| 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 |
Parts 1 (Subjects with F/MF genotypes) and 2 (Optional; Subjects with the F/F genotype)
• To evaluate the safety and tolerability of VX-121 in triple combination (TC) with tezacaftor (TEZ)/VX-561 (deuterated ivacaftor [IVA])
• To evaluate the efficacy of VX-121 in TC with TEZ/VX-561
Part 3 (Optional; Subjects with the F/MF genotype)
• To evaluate the safety and tolerability of VX-121 in TC with TEZ/IVA
• To evaluate the efficacy of VX-121 in TC with TEZ/IVA |
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| E.2.2 | Secondary objectives of the trial |
Parts 1 and 2
• To evaluate the pharmacodynamic (PD) effect of VX-121 in TC with TEZ/VX-561
• To evaluate the pharmacokinetics (PK) of VX-121 when administered in TC with TEZ/VX-561
• To evaluate the PK of TEZ, VX-561, and their respective metabolites when administered in TC with VX-121
Part 3
• To evaluate the PD effect of VX-121 in TC with TEZ/IVA
• To evaluate the PK of VX-121 when administered in TC with TEZ/IVA
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered in TC with VX-121 |
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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 (ICF).
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) aged 18 years or older on the date of informed consent.
4. Female subjects must have a negative serum pregnancy test at the Screening Visit.
5. Body weight ≥35 kg.
6. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening. If the initial screening collection results in insufficient sweat volume, then the sweat chloride collection may be repeated once.
Subjects must have a sweat chloride value ≥60 mmol/L at screening or documented in the form of a laboratory report in the subject’s medical record.
7. Confirmed diagnosis of CF as determined by the investigator.
8. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before the Run-in Period (Part 2) or randomization (Parts 1 and 3), a previous CFTR genotype laboratory report may be used to establisheligibility. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study
• Parts 1 and 3: Heterozygous for F508del with a second CFTR allele carrying a mutation that does not produce a protein, or produces a protein that is not responsive to TEZ, IVA, or TEZ/IVA therapy
• Part 2: Homozygous for F508del
9. Subjects must have a forced expiratory volume in 1 second (FEV1) ≥40% and ≤90% of predicted normal for age, sex, 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.
10. Stable CF disease as judged by the investigator.
11. Willing to remain on a stable CF treatment regimen (other than protocol-specified changes in CFTR modulator regimen) through the Safety Follow-up Visit. |
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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 to the subject.
2. History of clinically significant cirrhosis with or without portal hypertension.
3. Risk factors for Torsade de Pointes and other ventricular arrhythmias, including but not limited to, history of any of the following: familial long QT syndrome, chronic hypokalemia, heart failure, left ventricular hypertrophy, chronic bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia (ventricular or atrial fibrillation), obesity, acute neurologic events (subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or autonomic neuropathy.
4. 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), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) ≥3 × ULN
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease Study Equation)10,11 for subjects ≥18 years of age
5. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).
6. Lung infection with organisms associated with a more rapid decline in pulmonary status (e.g., 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 1 within the 6 months before the date of informed consent.
7. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).
8. Standard 12-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 450 msec, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine the subject’s eligibility.
9. History of solid organ or hematological transplantation.
10. History of alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
11. Ongoing or prior participation in a study of an investigational treatment with the exception of the following:
• Ongoing or prior participation in an investigational study of a Vertex CFTR modulator. A washout period of 28 days must elapse before Day 1.
• For prospective subjects with ongoing or prior participation in all other interventional studies, a washout period of 28 days or 5 terminal half-lives (whichever is longer) must elapse before screening. The duration of the elapsed time may be longer if required by local regulations.
• Ongoing participation in a noninterventional study (including observational studies and studies requiring assessments without administration of study drug or assignment to other interventions) is permitted.
12. Use of prohibited medications (as defined in Table 9-1 in the Protocol), within the specified window before the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).
13. Subject, or 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.
14. Pregnant or nursing female subjects. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety and tolerability, based on the assessment of adverse events (AEs), laboratory test results, standard 12-lead ECGs, vital signs, and spirometry
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Day 29 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Absolute change in sweat chloride concentrations from baseline through Day 29
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline at Day 29
• PK parameters of VX-121, TEZ, VX-561, IVA (Part 3), and relevant metabolites |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 8 |
| 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 | 15 |
| 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 |
| Germany |
| Netherlands |
| Portugal |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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