| 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] - Respiratory Tract Diseases [C08] |
| 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 |
| To evaluate the effectiveness of elexacaftor (VX-445; ELX)/tezacaftor (TEZ)/ivacaftor (IVA) in subjects 6 through 11 years old with cystic fibrosis (CF |
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA
•To evaluate the safety of ELX/TEZ/IVA
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects and their parent will sign and date an informed consent form (ICF), and an assent form.
2.Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures
3.Subjects (male and female) 6 through 11 years of age, inclusive, on the date of informed consent.
4.Subjects who weigh ≥15 kg without shoes at the Screening Visit.
5.Confirmed diagnosis of CF as determined by the investigator.
6.Subjects heterozygous for F508del and an MF mutation that is not responsive to IVA and TEZ/IVA (F/MF genotypes, Protocol Appendix A).
•Genotype should be confirmed at the Screening Visit.
•If the screening CFTR genotype result is not received before the first dose of study drug, a previous CFTR genotype laboratory report may be used to establish eligibility.
•Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study (Protocol Section 9.9).
7.Subjects with FEV1 value ≥70% of predicted normal for age, sex, and height using equations of the Global Lung Function Initiative (GLI)11 as determined by spirometry at screening (Protocol Section 11.3.1).
8.Subjects with a screening LCI2.5 result ≥ 7.5 (Protocol Section 11.3.2).
9.Subjects with stable CF disease at the start of the Treatment Period as deemed by the investigator.
10.Subjects who are willing to remain on a stable CF medication regimen (other than CFTR modulators) through Week 24 or, if applicable, through the Safety Follow up Visit
11.Subjects who are able to swallow tablets.
12. As deemed by the investigator, the subject’s legally appointed and authorized representative (e.g., parent or legal guardian) AND the subject must be able to understand protocol requirements, restrictions, and instructions. The subject’s legally appointed and authorized representative should be able to ensure that the subject will comply with and is likely to complete the study as planned.
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| E.4 | Principal exclusion criteria |
1.History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This includes, but is not limited to, the following:
•Clinically significant liver cirrhosis with or without portal hypertension
•Solid organ or hematological transplantation
•Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator
•Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years)
2.Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (as deemed by the investigator).
3.Any of the following abnormal laboratory values at screening:
•Hemoglobin <10 g/dL
•Total bilirubin ≥2 × ULN
•Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) ≥3 × ULN
•Abnormal renal function defined as glomerular filtration rate ≤45◦mL/min/1.73◦m2 (calculated by the Counahan-Barratt equation)12
4.An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
5.Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history of a positive culture, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms:
•The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent.
•The subject has had at least 2 respiratory tract cultures negative for such organisms within the 12 months before the date of informed consent, with the first and last of these separated by at least 3 months, and the most recent one within the 6 months before the date of informed consent.
6.An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug (Day 1).
7.Ongoing or prior participation in an investigational drug study (including studies investigating ELX with or without coadministration of other study drugs) within 28 days of the Screening Visit.
•A washout period of 5 terminal half lives of the previous investigational study drug, or 28 days, whichever is longer, must elapse before the Screening Visit.
•The duration of the elapsed time may be longer if required by local regulations.
8.Use of restricted medication within specified duration before the first dose of study drug as defined in Protocol Table 9 2.
9.Pregnant and breast-feeding females. All female subjects regardless of childbearing potential status (Protocol Section 11.5.6) must have a negative pregnancy test at the Screening Visit and the Day 1 Visit.
10.The subject or a close relative of the subject is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 24 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline at each post-baseline visit. |
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| E.5.2 | Secondary end point(s) |
•Absolute change in sweat chloride (SwCl) from baseline through Week 24
•Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12 lead electrocardiograms (ECGs), vital signs, and pulse oximetry
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From Baseline at each post-baseline visit. |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Denmark |
| France |
| Germany |
| Israel |
| Netherlands |
| Spain |
| Switzerland |
| 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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| Last scheduled visit (or scheduled contact) of the last subject. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 | 1 |
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