| 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 | 19.1 |
| 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 safety and tolerability of VX-440 in dual and triple combination with tezacaftor (TEZ) and ivacaftor (IVA)
• To evaluate the efficacy of VX-440 in dual and triple combination with TEZ and IVA |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the pharmacodynamic (PD) effect of VX-440 in dual and triple combination with TEZ and IVA on sweat chloride concentrations
• To evaluate the pharmacokinetics (PK) of VX-440 when administered in dual and triple combination with TEZ and IVA
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered with VX-440 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject (or subject’s 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. Subjects will be aged 18 years or older for Parts 1 and 2, and aged 12 years or older for Part 4, on the date of informed consent and, when appropriate, date of assent.
4. Body weight ≥35 kg.
5. Sweat chloride value ≥60 mmol/L from test results obtained during screening. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s medical record may be used to establish eligibility. (It is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator).
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before randomization (Parts 1 and 4) or before Day -28 (Part 2), a previous CFTR genotype laboratory report may be used to establish eligibility. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.5).
-Part 1 and Part 4: Heterozygous for F508del with a second CFTR allele carrying an MF mutation that is not likely to respond to TEZ and/or IVA therapy (Appendix A)
-Part 2: Homozygous for F508del
7. Parts 1, 2, and 4 subjects must have an 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.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow-up Visit. |
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| E.4 | Principal exclusion criteria |
1. History of any comorbidity that might confound the results of the study or pose an additional risk in administering study drug to the subject.
2. History of cirrhosis with portal hypertension.
3. Risk factors for Torsade de Pointes, 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 , obesity, acute neurologic events (subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or autonomic neuropathy.
4. History of hemolysis.
5. G6PD deficiency, defined as G6PD activity less than the lower limit of normal (LLN) or 70% of the mean of the LLN and the ULN.
6. Any of the following abnormal laboratory values at screening:
-Hemoglobin <10 g/dL
-Total bilirubin ≥2 × ULN
-Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), or alkaline phosphatase (ALP) ≥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
7. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before the first dose of study drug (Day 1 for Parts 1 and 4, Day -28 for Part 2).
8. Lung infection with organisms associated with a more rapid decline in pulmonary status. For subjects who have had a history of a positive culture in the past, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms:
-The subject has had 2 respiratory tract cultures negative for these organisms within the past 12 months, with no subsequent positive cultures.
-These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was obtained within the past 6 months.
9. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug (Day 1 for Parts 1 and 4, Day -28 for Part 2).
10. A standard digital ECG demonstrating QTc >450 msec at screening.
11. History of solid organ or hematological transplantation.
12. History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period.
13. History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
14. Ongoing or prior participation in an investigational drug study with the exception of the following:
-Ongoing or prior participation in an investigational study of TEZ/IVA, IVA, LUM/IVA, or other CFTR modulator. For Parts 1 and 4, a washout period of 28 days must elapse before Day 1. Subjects participating in Study 661-110 may have the Part 1 or Part 4 Screening Period extended by 4 weeks (Section 8.1.1.3). For Part 2, a washout period before Day -28 is not required, and subjects participating in Study 661-110 will transition directly from their prior treatment to the TEZ/IVA Run-in Period providing that they meet eligibility criteria. For all parts, subjects participating in Study 661-110 may have their screening assessments performed while continuing to participate in Study 661-110.
-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.
15. Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days before screening (Parts 1 and 4 only).
16. Use of restricted medications as defined in Table 9-1, within the specified window before the first dose of study drug (Day 1 in Parts 1 and 4, Day -28 in Part 2).
17. Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.
18. 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. An adult who is a relative of a study staff member may be randomized 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) |
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Through Day 29 (Parts 1 and 2) and through Week 12 (Part 4) |
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| E.5.2 | Secondary end point(s) |
1. Absolute change in sweat chloride concentrations from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
2. Relative change in ppFEV1 from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
3. Number of pulmonary exacerbations through Week 12 (Part 4)
4. Time-to-first pulmonary exacerbation through Week 12 (Part 4)
5. Absolute change in body mass index (BMI) from baseline at Week 12 (Part 4)
6. Absolute change in BMI z-score from baseline at Week 12 (Part 4)
7. Absolute change in weight from baseline at Week 12 (Part 4)
8. Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
9. PK parameters of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
2. through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
3. through Week 12 (Part 4)
4. through Week 12 (Part 4)
5.Week 12 (Part 4)
6. Week 12 (Part 4)
7. Week 12 (Part 4)
8. at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
9. Day 1, 8, 15, 29, 43 and ETT vist (part 1 Cohort A); Day 1, 15, 29, 43 , ETT visit (Part 1 Cohort B); Day1, 15, 29, 43, ETT vist (Part 2); Day 1, 15, Week 4, Week 8, Week 12, ETT visit (part 4) |
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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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 5 |
| 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 | 21 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Denmark |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 23 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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