A Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination With Ivacaftor in Subjects With CF, Homozygous for the F508del-CFTR Mutation

Study Overview
=================
Brief Summary
-----------------
To evaluate the efficacy and safety of lumacaftor in combination with ivacaftor in subjects aged 6 Through 11 years with cystic fibrosis (CF), homozygous for the F508del CF transmembrane conductance regulator (CFTR) mutation

Official Title
-----------------
A Phase 3, Double Blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

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

Intervention / Treatment
-----------------
* Drug: VX-809
* Drug: Placebo
* Drug: VX-770


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who weigh ≥15 kg without shoes a the Screening Visit Subjects with confirmed diagnosis of CF at the Screening Visit. Subjects who are homozygous for the F508del CFTR mutation Subjects with ppFEV1 of ≥70 percentage points adjusted for age, sex, and height Subjects with a screening LCI2.5 result greater than or equal to 7.5 Exclusion Criteria: History of any comorbidity reviewed at the Screening Visit 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 subject. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject Clinically significant abnormalities in hemoglobin, liver function, or renal function at the Screening Visit. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before Day 1 History of solid organ or hematological transplantation at the Screening Visit

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 11 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 |
| --- | --- |
| Experimental: LUM/IVA<br>Fixed-dose combination with lumacaftor (LUM) 200 mg every 12 hours (q12h)/ ivacaftor (IVA) 250 mg q12h | Drug: VX-809<br> <br> * Other names: lumacaftor;Drug: VX-770<br> <br> * Other names: ivacaftor;|
| Placebo Comparator: Placebo<br>Matching placebo q12h | Drug: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Lung Clearance Index 2.5 (LCI2.5) Through Week 24 | Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple breath washout test using Nitrogen (N2). LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. | Baseline, Through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Absolute Change From Baseline in Sweat Chloride at Day 15 and Week 4 | Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. Change from Baseline in sweat chloride at Day 15 and Week 4 was calculated. The average of the 2 values (Change at Day 15 and Week 4) was reported. | Baseline, Day 15 and Week 4 | 
| Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 | BMI was defined as weight in kg divided by height in square meter (m^2). | Baseline, Week 24 | 
| Absolute Change From Baseline 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 (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | Baseline, Through Week 24 | 
| Absolute Change From Baseline in Lung Clearance Index 5.0 (LCI5.0) Through Week 24 | LCI is a measure of ventilation inhomogeneity that is derived from a multiple breath washout test using Nitrogen (N2). LCI5.0 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/20th of its starting value. | Baseline, Through Week 24 | 
| Absolute Change From Baseline in Sweat Chloride at Week 24 | Sweat samples were collected using an approved collection device. | Baseline, Week 24 | 
| Absolute Change From Baseline 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. Wang standards were used to calculate ppFEV1 (for age, gender, race, and height). | Baseline, Through Week 24 | 
| Relative Change From Baseline in ppFEV1 Through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Wang standards were used to calculate ppFEV1 (for age, gender, race, and height). | Baseline, Through Week 24 | 
| Absolute Change From Baseline in BMI-for-age Z-score at Week 24 | BMI was defined as weight in kg divided by height in m^2. z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes 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). The BMI-for-age z-scores were calculated using National Center for Health Statistics growth charts. | Baseline, Week 24 | 
| Absolute Change From Baseline in Weight at Week 24 |  | Baseline, Week 24 | 
| Absolute Change From Baseline in Weight-for-age Z-score at Week 24 | Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard. Weight, adjusted for age and sex, was analyzed as weight-for-age z-score (weight z-score). The weight-for-age z-scores were calculated using National Center for Health Statistics growth charts. | Baseline, Week 24 | 
| Absolute Change From Baseline in Height at Week 24 |  | Baseline, Week 24 | 
| Absolute Change From Baseline in Height-for-age Z-score at Week 24 | Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard. Height, adjusted for age and sex, was analyzed as height-for-age z-score (height z-score). The height-for-age z-scores were calculated using National Center for Health Statistics growth charts. | Baseline, Week 24 | 
| Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains Through Week 24 | The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction. | Baseline, Through Week 24 | 
| Number of Pulmonary Exacerbation Events | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported. | Baseline through Week 24 | 
| Percentage of Participants With At Least 1 Pulmonary Exacerbation Event | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. | Baseline through Week 24 | 
| Time-to-first Pulmonary Exacerbation | Time-to-first pulmonary exacerbation was analyzed using the Kaplan-Meier estimates. Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. | Baseline 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. | Baseline up to Week 28 | 
| Average Pre-dose Concentration (Ctrough,Ave) and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Ave) For Lumacaftor and Ivacaftor | Ctrough,ave is average of individual pre-dose observed concentrations across Week 4 and 24. C3-6h,ave is average of individual 3 to 6 hours post-dose observed concentrations across Day 1, 15 and Week 4. This outcome was not planned to be assessed in Placebo arm. | For Ctrough,ave: before morning dose on Week 4 and 24; For C3-6h,ave: 3 to 6 hours after morning dose on Day 1, 15 and Week 4 |