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

Phase 3

Completed

• Conditions: Cystic Fibrosis
• Interventions: Drug: VX-809; Drug: Placebo; Drug: VX-770

• Registration Number: NCT02514473
• Lead Sponsor: Vertex Pharmaceuticals Incorporated

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

Detailed Description

Not available

Study Timeline

• Study Start: 2015-07
• Study First Submitted: 2015-07-23
• Study First Submitted QC: 2015-07-31
• Study First Posted: 2015-08-03
• Primary Completion: 2016-09
• Study Completion: 2016-09
• Status Verified: 2017-09
• Results First Submitted: 2017-09-19
• Results First Submitted QC: 2017-09-19
• Last Update Submitted: 2017-09-19
• Results First Posted: 2017-10-23
• Last Update Posted: 2017-10-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 206

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LUM/IVA	VX-809	Fixed-dose combination with lumacaftor (LUM) 200 mg every 12 hours (q12h)/ ivacaftor (IVA) 250 mg q12h
LUM/IVA	VX-770	Fixed-dose combination with lumacaftor (LUM) 200 mg every 12 hours (q12h)/ ivacaftor (IVA) 250 mg q12h
Placebo	Placebo	Matching placebo q12h

Primary Outcome Measures

Name	Time	Method
Absolute Change From Baseline in Lung Clearance Index 2.5 (LCI2.5) Through Week 24	Baseline, 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.

Secondary Outcome Measures

Name	Time	Method
Average Absolute Change From Baseline in Sweat Chloride at Day 15 and Week 4	Baseline, 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.
Absolute Change From Baseline in Body Mass Index (BMI) at Week 24	Baseline, Week 24	BMI was defined as weight in kg divided by height in square meter (m\^2).
Absolute Change From Baseline in Sweat Chloride at Week 24	Baseline, Week 24	Sweat samples were collected using an approved collection device.
Relative Change From Baseline in ppFEV1 Through Week 24	Baseline, 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).
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24	Baseline, 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.
Percentage of Participants With At Least 1 Pulmonary Exacerbation Event	Baseline through Week 24	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.
Absolute Change From Baseline in Lung Clearance Index 5.0 (LCI5.0) Through Week 24	Baseline, 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.
Absolute Change From Baseline in Weight at Week 24	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	Baseline, 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.
Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains Through Week 24	Baseline, 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.
Number of Pulmonary Exacerbation Events	Baseline through Week 24	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.
Time-to-first Pulmonary Exacerbation	Baseline through Week 24	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.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Baseline up to Week 28	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.
Average Pre-dose Concentration (Ctrough,Ave) and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Ave) For Lumacaftor and Ivacaftor	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	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.
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24	Baseline, 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).
Absolute Change From Baseline in BMI-for-age Z-score at Week 24	Baseline, 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.
Absolute Change From Baseline in Weight-for-age Z-score at Week 24	Baseline, 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.