A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of VX-661/Ivacaftor in Pediatric Subjects With Cystic Fibrosis (CF)

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 pharmacokinetic (PK), safety, and tolerability of multiple doses of tezacaftor (TEZ) in combination with ivacaftor (IVA) in subjects 6 through 11 years of age with CF who are homozygous or heterozygous for the F508del- CF transmembrane conductance regulator protein (CFTR) mutation.

Official Title
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A Phase 3, Open Label Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of VX-661 in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous or Heterozygous for the F508del CFTR Mutation

Conditions
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Cystic Fibrosis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who weigh ≥15 kg without shoes at the Screening Visit. All genotypes as specified by the study protocol are eligible in Part A. The following genotypes are eligible in Part B: homozygous for the F508del CFTR mutation heterozygous for the F508del CFTR mutation and with a second allele with a CFTR mutation predicted to have residual function. heterozygous for the F508del CFTR mutation and with a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive Subjects with a confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L or chronic sinopulmonary and/or gastrointestinal disease consistent with a diagnosis of CF. Subjects who are homozygous for the F508del-CFTR mutation must have a sweat chloride value ≥60 mmol/L. Subjects with ppFEV1 of ≥40 percentage points at the Screening Visit Subjects with stable CF disease as deemed by the investigator at the Screening Visit. Subjects who are willing to remain on their stable CF medication regimen through Day 14 (Part A) or through Week 24 (Part B) or, if applicable, through the Safety Follow up Visit. Subjects who are able to swallow tablets. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Day 1 Visit before receiving the first dose of study drug. Subjects of childbearing potential who are sexually active must meet the contraception requirements 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. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before Day 1 Colonization with organisms associated with a more rapid decline in pulmonary status. A standard 12 lead ECG demonstrating QTc >450 msec at the Screening Visit. History of solid organ or hematological transplantation at the Screening Visit. Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator (except physician-prescribed Kalydeco for approved indications) within 30 days of screening. Use of restricted medication or food within a specified duration before the Screening Visit or first dose of study drug and/or unwillingness to maintain the restrictions. History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be clinically significant by the ophthalmologist during the ophthalmologic examination at the Screening Visit. Pregnant and nursing females.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>Participants weighing <25 kg received TEZ 50 mg once daily/IVA 75 mg q12h orally for 14 days. Participants weighing ≥25 kg received TEZ 50 mg once daily/IVA 150 mg q12h orally for 14 days. | Drug: TEZ<br> <br> * Other names: VX-661;Drug: IVA<br> <br> * Other names: VX-770;|
| Experimental: Part B<br>Participants weighing <40 kg received TEZ 50 mg/IVA 75 mg as fixed dose combination orally once daily in the morning and IVA 75 mg orally once daily in the evening for 24 weeks. Participants weighing ≥40 kg received TEZ 100 mg/IVA 150 mg as fixed dose combination orally once daily in the morning and IVA 150 mg orally once daily in the evening for 24 weeks. | Drug: TEZ/IVA<br> <br> * Other names: VX-661/VX-770;Drug: IVA<br> <br> * Other names: VX-770;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA |  | Day 1 and Day 14 | 
| Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA |  | Day 1 and Day 14 | 
| Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Day 1 up to Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) |  | Day 1 and Day 14 | 
| Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) |  | Day 1 and Day 14 | 
| Part A: Number of Participants With AEs and SAEs |  | Day 1 up to Day 28 | 
| Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) |  | Week 16 | 
| Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) |  | Week 16 | 
| 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. | From Baseline through Week 24 | 
| Part B: Relative Change in ppFEV1 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline through Week 24 | 
| Part B: Absolute Change in Weight |  | From Baseline at Week 24 | 
| Part B: Absolute Change in Weight-for-age Z-Score | 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. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher weight. | From Baseline at Week 24 | 
| Part B: Absolute Change in Height |  | From Baseline at Week 24 | 
| Part B: Absolute Change in Height-for-age z-Score | z-score is a statistical measure to describe whether a mean was above or below the standard. Height, adjusted for age and sex, was analyzed as height-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher height. | From Baseline at Week 24 | 
| Part B: Absolute Change in Body Mass Index (BMI) | BMI was defined as weight in kg divided by height in square meter (m^2). | From Baseline at Week 24 | 
| Part B: Absolute Change in BMI-for-age z-Score | 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. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI. | From Baseline at Week 24 | 
| Part B: Absolute Change in Sweat Chloride | Sweat samples were collected using an approved collection device. | From Baseline through Week 4 | 
| Part B: Absolute Change in Sweat Chloride | Sweat samples were collected using an approved collection device. | 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. | From Baseline through Week 24 |