| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011762 |
| E.1.2 | Term | Cystic fibrosis |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A:
Evaluate the safety of ivacaftor treatment in subjects with CF who are <24 months of age at treatment initiation & have a CF transmembrane conductance regulator gene gating mutation
Evaluate the pharmacokinetics of ivacaftor & metabolites hydroxymethyl-ivacaftor (M1) & ivacaftor carboxylate (M6) in subjects with CF who are <24 months of age at treatment initiation and have a CFTR gating mutation
Part B:
Evaluate the safety of ivacaftor treatment in subjects with CF who are <24 months of age at treatment initiation and have a CFTR gating mutation
Part A/B:
Evaluate the safety of ivacaftor treatment in subjects with CF who are 1 to <4 months of age at treatment initiation and have an ivacaftor-responsive CFTR mutation (consistent with the approved mutations in the region)
Evaluate the PK of ivacaftor and the ivacaftor metabolites M1 and M6 in subjects with CF who are 1 to <4 months of age at treatment initiation and have an ivacaftor-responsive CFTR mutation |
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| E.2.2 | Secondary objectives of the trial |
Part A: Not applicable
Part B :
- To evaluate the PK of ivacaftor and metabolites M1 and M6 in subjects with CF who are <24 months of age at treatment initiation and have a CFTR gating mutation
- To evaluate the pharmacodynamics (PD) of ivacaftor treatment in subjects with CF who are <24 months of age at treatment initiation and have a
Part A/B Objectives - Cohort 8
• To evaluate the PD of ivacaftor treatment in subjects with CF who are 1 to <4 months of age at treatment initiation and have an ivacaftor-responsive CFTR mutation (consistent with the approved mutations in the region)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female with confirmed diagnosis of CF, defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis OR 2 CF causing mutations.
• A sweat chloride test must be performed if the sweat chloride value is not available in the subject’s medical records and the value is needed to establish eligibility. For subjects with sweat chloride values documented in their medical records and for whom it is not needed to establish eligibility, the sweat chloride test at screening is optional.
2. Have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. Subjects who have an R117H-CFTR mutation will be eligible in regions where ivacaftor is approved for use in subjects with an R117H-CFTR mutation. Subjects eligible for Part A/B Cohort 8 may also have other ivacaftor-responsive mutations.
• If a genotype test has been performed previously and is documented in the subject’s medical record, the subject's eligibility must be approved by the Vertex medical monitor. If a historic genotype result is not available at screening or if the historic genotype result is not approved by the Vertex medical monitor, the subject will be tested for CFTR genotype at screening and the results must be reviewed before the first dose of ivacaftor. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility will not receive study drug.
• Subjects who have an ivacaftor-responsive mutation on at least 1 allele will be eligible to enroll in Part A/B Cohort 8 in regions where ivacaftor is approved (consistent with the approved mutations in the region).
o Subjects must be ≥1 to <4 months of age, ≥38 weeks gestation, and weigh ≥3 kg at Day 1 (treatment initiation); subjects 3 months of age must weigh ≥5 kg on Day 1
o Subjects must have a documented genotype test (performed to applicable national standards). Genotype testing is expected to be initiated prior to screening. Results of the genotype test are to be reviewed and approved by the Vertex medical monitor prior to Day 1.
Subjects with the R117H genotype should have the 5T variant or a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis.
3. Aged 0 to <24 months at Day 1; subjects who completed Part A who are ≥24 months of age on Day 1 in Part B are not eligible to enroll in Part B.
4. For Cohorts 7 and 8 only, gestational age ≥38 weeks.
5. 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.
6. Weight at screening must be within the weight limits as defined for the study drug dose levels.
7. As judged by the investigator, the individual (i.e., parent or legal guardian) signing the informed consent on behalf of the subject must be able to understand the protocol requirements, restrictions, and instructions and should be able to ensure the subject’s compliance with study requirements and the subject’s likelihood for completing the study as planned.
8. Parent or legal guardian must sign the informed consent form (ICF).
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| E.4 | Principal exclusion criteria |
1. 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 subject.
2. An acute upper or lower respiratory infection, or pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1
3. This exclusion criterion is waived for subjects enrolling in Part A/B Cohort 8. Colonization with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at screening. The investigator could be guided by the following suggested criteria for a subject to be considered free of colonization:
• The subject should have had 2 respiratory tract cultures negative for these organisms within the past 12 months, with no subsequent positive cultures.
• These 2 respiratory tract cultures should have been separated by at least 3 months.
• One of these 2 respiratory tract cultures should have been obtained within the past 6 months.
4. Abnormal liver function at screening or any prior history of clinically relevant elevated (>2 × upper limit of normal [ULN]) serum aspartate transaminase (AST), serum alanine transaminase (ALT), or bilirubin (excluding newborn hyperbilirubinemia)
5. History of solid organ or hematological transplantation
6. Any clinically significant "non-CF-related" illness within 2 weeks before Day 1. "Illness" is defined as an acute (serious or nonserious) condition (e.g., gastroenteritis)
7. Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1
8. Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer or as determined by the local requirements) before screening
9. Hemoglobin <9.5 g/dL at screening
10. Chronic kidney disease of Stage 3 or above
11. An adequate slit-lamp examination could not be conducted at the screening OE
12. Presence of a lens opacity or cataract identified at the screening OE (excluding those considered congenital and nonprogressive, such as a suture cataract)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A:
- Safety, as determined by adverse events, clinical laboratory values (serum chemistry and hematology), standard 12-lead electrocardiograms (ECGs), vital signs, and ophthalmologic examinations (OEs)
- PK parameter estimates of ivacaftor and metabolites M1 and M6 after 4 days of ivacaftor treatment
Part B:
- Safety, as determined by adverse events, clinical laboratory values (serum chemistry and hematology), ECGs, vital signs, and OEs
Part A/B Endpoints Cohort 8:
• Safety, as determined by adverse events, clinical laboratory values (serum chemistry and hematology), standard 12 lead ECGs, vital signs, and OEs
• PK parameter estimates of ivacaftor and metabolites M1 and M6
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
- Safety: Through 14 days (ophthalmologic examinations at 8 weeks)
- PK parameters: Day 4
Part B:
- Safety: Through 24 weeks
Part A/B Endpoints Cohort 8:
- Safety: Through 15 days (ophthalmologic examinations at 12 weeks)
- PK parameters: Day 4
- Safety: Through 24 weeks |
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| E.5.2 | Secondary end point(s) |
Part A:
- Not applicable
Part B:
- PK parameter estimates of ivacaftor and metabolites M1 and M6
- Absolute change from baseline in sweat chloride
Part A/B Endpoints Cohort 8:
- Absolute change from baseline in sweat chloride |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United States |
| Ireland |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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