| 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 efficacy of tezacaftor in combination with ivacaftor (TEZ/IVA) in subjects with cystic fibrosis (CF) aged 6 through 11 years, homozygous or heterozygous for F508del |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety of TEZ/IVA in subjects with CF aged 6 through 11 years, homozygous or heterozygous for F508del |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject’s legally appointed and authorized representative will sign and date an informed consent form (ICF) and the subject will sign and date an assent form (if applicable).
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) will be between the ages of 6 and 11 years, inclusive, on the date(s) of informed consent (and assent, if applicable).
4. Subjects who weigh ≥15 kg without shoes at the Screening Visit.
5. Genotypes as presented in Appendix 1 of the Protocol. Genotype is to be confirmed during screening. If the CFTR screening genotype result is not received before enrollment, a previous CFTR genotype lab 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 as described in Section 10.7 of the Protocol. Note: Additional mutations may be evaluated and updates to approved mutations will be communicated to investigative sites through a memorandum.
6. A confirmed diagnosis of CF4 as determined by the following criteria:
a. For subjects who are F508del homozygous: confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis (as documented in the subject’s medical record OR from the sweat chloride test result obtained at the Screening Visit).
b. For subjects who are F508del heterozygous:
• Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis (as documented in the subject’s medical record [this value may be obtained from a record collected prior to use of Kalydeco] OR from the sweat chloride test result obtained at the Screening Visit); OR
• If the sweat chloride value is <60 mmol/L, there must be documented evidence of chronic sinopulmonary disease4 and/or gastrointestinal disease consistent with a diagnosis of CF as judged by the principal investigator, manifest by at least 1 of the following:
o Persistent colonization/infection, defined as ≥2 positive respiratory cultures within a 6 month period, with 1 or more typical CF pathogens (e.g., Staphylococcus aureus, Haemophilus influenzae, mucoid and nonmucoid Pseudomonas aeruginosa)
o Chronic cough and sputum production
o Persistent chest radiograph abnormalities consistent with CF pulmonary disease (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation)
o Nasal polyps, chronic sinusitis as manifest by radiographic or computed tomographic abnormalities of the paranasal sinuses
o Evidence of gastrointestinal disease consistent with the diagnosis of CF
o Significant delays in growth and/or weight gain consistent with the diagnosis of CF
9. Subjects with ppFEV1 of ≥70 percentage points adjusted for age, sex, height, and ethnicity using the Global Lung Function Initiative (GLI) equation5 at the Screening Visit (Section 11.4.2 of the Protocol).
10. Subjects with a screening LCI2.5 result ≥7.5.
11. Subjects with stable CF disease as deemed by the investigator at the Screening Visit.
12. Subjects who are willing to remain on their stable CF medication regimen through Week 8 or, if applicable, through the Safety Follow-up Visit.
13. Subjects who are able to swallow tablets.
14. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Day 1 Visit before receiving the first dose of study drug.
15. Subjects of childbearing potential who are sexually active must meet the contraception requirements outlined in Section 11.5.8.1 of the Protocol.
16. As deemed by the investigator, the subject’s legally appointed and authorized representative (e.g., parent or legal guardian) 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 comorbidity reviewed at the Screening Visit 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.
For example, history of cirrhosis with portal hypertension and/or history of risk factors for Torsades de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia [ventricular and atrial fibrillation], obesity, acute neurologic events [subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, intracranial trauma], and autonomic neuropathy).
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 the Screening Visit:
• Hemoglobin <10 g/dL
• Abnormal liver function defined as any 2 or more of the following:
o ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST)
o ≥3 × ULN alanine aminotransferase (ALT)
o ≥3 × ULN gamma-glutamyl transpeptidase (GGT)
o ≥3 × ULN alkaline phosphatase (ALP)
o ≥2 × ULN total bilirubin
• Abnormal liver function defined as any increase of ≥5 × ULN ALT or AST
• Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation)6
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. Colonization with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at the Screening Visit. The investigator could be guided by the following suggested criteria for a subject to be considered free of colonization:
• The subject should have had at least 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.
6. A standard 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. If QTc exceeds 450 msec at the Screening Visit, the ECG should be repeated 2 more times during the Screening Period, and the average of the 3 QTc values should be used to determine the subject's eligibility.
7. History of solid organ or hematological transplantation at the Screening Visit.
8. Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator that does not align with the following requirements:
• A washout period of 30 days or 5 terminal half-lives of the previous investigational study drug, whichever is longer, must elapse before screening.
o The duration of the elapsed time may be longer if required by local regulations.
• A washout period of 28 days for investigational lumacaftor/IVA, or physician-prescribed Orkambi® or Kalydeco® must elapse before the Day 1 Visit.
Note: Ongoing participation in a noninterventional study (including observational studies) is permitted.
9. Use of restricted medication or food within a specified duration before the Screening Visit or first dose of study drug and/or unwillingness to maintain the restrictions as defined in Section 9.4 of the Protocol.
10. Pregnant and nursing females.
11. 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change in lung clearance index2.5 (LCI2.5) from baseline through Week 8 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline through week 8 |
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| E.5.2 | Secondary end point(s) |
•Absolute change from baseline in sweat chloride at Week 8
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline through Week 8
• Safety and tolerability as measured by adverse events (AEs), clinically significant changes in laboratory values (serum chemistry, hematology, coagulation studies, lipids, vitamin levels, and urinalysis), standard 12-lead ECGs, vital signs, pulse oximetry, serial lung function measurement, and ophthalmologic examinations. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
From Baseline through week 8.
Safety and tolerability will be measured thorough 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 | 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Denmark |
| Germany |
| Ireland |
| Poland |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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