fibrocystic disease of the pancreas / monogeic disease
Conditions
Interventions
Sponsors
Vertex Pharmaceuticals
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Parts D and E;1. Subject will sign and date an 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, in addition to having a sweat chloride value >=60 mmol/L documented at screening or in a previous laboratory report. 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. For the laboratory report requirement, it is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator, if applicable. 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 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 9.9). • Part D and F: Heterozygous for F508del with a second CFTR allele carrying a MF mutation that is not expected to respond to TEZ, IVA, and TEZ/IVA (Appendix A) • Part E: Homozygous for F508del 7. Subjects must have an FEV1 >=40% and
Exclusion criteria
Exclusion criteria: Parts D and E 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. History of hemolysis. 5. G6PD deficiency, defined as G6PD activity less than the LLN or 70% of the mean of the LLN and the ULN, whichever is greater. 6. Any of the following abnormal laboratory values at screening: • Hemoglobin =2 × ULN • Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), or alkaline phosphatase (ALP) >=3 × ULN • Abnormal renal function defined as glomerular filtration rate 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. As stated in Section 11.7.5.1, study sites should use QTcF unless they receive approval in advance from the medical monitor to use QTcB. 11. History of solid organ or hematological transplantation. 12. History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator. 13. 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. 14. Use of prohibited medications as defined in Table 9-4, within the specified window before the first dose of study drug. 15. For female subjects: Pregnant or nursing females. Females of childbearing potential must have a negative pregnancy t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Parts D and E: • Safety and tolerability assessments of AEs, clinical laboratory values, standard 12-lead ECGs, vital signs, pulse oximetry and spirometry • Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Day 29 Part F (optional) * To evaluate the safety and tolerability of VX-445 in TC with TEZ and VX-561 (deuterated IVA, also known as CTP-656) in subjects with CF * To evaluate the efficacy of VX-445 in TC with TEZ and VX-561 in subjects with CF | — |
Secondary
| Measure | Time frame |
|---|---|
| Parts D and E • Absolute change in sweat chloride concentrations from baseline through Day 29 • Relative change in ppFEV1 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-445, TEZ, M1-TEZ, IVA, and M1-IVA Part F (Optional): * To evaluate the PD effect of VX-445 in TC with TEZ and VX-561 on CFTR function in subjects with CF * To evaluate the PK of VX-445 when administered in TC with TEZ and VX-561 in subjects with CF * To evaluate the PK of TEZ and metabolite (M1-TEZ), and VX-561 when administered in TC with VX-445 in subjects with CF | — |
Countries
Austria, Belgium, Czechia, Denmark, France, Germany, Ireland, Italy, Netherlands, Slovakia, Spain, Sweden, United Kingdom
Outcome results
None listed