fibrocystic disease of the pancreas / monogenic disease
Conditions
Interventions
Sponsors
Vertex Pharmaceuticals
Eligibility
Age
12 Years to 64 Years
Inclusion criteria
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
Exclusion criteria
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 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 (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 lower limit of normal (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 aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), or alkaline phosphatase (ALP) >=3 × ULN • Abnormal renal function defined as glomerular filtration rate =18 years of age and 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. 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. If there is documentation of an examination meeting protocol criteria that was conducted within 3 months before the date of informed consent (or assent, when applicable), then the ophthalmologic examination does not need to be repeated during the Screening Period. This criterion does not apply to subjects with documentation of bilateral lens removal, and the ophthalmologic examination is not required
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Endpoints • 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) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints • Absolute change in sweat chloride concentrations from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4) • Relative change in ppFEV1 from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4) • Number of pulmonary exacerbations through Week 12 (Part 4) • Time to first pulmonary exacerbation through Week 12 (Part 4) • Absolute change in body mass index (BMI) from baseline at Week 12 (Part 4) • Absolute change in BMI z score from baseline at Week 12 (Part 4) • Absolute change in weight from baseline at Week 12 (Part 4) • 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) • PK parameters of VX 440, TEZ, M1 TEZ, IVA, and M1 IVA Other Endpoints • Absolute change in CFQ R non-respiratory domain scores from baseline at Day 29 (Parts 1 and 2) and at Week 12 (Part 4) • Absolute change in inflammatory mediators from baseline at Week 12 (Part 4) | — |
Countries
The Netherlands
Outcome results
None listed