| 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 |
Ivacaftor Arm
To evaluate the safety of long-term ivacaftor treatment in subjects with CF who are <24 months of age at treatment initiation and have an approved ivacaftor-responsive mutation
Observational Arm
To evaluate the long-term safety after discontinuation of ivacaftor treatment in subjects with CF who were <24 months of age at treatment initiation and have an approved ivacaftor-responsive mutation. |
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| E.2.2 | Secondary objectives of the trial |
Ivacaftor Arm
To evaluate the pharmacodynamics (PD) of long-term ivacaftor treatment in subjects with CF who are <24 months of age at treatment initiation and have an approved ivacaftor-responsive mutation
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Ivacaftor Arm: Subjects From Study 124 Part B
1. Subjects transitioning from Study 124 Part B must have completed the last study visit of Study 124 Part B
Added guidance:
- Subjects who had a study drug interruption at the last scheduled visit of Study 124 Part B, subjects who required study drug interruption that was to be continued or initiated at Day 1 in Study 126, or subjects who resumed study drug in Study 124 Part B after a study drug interruption due to elevated transaminases but who did not complete at least 4 weeks of rechallenge with study drug (due to the timing of the rechallenge versus the time remaining in Study 124 Part B) must meet eligibility criteria and have received approval from the Vertex medical monitor.
2. For Gap Transition subjects: hematology and serum chemistry results at baseline with no clinically significant abnormalities that would confound the study assessments or pose an additional risk to administering ivacaftor to the study subject, as judged by the investigator.
3. As judged by the investigator, parent or legal guardian must be able to understand protocol requirements, restrictions, and instructions; and must sign the informed consent form (ICF).
Ivacaftor Arm: Subjects Not From Study 124 Part B
1. Age <24 months at the Day 1 Visit
2. Confirmed diagnosis of CF, defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis or 2 CF-causing mutations
- If the results of the sweat chloride and/or the genotype test are documented in the subject’s medical record, and the historic genotype result is approved by the Vertex medical monitor, the tests do not need to be performed at screening. 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.
3. An ivacaftor-responsive CFTR mutation on at least 1 allele. Subjects will be eligible in countries/regions where ivacaftor is approved for use in subjects 2 years of age and older.
- 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 undergo CFTR genotype 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.
4. Hematology, serum chemistry, and vital signs results have no clinically significant abnormalities that would confound the study assessments, as judged by the investigator.
5. Weight at screening must be within the weight limites as defined for the study drug dose levels or according to the dosing guidelines identified in the 'Justification for Dose Selection' memorandum effective at the time a subject is screened
6. For subjects <3 months of age only, gestational age ≥38 weeks.
7. As judged by the investigator, parent or legal guardian must be able to understand protocol requirements, restrictions, and instructions; and must sign the ICF.
Observational Arm
1. Completed ivacaftor treatment in Study 124 Part B and elected not to enroll in the ivacaftor arm of Study 126, or received at least 1 dose of ivacaftor and prematurely discontinued ivacaftor treatment in Study 124 Part B and received at least 1 dose of ivacaftor treatment in Study 124 Part B |
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| E.4 | Principal exclusion criteria |
Ivacaftor Arm: Subjects From Study 124 Part B
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 ivacaftor to the subject.
Examples of subjects who may not be eligible include
- subjects with a history of allergy or hypersensitivity to the study drug; and
- subjects with severe or life-threatening reactions to the study drug in Study 124.
2. Subjects receiving commercially available ivacaftor treatment
Ivacaftor Arm: Subjects Not From Study 124 Part B
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 ivacaftor 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 of Day 1
3. Known colonization with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). A subject is excluded if they have a positive culture of one of these organisms.
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, e.g., physiologic jaundice or breastmilk jaundice of the newborn)
5. Hemoglobin <9.5 g/dL at screening
6. History of solid organ or hematological transplantation
7. Any clinically significant “non-CF-related” illness within 2 weeks of Day 1. “Illness” is defined as an acute (serious or nonserious) condition (e.g., gastroenteritis)
8. Use of any moderate or strong inducers or inhibitors of cCYP3A within 2 weeks of Day 1
9. 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. Note: Participation in a noninterventional study (including observational studies, registry studies, and studies requiring blood collections without administration of study drug) is permitted.
10. Chronic kidney disease of Stage 3 or above
11. Unable to undergo an adequate slit-lamp examination at screening
12. Presence of a lens opacity or cataract identified at the screening OE (excluding those considered congenital and nonprogressive, such as a suture cataract)
Observational arm
1. Receiving ivacaftor treatment |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Ivacaftor Arm
Safety, as determined by:
- Adverse events
- Laboratory values (serum chemistry and hematology)
- 12-Lead ECGs) and vital signs
- Ophthalmologic examinations (OEs)
Observational Arm
Safety after stopping ivacaftor treatment in Study VX15-770-124 (Study 124) Part B as determined by serious adverse events (SAEs) and results from an OE approximately 24 weeks after the last dose of ivacaftor in Study 124 Part B. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ivacaftor Arm
Regularly throughout the study
Observational Arm
OE at Week 24 after the last dose
Telephone contact at Week 48 and Week 96 after last dose |
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| E.5.2 | Secondary end point(s) |
Ivacaftor Arm
Absolute change from baseline in sweat chloride through Week 96 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Regularly throughout the study |
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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 | No |
| 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 | 2 |
| 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 | 8 |
| 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 |
| Germany |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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