Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del

Study Overview
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Brief Summary
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This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study evaluating the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (PD) of multiple doses of lumacaftor/ivacaftor (LUM/IVA) in subjects 2 through 5 years of age (inclusive) with cystic fibrosis (CF), homozygous for F508del. Subjects who participate in Part A may participate in Part B, if they meet the eligibility criteria.

Official Title
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A Phase 3, 2-Part, Open-label Study to Evaluate the Safety and Pharmacokinetics of Lumacaftor/Ivacaftor Combination Therapy in Subjects Aged 2 Through 5 Years 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who weigh ≥8 kilogram (kg) without shoes and wearing light clothing at the Screening Visit Subjects with confirmed diagnosis of CF at the Screening Visit Subjects who are homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation Exclusion Criteria: Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 A standard 12-lead ECG demonstrating QTc >450 millisecond (msec) at the Screening Visit. History of solid organ or hematological transplantation. Ongoing or prior participation in an investigational drug study (including studies investigating LUM and/or IVA) within 30 days of the Screening Visit. History of cataract/lens opacity or evidence of cataract/lens opacity determined to be clinically significant by a licensed ophthalmologist during the ophthalmologic examination at the Screening Visit

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 5 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lumacaftor/Ivacaftor (LUM/IVA)<br>Part A (<14 kg): Participants weighing less than (<) 14 kilograms (kg) at screening received LUM 100 milligram (mg)/IVA 125 mg fixed-dose combination every 12 hours for 15 days in Part A. Part A (>=14 kg): Participants weighing greater than or equal to (>=) 14 kg at screening received LUM 150 mg/IVA 188 mg fixed-dose combination every 12 hours for 15 days in Part A. Part B (<14 kg): Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg fixed-dose combination every 12 hours for 24 weeks in Part B. Part B (>=14 kg): Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg fixed-dose combination every 12 hours for 24 weeks in Part B. | Drug: LUM/IVA<br> <br> * Other names: VX-809+VX-770;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pre-dose Concentration (Ctrough) of LUM and IVA |  | Day 15 | 
| Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Day 1 up to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pre-dose Concentration (Ctrough) of LUM and IVA Metabolites |  | Day 15 | 
| Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Day 1 up to Day 25 | 
| Part B: Absolute Change From Baseline in Sweat Chloride at Week 24 | Sweat samples were collected using an approved collection device. | Baseline, Week 24 | 
| Part B: 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 | 
| Part B: Absolute Change From Baseline in Body Mass Index (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 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). | Baseline, Week 24 | 
| Part B: Absolute Change From Baseline in Weight at Week 24 |  | Baseline, Week 24 | 
| Part B: Absolute Change From Baseline in Weight-for-age Z-Score at Week 24 | z-score is a statistical measure to describe 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). | Baseline, Week 24 | 
| Part B: Absolute Change From Baseline in Stature (Height) at Week 24 |  | Baseline, Week 24 | 
| Part B: Absolute Change From Baseline in Stature-for-Age Z-Score | z-score is a statistical measure to describe whether a mean was above or below the standard. Stature (height), adjusted for age and sex, was analyzed as Stature-for-age z-score (Stature z-score). | Baseline, Week 24 | 
| Part B: Number of Pulmonary Exacerbations | Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. | Through Week 24 | 
| Part B: Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24 | Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. Time to event data was not collected and instead, number of participants 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. | Through Week 24 | 
| Part B: Number of Cystic Fibrosis (CF)-Related Hospitalizations |  | Through Week 24 | 
| Part B: Absolute Change From Baseline in Fecal Elastase-1 (FE-1) Levels at Week 24 |  | Baseline, Week 24 | 
| Part B: Absolute Change From Baseline in Serum Levels of Immunoreactive Trypsinogen (IRT) Through Week 24 |  | Baseline, Through Week 24 | 
| Part B: Number of Participants With Microbiology Culture Status (Positive or Negative) at Week 24 | Following microbial tests were performed: Burkholderia, Methicillin Resistant Staphylococcus Aureus (MRSA), Methicillin Susceptible Staphylococcus Aureus (MSSA), Pseudomonas Aeruginosa Mucoid (P. Aeruginosa Mucoid), P. Aeruginosa Non-Mucoid, P. Aeruginosa Small Colony Variant and Stenotrophomonas Maltophilia. | Baseline and Week 24 | 
| Part B: 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 | 
| Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26 | Sweat samples were collected using an approved collection device. | Week 24, Week 26 | 
| Part B: Acceptability/Palatability of LUM/IVA Granules Measured Using Hedonic Scale | The acceptability and palatability of LUM/IVA granules was assessed by a visual analog scale that incorporates a 5 point facial hedonic scale (Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much). The assessment was conducted in 2 steps: assessment of approved food/liquid (Evaluation 1), and assessment of approved food/liquid with LUM/IVA granules (Evaluation 2). | Day 1 | 
| Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 2.5 at Week 24 | Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple breath washout test using Nitrogen (N2). LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. | Baseline, Week 24 | 
| Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 5.0 at Week 24 | LCI is a measure of ventilation inhomogeneity that is derived from a multiple breath washout test using Nitrogen (N2). LCI 5.0 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/20th of its starting value. | Baseline, Week 24 | 
| Part B: Pre-dose Concentration (Ctrough) of LUM and IVA and Its Metabolites |  | Week 24 | 

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