| 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 long-term safety and tolerability of TEZ/IVA in subjects with CF aged 6 years and older, who are homozygous or heterozygous for F508del in Part A |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the long-term efficacy of TEZ/IVA in subjects with CF aged 6 years and older, who are homozygous or heterozygous for F508del in Part A
To evaluate the long-term safety and tolerability of TEZ/IVA in subjects with CF aged 6 years and older, homozygous or heterozygous for the F508del mutation in Part B |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A
1. Subject’s legally appointed and authorized representative will sign and date an informed consent form (ICF) and the subject will sign 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. Completed the Week 24 Visit in Study 113B or the Week 8 Visit in Study 115.
4. Did not withdraw consent from the parent study.
5. Subjects must have a genotype listed in Appendix 1: CFTR Mutations. Note: Additional mutations may be evaluated and updates to the list of eligible mutations will be communicated to investigative sites through a memorandum. If TEZ/IVA receives marketing authorization for additional mutations in any country/region for patients ≥12 years old, a memorandum will be sent to investigative sites in that country/region and the newly approved mutations will also be eligible.
6. Willing to remain on a stable CF medication regimen through the Safety Follow-up Visit.
Part B
1. Subject’s legally appointed and authorized representative will sign and date an informed consent form (ICF) and the subject will sign 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. Completed the Week 96 Visit in Part A.
4. Did not withdraw consent from Part A.
5. Willing to remain on a stable CF medication regimen through the Safety Follow up Visit.
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| E.4 | Principal exclusion criteria |
Part A
1. History of any comorbidity 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 Torsade 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, and intracranial trauma], and autonomic neuropathy).
2. Pregnant and nursing females. Females who have achieved menarche must have a negative pregnancy test at the Day 1 Visit before receiving the first dose of study drug.
3. Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements outlined.
4. History of drug intolerance in the parent study that would pose an additional risk to the subject in the opinion of the investigator, and which should be discussed with the Vertex medical monitor. Examples of subjects who may not be eligible for the study include (but are not limited to) the following:
- Subjects with a history of allergy or hypersensitivity to the study drug
- LFT abnormality during study drug treatment in the parent study or other qualified Vertex study that required permanent study drug discontinuation
- Other severe or life-threatening reactions to the study drug in the previous study
5. History of poor compliance with study drug and/or procedures in a previous study as deemed by the investigator.
6. Ongoing participation in another study with investigational drug. Ongoing participation in a non-interventional study (including observational studies) is permitted. During the Part A Treatment Period, subjects may screen for another Vertex-sponsored study of CFTR modulators, excluding studies of IVA monotherapy and lumacaftor in combination with IVA. If a subject chooses to enroll in the other Vertex-sponsored study, they will be terminated from Study 116 and will not be allowed to re-enroll in Study 116 Part A.
Part B
1. History of any comorbidity 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 Torsade de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left ventricular hypertrophy, bradycardia, cardiomyopathy, history of arrhythmia [ventricular and atrial fibrillation], obesity, acute neurologic events [subarachnoid hemorrhage, intracranial hemorrhage, and intracranial trauma], and autonomic neuropathy).
2. Pregnant and nursing females. All female subjects must have a negative pregnancy test at the Day 1 Visit of Part B before receiving the first dose of study drug (Section 11.4.2.
3. Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements outlined in Section 11.4.8.
4. History of drug intolerance in the parent study or Part A that would pose an additional risk to the subject in the opinion of the investigator, and which should be discussed with the Vertex medical monitor. Examples of subjects who may not be eligible for the study include (but are not limited to) the following:
• Subjects with a history of allergy or hypersensitivity to the study drug
• LFT abnormality during study drug treatment in the parent study or Part A that required permanent study drug discontinuation
• Other severe or life-threatening reactions to the study drug in the parent study or Part A
5. History of poor compliance with study drug and/or procedures in a previous study, the parent study, or Part A, as deemed by the investigator.
6. Ongoing participation in another study with investigational drug. Ongoing participation in a non-interventional study (including observational studies) is permitted. During the Part B Treatment Period, subjects may screen for another Vertex-sponsored study of CFTR modulators, excluding studies of IVA monotherapy and lumacaftor in combination with IVA. If a subject chooses to enroll in the other Vertex-sponsored study, they will be terminated from Study 116 and will not be allowed to re-enroll in Study 116 Part B.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Part A: Safety and tolerability of long-term TEZ/IVA treatment based on adverse events (AEs), clinical laboratory values (serum chemistry, hematology, lipids, and vitamins), standard 12-lead ECGs, physical examinations (PEs), vital signs, ophthalmologic examinations, and pulse oximetry. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline through week 96 |
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| E.5.2 | Secondary end point(s) |
Part A
- Absolute change from baseline in lung clearance index2.5 (LCI2.5; for subjects from Study 115 and the Study 113 Part B LCI Substudy only)
- Absolute change from baseline in sweat chloride
- Absolute change from baseline in Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain score
- Absolute change from baseline in body mass index (BMI)
Part B
Safety and tolerability of long-term TEZ/IVA treatment based on AEs, serum liver function tests (LFTs), and ophthalmologic examinations. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From Baseline through week 96 |
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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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| Germany |
| Ireland |
| Poland |
| Switzerland |
| United Kingdom |
| United States |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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