| 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 and 2: To evaluate the safety and tolerability of VX-659 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA)
Part 3 (optional): To evaluate the safety and tolerability of VX-659 in TC with TEZ and VX-561 (also known as CTP-656, deuterated IVA)
All parts: To evaluate the efficacy of VX-659 in TC with TEZ and either IVA or VX-561 |
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| E.2.2 | Secondary objectives of the trial |
Parts 1 and 2: To evaluate the pharmacodynamic (PD) effects of VX-659 in TC with TEZ and IVA on CFTR function
Part 3 (optional): To evaluate the PD effects of VX-659 in TC with TEZ and VX-561 on CFTR function
All parts:
• To evaluate the pharmacokinetics (PK) of VX-659 when administered in TC with TEZ and either IVA or VX-561
• To evaluate the PK of TEZ, IVA, VX-561 and their respective metabolites when administered with VX-659 (as applicable) |
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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 will be aged 18 years or older on the date of informed consent.
4. Body weight ≥35 kg.
5. 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, after approval by the medical monitor.
-Parts 1 and 3: 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. If the sweat chloride value cannot be determined from the screening test for a reason other than insufficient sweat volume (i.e., because of laboratory error, damaged specimen, or equipment malfunction), it is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator.
-Part 2: For subjects with a sweat chloride value ≥60 mmol/L at screening or documented in the form of a laboratory report in the subject’s medical record, medical monitor approval is not required. For subjects with a sweat chloride value <60 mmol/L at screening and no documented historical value ≥60 mmol/L, medical monitor approval is required based on documented evidence of chronic sinopulmonary disease manifested by at least 1 of the following:
o Persistent colonization/infection with typical CF pathogens, including but not limited to, Staphylococcus aureus, Haemophilus influenzae, and/or Pseudomonas aeruginosa
o Chronic cough and sputum production
o Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation)
o Nasal polyps, chronic sinusitis, or radiographic or computed tomographic abnormalities of the paranasal sinuses
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype laboratory report may be used as a source document to establish eligibility and avert the risk of screening period expiration. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study.
-Part 1 and Part 3: Heterozygous for F508del with a second CFTR allele carrying an MF mutation that are not expected to respond to TEZ, IVA, or TEZ/IVA (Appendix A)
-Part 2: Homozygous for F508del
7. FEV1 value ≥40% and ≤90% of predicted mean 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 treatment 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, 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, 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. Current or past history of peptic ulcer disease.
5. History of hemolysis.
6. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, defined as G6PD activity less than the lower limit of normal (LLN) or 70% of the mean of the LLN and the upper limit of normal (ULN), whichever is greater.
7. Any of the following abnormal laboratory values at screening:
-Hemoglobin <10 g/dL
-Total bilirubin ≥2 × ULN
-Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase, or alkaline phosphatase ≥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)
8. 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 study drug.
9. 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 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 12 months before the screening visit, with no subsequent positive cultures.
-These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was obtained within 6 months before the screening visit.
10. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug.
11. A standard digital ECG demonstrating QTc >450 msec at screening. If QTc exceeds 450 msec for the screening ECG, the ECG should be repeated 2 more times during the Screening Period, and the subject will be excluded if the average of the 3 QTc values is >450 msec. Study sites should use QTcF unless they receive approval in advance from the medical monitor to use QTcB
12. History of solid organ or hematological transplantation.
13. History of alcohol or drug of 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 a study of an investigational treatment other than a 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.
15. Use of prohibited medications as defined in Table 9-3, within the specified window before the first dose of study drug.
16. Pregnant or nursing females. Females of childbearing potential must have a negative pregnancy test at screening and the Day 1 Visit (Part 1 and Part 3) or Day -28 Visit (Part 2).
17. 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 (aged 18 years or older) 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 ECGs, vital signs, and pulse oximetry
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through the Day 29 Visit
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Screening Visit, Treatment Period, ETT Visit, Safety Follow-up
2. from baseline through the Day 29 Visit |
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| E.5.2 | Secondary end point(s) |
•Absolute change in sweat chloride concentrations from baseline through the Day 29 Visit
•Relative change in ppFEV1 from baseline through the Day 29 Visit
•Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ R) respiratory domain score from baseline at the Day 29 Visit
•PK parameters of VX 659, TEZ, M1 TEZ, IVA, M1 IVA , and VX-561 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. from baseline through the Day 29 Visit
2. from baseline through the Day 29 Visit
3. from baseline at the Day 29 Visit
4. Treatment Period, ETT Visit |
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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 | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Ireland |
| Israel |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 9 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 9 |
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