| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 |
| To evaluate the efficacy of ivacaftor treatment in subjects with cystic fibrosis (CF) who have a specified CF transmembrane conductance regulator (CFTR) gating mutation, and who are 3 through 5 years of age at the start of the study, as measured by lung clearance index (LCI) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate disease progression as measured by changes in computed tomography (CT) scan
• To evaluate disease progression as measured by changes in pancreatic function
• To evaluate the safety of ivacaftor treatment, as measured by clinical laboratory measures (including liver function tests [LFTs]), ophthalmologic examinations, and adverse events (AEs)
|
|
| 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:
o a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis
OR
2 CF causing mutations (all as documented in the subject's medical record)
AND
o Clinical manifestations of CF
2. Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D.
3. Subjects will be between the ages of 3 and 5 years, inclusive, at Screening and Day 1
4. Weight ≥8 kg to <25 kg at Screening and Day 1
5. Hematology, serum chemistry, and coagulation at Screening with no clinically significant abnormalities or concomitant diagnosis that would interfere with the LCI and CT scan study assessments, as judged by the investigator
|
|
| 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, impact use of the LCI or CT scan as assessments or pose an additional risk in administering study drug to the subject
2. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1
3. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (in the opinion of the investigator)
4. Abnormal liver function, at Screening, defined as 3 × upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), and total bilirubin
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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
Absolute change from baseline in LCI2.5 through 8 weeks of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Part 1
• Absolute change from baseline in serum levels of immunoreactive
trypsinogen at 8 weeks of treatment
• Absolute change from baseline in fecal elastase-1 at 8 weeks of treatment
• Absolute change from baseline in weight at 8 weeks of treatment
• Absolute change from baseline in body mass index (BMI) at 8 weeks of treatment
• Safety, as determined by AEs, clinical laboratory values (including LFTs), and other relevant assessments
Part 2:
• Absolute change from baseline in LCI2.5 at Weeks 48, 96, and 144
• Absolute change from baseline in CT scan at Week 96
• Absolute change from baseline in serum levels of immunoreactive trypsinogen at Weeks 48, 96, and 144
• Absolute change from baseline in fecal elastase-1 at Weeks 48, 96, and 144
• Absolute change from baseline in weight-for-age z-score at Weeks 48, 96, and 144
• Absolute change from baseline in height-for-age z-score at Weeks 48, 96, and 144
• Absolute change from baseline in BMI-for-age z-score at Weeks 48, 96, and 144
• Safety, as determined by AEs, clinical laboratory values (including LFTs), and ophthalmologic examinations
Following a review of study enrollment and assessment of the available number of potential subjects for this study, Vertex decided to close enrollment as of 21 February 2017 and withdraw subjects in order to terminate the study. After the protocol amendment has been approved at a
site:
Subjects in Part 1 of the study will be withdrawn from the study at their Week 24 Visit.
Subjects in Part 2 will be withdrawn from the study and requested to complete the Early Termination of Treatment Visit. Subjects who have been treated with open-label ivacaftor for <4 weeks in Part 2 are not required to complete an ophthalmologic examination at their Early Termination of Treatment Visit.
Safety Follow-up Visit for subjects who prematurely discontinue study drug treatment (approximately 4 weeks (± 7 days) after their last dose of study drug).
o A Safety Follow-up Visit will not be required of subjects withdrawn from the study due to early study termination. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1: 8 weeks
Part 2:
Following a review of study enrollment and assessment of the available number of potential subjects for this study, Vertex decided to close
enrollment as of 21 February 2017 and withdraw subjects in order to terminate the study. After the protocol amendment has been approved at a
site:
Subjects in Part 1 of the study will be withdrawn from the study at their Week 24 Visit.
Subjects in Part 2 will be withdrawn from the study and requested to complete the Early
Termination of Treatment Visit. Subjects who have been treated with open-label ivacaftor for <4 weeks in Part 2 are not required to complete an ophthalmologic examination at their Early Termination of Treatment Visit. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 2 of the study is a long-term open-label period |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Australia |
| Canada |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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