 1 of the OLE Phase. | Baseline (OLE Phase), Through Week 40 | 
| PC Phase: Relative Change From Baseline in Percent Predicted FEV1 Through Week 12 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Baseline was defined as Day 1 of PC Phase. | Baseline (PC Phase), Through Week 12 | 
| OLE Phase: Relative Change From Baseline in Percent Predicted FEV1 Through Week 40 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Baseline was defined as Day 1 of the OLE Phase. | Baseline (OLE Phase), Through Week 40 | 
| PC Phase: Absolute Change From Baseline in Sweat Chloride Through Week 12 | Sweat samples were collected using an approved collection device. Baseline was defined as Day 1 of PC Phase. | Baseline (PC Phase), Through Week 12 | 
| OLE Phase: Absolute Change From Baseline in Sweat Chloride Through Week 40 | Sweat samples were collected using an approved collection device. Baseline was defined as Day 1 of the OLE Phase. | Baseline (OLE Phase), Through Week 40 | 
| PC Phase: Absolute Change From Baseline in Body Weight at Week 12 | Baseline was defined as Day 1 of PC Phase. | Baseline (PC Phase), Week 12 | 
| OLE Phase: Absolute Change From Baseline in Body Weight at Week 40 | Baseline was defined as Day 1 of the OLE Phase. | Baseline (OLE Phase), Week 40 | 
| PC Phase: Absolute Change From Baseline Body Mass Index (BMI) at Week 12 | BMI was calculated using following formula: BMI = Weight in kg/height in square meter (m^2). Baseline was defined as Day 1 of PC Phase. | Baseline (PC Phase), Week 12 | 
| OLE Phase: Absolute Change From Baseline BMI at Week 40 | BMI was calculated using following formula: BMI = Weight in kg/height in m^2. Baseline was defined as Day 1 of the OLE Phase. | Baseline (OLE Phase), Week 40 | 
| PC Phase: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12 | 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 (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as Day 1 of PC Phase. | Baseline (PC Phase), Through Week 12 | 
| OLE Phase: Absolute Change From Baseline in CFQ-R Respiratory Domain Score Through Week 40 | 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 (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as Day 1 of the OLE Phase. | Baseline (OLE Phase), Through Week 40 | 
| PC Phase: Maximum Plasma Concentration (Cmax) of VX-661 and IVA |  | Pre-dose, 2, 3, 4, 6, 9 and 12 hours post-dose on Day 85 | 
| PC Phase: Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24h) of VX-661 | Pharmacokinetic (PK) sampling was performed up to 12 hours post-dose on Day 85. For Arm VX-661 50 mg q12h + IVA 150 mg q12h (VX-661 q12h regimen), area under the concentration versus time curve from time 0 to 12 hours (AUC0-12h) was multiplied by 2 to obtain AUC0-24h. | Pre-dose, 2, 3, 4, 6, 9 and 12 hours post-dose on Day 85 | 
| PC Phase: Area Under the Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12h) of IVA |  | Pre-dose, 2, 3, 4, 6, 9 and 12 hours post-dose on Day 85 | 
| PC Phase: Time to Reach Cmax (Tmax) of VX-661 and IVA |  | Pre-dose, 2, 3, 4, 6, 9 and 12 hours post-dose on Day 85 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CF