| 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 |
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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-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA) in cystic fibrosis (CF) subjects who are heterozygous for F508del and a minimal function mutation (F/MF subjects)
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety of VX-121/TEZ/D-IVA
To evaluate the pharmacokinetics (PK) of VX-121/TEZ/D-IVA
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject will sign and date an informed consent form, 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. Subjects aged 12 years or older, on the date of informed consent
4. Confirmed diagnosis of CF as determined by the investigator
5. Heterozygous for F508del and an MF mutation, defined as a mutation that either results in no translated CFTR protein or that is non-responsive to TEZ, IVA, or TEZ/IVA based on in vitro testing.
6. For subjects currently receiving ELX/TEZ/IVA, FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height at the Screening Visit. All subjects not currently receiving ELX/TEZ/IVA must have an FEV1 value ≥40% and ≤80% of predicted mean.
7. Stable CF disease as judged by the investigator.
8. Willing to remain on a stable CF treatment regimen through completion of study participation.
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| E.4 | Principal exclusion criteria |
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(s) to the subject.
2. History of intolerance to study drug that would pose an additional risk to the subject in the opinion of the investigator.
3. Any of the following abnormal laboratory values at screening:
• Hemoglobin <10 g/dL
• Total bilirubin ≥2 × upper limit of normal
• Aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, or alkaline phosphatase ≥3 × ULN
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 for subjects ≥18 years of age and ≤45 mL/min/1.73 m2 for subjects aged 12 to 17 years.
4. An acute upper or lower respiratory infection, PEx, or changes in therapy for sinopulmonary disease within 28 days before the first dose of ELX/TEZ/IVA in the Run-in Period.
5. Lung infection with organisms associated with a more rapid decline in pulmonary status. 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 within 14 days before the first dose of ELX/TEZ/IVA in the Run-in Period.
7. 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 before screening, or participation in an interventional study of a non-investigational treatment from screening through end of study participation. The duration of the elapsed time may be longer if required by local regulations.
8. Use of prohibited medications as defined in Table 9 2, within the specified window before the first dose of ELX/TEZ/IVA in the Run-in Period.
9. Pregnant or breast-feeding females. Female subjects must have a negative pregnancy test at screening and Run-in Period/Day -28.
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. However, an adult 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 from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) through Week 24
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline through 24 weeks |
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| E.5.2 | Secondary end point(s) |
• Absolute change from baseline in sweat chloride (SwCl) through Week 24
• Proportion of subjects with SwCl <60 mmol/L through Week 24 (pooled with data from Study VX20-121-103)
• Proportion of subjects with SwCl <30 mmol/L through Week 24 (pooled with data from Study VX20-121-103)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline through 24 weeks |
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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 | 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 | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| New Zealand |
| Australia |
| Israel |
| United Kingdom |
| United States |
| Czechia |
| Germany |
| Hungary |
| Ireland |
| Portugal |
| Spain |
| Sweden |
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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 | 7 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 23 |
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