| 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 VX-445/tezacaftor (TEZ)/ivacaftor (IVA) in CF subjects who are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes) |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of VX-445/TEZ/IVA
- To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject (or his or her legally appointed and authorized representative) will sign and date an informed consent form (ICF), and, when appropriate, 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. Age 12 years or older, at the date of informed consent.
4. Confirmed diagnosis of CF as determined by the investigator.
5. Subject is heterozygous for F508del and either a gating or residual function mutation (F/G and F/RF genotypes) and is in a region where their genotype and age group are approved indications for treatment with IVA and/or TEZ/IVA (see Appendix A for qualifying mutations).
6. Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for age, sex, race, and height (equations of the Global Lung Function Initiative [GLI]) at the Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria for acceptability and repeatability.
7. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF treatment regimen through completion of study participation. |
|
| 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 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 (each being disease-free for the last 5 years).
2. Any of the following abnormal laboratory values at screening.
- Hemoglobin <10 g/dL
- Total bilirubin ≥2 × upper limit of normal (ULN)
- Aspartate transaminase (AST), alanine transaminase (ALT), or gamma-glutamyl transferase (GGT) ≥3 × ULN
- Abnormal renal function defined as estimated glomerular filtration rate ≤50 mL/min/1.73 m^2 (calculated by the Modification of Diet in Renal Disease Study Equation) for subjects ≥18 years of age, or ≤45 mL/min/1.73 m^2 (calculated by the Counahan-Barratt equation) for subjects 12 to 17 years of age (inclusive)
3. An acute upper or lower respiratory infection, pulmonary exacerbation (PEx), or change in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of study drug in the Run-in Period (Day -28).
4. Lung infection with a microbial pathogen that is 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 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.
5. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug in the Run-in Period (Day -28).
6. Ongoing or prior participation in a study of an investigational treatment other than a Vertex CFTR modulator within 28 days or 5 terminal half-lives (whichever is longer) before screening. The duration of the elapsed time may be longer if required by local regulations.
7. Use of prohibited medications as defined in the protocol within the specified window before the first dose of study drug in the Run-in Period (Day -28).
8. Pregnant or breast-feeding females. All female subjects, regardless of childbearing potential status, must have negative pregnancy tests at the Screening Visit (Day -56) and at the Day -28 Visit, before the first dose of study drug in the Run-in Period.
9. 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. However, an adult (aged 18 years or older) who is a relative of a study staff member may be enrolled in the study provided that
- the adult lives independently of and does not reside with the study staff member, and
- the adult participates in the study at a site other than the site at which the family member is employed. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Week 8 for the VX-445/TEZ/IVA group |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8; Early Treatment Termination (ETT) visit (if applicable) |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints
- Absolute change in sweat chloride (SwCl) from baseline through Week 8 for the VX-455/TEZ/IVA group
- Absolute change in ppFEV1 from baseline through Week 8 for the VX-455/TEZ/IVA group compared to the control group
- Absolute change in SwCl from baseline through Week 8 for the VX-455/TEZ/IVA group compared to the control group
Other Secondary Endpoints
- Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain (RD) score from baseline through Week 8 for the VX-455/TEZ/IVA group
- Absolute change in CFQ-R RD score from baseline through Week 8 for the VX-455/TEZ/IVA group compared to the control group
- Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse oximetry |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key Secondary Endpoints:
- SwCl: Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable)
- ppFEV1: Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable)
Other Secondary Endpoints
- CFQ-R RD score: Run-In period: Day -28; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable)
- Safety and tolerability assessments:
a. AEs: Continuous (signing of ICF until completion of study participation)
b. clinical laboratory values, ECGs, vital signs, pulse oximetry: Day -28; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable); SFU visit (if applicable) |
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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 | Yes |
| 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 | Yes |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| 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 States |
| Belgium |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Spain |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 3 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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