A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis Who Are Less Than 24 Months of Age and Have an Ivacaftor-Responsive CFTR Mutation

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety of ivacaftor treatment, and PK of ivacaftor and metabolites in participants with cystic fibrosis (CF) who are <24 months of age at treatment initiation and have an ivacaftor-responsive CF transmembrane conductance regulator (CFTR) gene mutation.

Official Title
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A Phase 3, 2 Part, Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis Who Are Less Than 24 Months of Age and Have an Ivacaftor-Responsive CFTR Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: IVA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CF by sweat chloride value or CF mutation criteria. Have 1 of the following 10 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D or R117H (eligible in regions where ivacaftor is approved for use). Part A/B group may also have other ivacaftor-responsive mutations. Hematology, serum chemistry, and vital signs results at screening with no clinically significant abnormalities that would interfere with the study assessments, as judged by the investigator. Exclusion Criteria: History of any illness or condition 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 participant Colonization with organisms associated with a more rapid decline in pulmonary status at screening (Only for Parts A and B) History of abnormal liver function or abnormal liver function at screening History of solid organ or hematological transplantation Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1 Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives before screening Hemoglobin (Hgb) <9.5 g/dL at screening Chronic kidney disease of Stage 3 or above Presence of a non-congenital or progressive lens opacity or cataract at Screening Other protocol defined Inclusion/Exclusion Criteria may apply.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 24 Months

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: 3 to <24 months<br>Participants weighing 5 to less than (<) 7 kilogram (kg) received 25 milligram (mg) IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA administered every 12 hours (q12h) on Days 1 through 3 and 1 morning dose on Day 4. | Drug: IVA<br>* Granules in sachet for oral administration.<br>* Other names: ivacaftor;|
| Experimental: Part B + A/B:1 to < 24 months<br>Participants 4 to <6 months of age and weighing greater than or equal to (≥) 5 kg received 25 mg IVA q12h. At 6 months of age and older, participants weighing 5 to <7 kg received 25 mg IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA q12h for 24 weeks on Part B. For Part A/B, participants 1 to <4 months weighing 3 kg to <5 kg received an initial low dose of 5.7 mg q12h IVA and those weighing ≥5 kg received 11.4 mg q12h IVA for the first 15 days of IVA treatment. Doses were maintained or adjusted upward at Day 15 and based on weight and/or age once they reached 4 months of age. | Drug: IVA<br>* Granules in sachet for oral administration.<br>* Other names: ivacaftor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious (TEAEs) |  | Day 1 through Day 70 | 
| Part A: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA) |  | Pre-dose, 2-4 hours, 6-8 hours, 24-60 hours post-dose | 
| Part B +A/B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious (TEAEs) |  | Day 1 through Week 38 | 
| Part A/B: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA) |  | Day 4 (pre-dose, 2-4 hours, 6-8 hours post-dose); Day 15 (pre-dose); Week 4 (pre-dose); Week 8 (pre-dose, 2-4 hours, 6-8 hours post-dose); Week 12 (pre-dose); Week 18 (pre-dose) and Week 24 (pre-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA) |  | Week 2 (pre-dose, 2-4 hours, 6-8 hours post-dose); Week 8 (pre-dose,1 hour, 4-hour post-dose); Week 24 (pre-dose, 2-4 hours post dose) | 
| Part B + A/B: Absolute Change From Baseline in Sweat Chloride | Sweat samples were collected using an approved collection device. | From Baseline at Week 24 |