A Study of the Effects of Lumacaftor/Ivacaftor (LUM/IVA) on Exercise Tolerance in Subjects With Cystic Fibrosis (CF), Homozygous for the F508del-CFTR Mutation

Study Overview
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Brief Summary
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This is a Phase 4, randomized, double-blind, placebo-controlled, parallel-group study in subjects aged 12 years and older with CF who are homozygous for the F508del-CFTR mutation. This study is designed to evaluate the effect of LUM/IVA on exercise tolerance in subjects with CF, homozygous for the F508del-CFTR mutation.

Official Title
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A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Study of the Effect of Lumacaftor/Ivacaftor Combination Therapy on Exercise Tolerance in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: LUM/IVA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Homozygous for the F508del-CFTR mutation Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis Stable CF disease as judged by the investigator Forced expiratory volume in 1 second (FEV1) at least 40% and not greater than 90% of predicted Exclusion Criteria: History of any comorbidity that might confound the results of the study, interfere with the use of cardiopulmonary exercise tests (CPETs) as an assessment, or pose an additional risk in administering study drug to the subject Any previous exposure to LUM or IVA History of cardiac arrhythmia, ischemic heart disease, congestive heart failure, or other clinically significant cardiac condition, or medical condition requiring chronic use of a beta blocker, non-dihydropyridine calcium channel blocker, or other cardiac medication known to affect exercise tolerance History of solid organ or hematological transplantation For subjects under 18 years of age at Screening, except those who have had bilateral lens removal, selected findings on a screening ophthalmologic examination will be exclusionary Using or expected to require any concomitant medication that is prohibited in this study History of alcohol or drug abuse, as deemed by the investigator, in the past year, including but not limited to cannabis, cocaine, and opiates Participation in an investigational drug study within 30 days before the Screening Visit Pregnant or nursing females; males with a female partner who is pregnant or nursing Colonization with organisms associated with a more rapid decline in pulmonary status

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo matched to LUM/IVA fixed-dose combination tablet orally every 12 hours (q12h) for 24 weeks. | Drug: Placebo<br> <br> |
| Experimental: LUM/IVA<br>LUM 400 milligram (mg)/IVA 250 mg fixed-dose combination tablet orally q12h for 24 weeks. | Drug: LUM/IVA<br> <br> * Other names: Lumacaftor/Ivacaftor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative (Percent) Change From Baseline in Maximal Oxygen Consumption (VO2max) During Cardiopulmonary Exercise Testing (CPET) at Week 24 | CPET was used to assess change in exercise tolerance, as measured by VO2max. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative (Percent) Change From Baseline in Exercise Duration During CPET at Week 24 | Exercise duration is defined as the time at the termination of CPET exercise minus the corresponding time when CPET starts for each CPET exercise. | Baseline, Week 24 | 
| Absolute Change From Baseline in Exercise Duration During CPET at Week 24 | Exercise duration is defined as the time at the termination of CPET exercise minus the corresponding time when CPET starts for each CPET exercise. | Baseline, Week 24 | 
| Absolute Change From Baseline in VO2max During CPET at Week 24 | CPET was used to assess change in exercise tolerance, as measured by VO2max. | Baseline, Week 24 | 
| Absolute Change From Baseline in Oxygen Consumption (VO2) at Anaerobic Threshold at Week 24 | Anaerobic threshold was defined as the exercise intensity at which lactate starts to accumulate. | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in VO2 at Anaerobic Threshold at Week 24 | Anaerobic threshold was defined as the exercise intensity at which lactate starts to accumulate. | Baseline, Week 24 | 
| Absolute Change From Baseline in Functional VO2 Gain at Week 24 |  | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in Functional VO2 Gain at Week 24 |  | Baseline, Week 24 | 
| Absolute Change From Baseline in Pulmonary Ventilation (VE) Versus Carbon Dioxide Production (VCO2) Slope at Week 24 |  | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in Pulmonary Ventilation (VE) Versus Carbon Dioxide Production (VCO2) Slope at Week 24 |  | Baseline, Week 24 | 
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Week 24 | 
| Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 | BMI was defined as weight in kilograms (kg) divided by height in square meter (m^2). | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in BMI at Week 24 | BMI was defined as weight in kg divided by height in m^2. | Baseline, Week 24 | 
| Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 | The CFQ-R assessed respiratory symptoms on a scale with scores ranging from 0 to 100; where higher scores indicated fewer symptoms and better health-related quality of life. | Baseline, Week 24 | 
| Number of Participants in Each Severity Category of Patient Health Questionnaire (PHQ-8) | The PHQ-8 is an eight item self-reported measure of depression. Each item is rated on a scale ranging from 0 (not at all) to 3 (nearly every day). Total score is the sum of individual eight items and ranges from 0 to 24, with higher scores indicating more severe depression symptoms. Total score of 0 to 5 indicates none to minimal depression, 6 to 10 indicates mild depression, 11 to 15 indicates moderate depression, 16 to 20 indicates moderately severe depression and 21 to 24 indicates severe depression. | Baseline, Week 24 | 
| Number of Participants in Each Severity Category of Generalized Anxiety Disorder (GAD-7) Scores | The GAD-7 is a seven item, self-reported measurement of GAD severity. Each item is rated on a scale ranging from 0 (not at all) to 3 (nearly every day). Total score is the sum of individual seven items and ranges from 0 to 21, with higher scores indicating more severe anxiety symptoms. Total score of 0 to 5 indicates none to minimal anxiety, 6 to 10 indicates mild anxiety, 11 to 15 indicates moderate anxiety, 16 to 21 indicates severe anxiety. | Baseline, Week 24 | 
| Absolute Change From Baseline in Daily Physical Activity Counts as Determined by Actigraphy at Week 24 | Participants were provided with a wrist-worn actigraphy device which continuously collected data about daily physical activity counts. | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in Physical Activity as Determined by Actigraphy at Week 24 | Participants were provided with a wrist-worn actigraphy device which continuously collected data about daily physical activities. | Baseline, Week 24 | 
| Absolute Change From Baseline in Duration of Sleep Time at Week 24 | Participants were provided with a wrist-worn actigraphy device which continuously collected data about sleep duration and quality. | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in Duration of Sleep Time at Week 24 | Participants were provided with a wrist-worn actigraphy device which continuously collected data about sleep duration and quality. | Baseline, Week 24 | 
| Absolute Change From Baseline in Time Above Sedentary Duration at Week 24 | Participants were provided with a wrist-worn actigraphy device which continuously collected data about daily activities and sleep duration and quality. | Baseline, Week 24 | 
| Relative (Percent) Change From Baseline in Time Above Sedentary Duration at Week 24 | Participants were provided with a wrist-worn actigraphy device which continuously collected data about daily activities and sleep duration and quality. | Baseline, Week 24 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Day 1 up to Week 28 |