A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis

Phase 1

• Conditions: Cystic fibrosis; MedDRA version: 19.1Level: PTClassification code 10011762Term: Cystic fibrosisSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

• Registration Number: EUCTR2016-000454-36-DE
• Lead Sponsor: Vertex Pharmaceuticals Incorporated

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-10-12
• Last Update Posted: 10 October 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 198

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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 30
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 168
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified