Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age

Study Overview
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Brief Summary
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This study will evaluate the pharmacokinetics (PK), safety, tolerability, efficacy, and pharmacodynamic effect of VX-445, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple combination (TC) in Cystic Fibrosis (CF) subjects 6 through 11 years of age with F/F and F/MF genotypes.

Official Title
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A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: ELX/TEZ/IVA
* Drug: IVA


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Homozygous or heterozygous for F508del mutation (F/F or F/MF genotypes) Forced expiratory volume in 1 second (FEV1) value ≥40% of predicted mean for age, sex, and height. Key Exclusion Criteria: Clinically significant cirrhosis with or without portal hypertension Lung infection with organisms associated with a more rapid decline in pulmonary status. Solid organ or hematological transplantation. Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 11 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: ELX/TEZ/IVA<br>Participants in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days. | Drug: ELX/TEZ/IVA<br>* Fixed-dose combination tablet orally once daily in the morning.<br>* Other names: elexacaftor/tezacaftor/ivacaftor;Drug: IVA<br>* IVA tablet orally once daily in the evening.<br>* Other names: ivacaftor;|
| Experimental: Part B: ELX/TEZ/IVA<br>Participants in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing greater than equals to (>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Drug: ELX/TEZ/IVA<br>* Fixed-dose combination tablet orally once daily in the morning.<br>* Other names: elexacaftor/tezacaftor/ivacaftor;Drug: IVA<br>* IVA tablet orally once daily in the evening.<br>* Other names: ivacaftor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA |  | Part A: Day 15 | 
| Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA |  | Part A: Day 15 | 
| Part A: Area Under the Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24h) of ELX, TEZ, and IVA |  | Part A: Day 15 | 
| Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Part B: Day 1 Through Safety Follow-up Visit (up to Week 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) |  | Part A: Day 15 | 
| Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) |  | Part A: Day 15 | 
| Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ) |  | Part A: Day 15 | 
| Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA) | The AUC data was analyzed for up to 6 hours for IVA metabolite (M1-IVA). Therefore, AUC0-6h is reported for M1-IVA metabolite. | Part A: Day 15 | 
| Part A: Safety and Tolerability as Assessed by Number of Participants With TEAEs and SAEs |  | Part A: Day 1 Through Safety Follow-up Visit (up to Day 43) | 
| Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Part B: From Baseline Through Week 24 | 
| Part B: Absolute Change in Sweat Chloride (SwCl) | Sweat samples were collected using an approved collection device. | Part B: From Baseline Through Week 24 | 
| Part B: Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score | 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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | Part B: From Baseline Through Week 24 | 
| Part B: Absolute Change in Body Mass Index (BMI) | BMI was defined as weight in kg divided by squared height in meters (m^2). | Part B: From Baseline at Week 24 | 
| Part B: Absolute Change in BMI For-Age Z-Score | BMI was defined as weight in kg divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. | Part B: From Baseline at Week 24 | 
| Part B: Absolute Change in Weight |  | Part B: From Baseline at Week 24 | 
| Part B: Absolute Change in Weight-for-age Z-Score | The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. | Part B: From Baseline at Week 24 | 
| Part B: Absolute Change in Height |  | Part B: From Baseline at Week 24 | 
| Part B: Absolute Change in Height-for-Age Z-Score | The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. | Part B: From Baseline at Week 24 | 
| Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale | The study drug acceptability (participant reaction) 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). Number of participants with the indicated categorical response in the drug acceptability assessment were reported. | Part B: At Week 24 | 
| Part B: Number of Pulmonary Exacerbations Events | Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. The total number of pulmonary exacerbations events across all participants were reported. | Part B: From Baseline Through Week 24 | 
| Part B: Number of CF Related Hospitalizations | The total number of CF related hospitalization events across all participants were reported. | Part B: From Baseline Through Week 24 | 
| Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA) |  | Part B: At Week 4 | 
| Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5) | 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. | Part B: From Baseline Through Week 24 |