A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis
- Conditions
- Cystic Fibrosis
- Interventions
- Registration Number
- NCT03227471
- Lead Sponsor
- Vertex Pharmaceuticals Incorporated
- Brief Summary
This is a first-in-human and proof-of-concept study of VX-445. The study includes 6 parts. Parts A, B, and C were conducted in healthy subjects. Parts D, E, and F were conducted in subjects with Cystic Fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 225
Parts A, B, and C:
- Female subjects must be of non-childbearing potential.
- Between the ages of 18 and 55 years, inclusive.
- Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg
Parts D, E, and F:
-
Body weight ≥35 kg.
-
Subjects must have an eligible CFTR genotype:
- Parts D and F: Heterozygous for F508del and an MF mutation (F/MF)
- Part E: Homozygous for F508del (F/F)
-
FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height.
Key
Parts A, B, and C:
- Any condition possibly affecting drug absorption.
- History of febrile illness within 14 days before the first study drug dose.
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Parts D, E, and F:
- History of clinically significant cirrhosis with or without portal hypertension.
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- Lung infection with organisms associated with a more rapid decline in pulmonary status.
- History of solid organ or hematological transplantation.
Other protocol defined Inclusion/Exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part A: VX-445 (Except Cohort A7) VX-445 Participants without CF who received single ascending dose of VX-445 tablet starting from 20 milligrams (mg) to 360 mg in Cohort A1 to A5. Part D: VX-445/TEZ/IVA TC - High Dose VX-445 Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part B: VX-445 (Cohort B1 to B4) VX-445 Participants without CF who received VX-445 tablet qd for 10 days in Cohort B1 (60 mg), B2 (120 mg), B3 (240 mg) and B4 (340 mg). Part D: VX-445/TEZ/IVA TC - Low Dose VX-445 Participants with CF, F/MF genotype who received VX-445 50 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part E: VX-445/TEZ/IVA TC VX-445 Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received VX-445 200 mg qd/TEZ 100 mg qd /IVA 150 mg q12h for 4 weeks in the TC treatment period. Part C: Pooled Placebo (Cohort C1 to C3) Matched Placebo Participants without CF who received placebo matched to VX-445/TEZ/IVA triple combination (TC) qd in the morning and placebo matched to IVA in the evening for 14 days. Part A: VX-445 (Cohort A7) VX-445 Participants without CF who received single dose of VX-445 100 mg tablet on Day 1 in fasted state and on Day 7 in fed state, followed by VX-445 20 mg intravenous (IV) injection on Day 13 in fed state in Cohort A7. Part D: VX-445/TEZ/IVA TC - Low Dose IVA Participants with CF, F/MF genotype who received VX-445 50 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part D: VX-445/TEZ/IVA TC - Low Dose TEZ/IVA Participants with CF, F/MF genotype who received VX-445 50 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part E: VX-445/TEZ/IVA TC IVA Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received VX-445 200 mg qd/TEZ 100 mg qd /IVA 150 mg q12h for 4 weeks in the TC treatment period. Part A: Pooled Placebo (Except Cohort A7) Matched Placebo Participants without CF who received single dose of placebo matched to VX-445 in Cohort A1 to A5. Part B: Pooled Placebo (Cohort B1 to B4) Matched Placebo Participants without CF who received multiple doses of placebo matched to VX-445 once daily (qd) for 10 days in Cohort B1 to B4. Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3) IVA Participants without CF who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C1; VX-445 280 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C2 and VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C3 for 14 days. Part D: VX-445/TEZ/IVA TC - High Dose IVA Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3) VX-445 Participants without CF who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C1; VX-445 280 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C2 and VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C3 for 14 days. Part D: VX-445/TEZ/IVA TC - Medium Dose IVA Participants with CF, F/MF genotype who received VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part D: VX-445/TEZ/IVA TC - High Dose TEZ/IVA Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part F: VX-445/TEZ/VX-561 TC TEZ Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/VX-561 150 mg qd for 4 weeks in the TC treatment period. Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3) TEZ/IVA Participants without CF who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C1; VX-445 280 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C2 and VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C3 for 14 days. Part D: Placebo Matched Placebo Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/IVA TC qd in the morning and placebo matched to IVA qd in the evening for 4 weeks in the TC treatment period. Part D: VX-445/TEZ/IVA TC - Medium Dose TEZ/IVA Participants with CF, F/MF genotype who received VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part D: VX-445/TEZ/IVA TC - Medium Dose VX-445 Participants with CF, F/MF genotype who received VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. Part E: TEZ/IVA TEZ/IVA Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received TEZ 100 mg qd/IVA 150 mg q12h and placebo matched to VX-445 for 4 weeks in the TC treatment period. Part E: VX-445/TEZ/IVA TC TEZ/IVA Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received VX-445 200 mg qd/TEZ 100 mg qd /IVA 150 mg q12h for 4 weeks in the TC treatment period. Part F: Placebo Matched Placebo Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period. Part F: VX-445/TEZ/VX-561 TC VX-561 Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/VX-561 150 mg qd for 4 weeks in the TC treatment period. Part F: VX-445/TEZ/VX-561 TC VX-445 Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/VX-561 150 mg qd for 4 weeks in the TC treatment period.
- Primary Outcome Measures
Name Time Method Parts A, B and C: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) From first dose of study drug in treatment period up to safety follow-up (up to 28 days) Parts D, E and F: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) From first dose of study drug in TC treatment period up to 28 days after last dose of study drug (up to 5 weeks) Part D: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part E: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part F: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
- Secondary Outcome Measures
Name Time Method Part A: Maximum Observed Concentration (Cmax) of VX-445 Cohort A1-A5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose Part A: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 Cohort A1-5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose Part B: Maximum Observed Concentration (Cmax) of VX-445 Pre-dose to 96 hours post-dose on Day 1 and Day 10 Part B: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 Pre-dose to 96 hours post-dose on Day 1 and Day 10 Part B: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445 Pre-dose on Day 10 Part C: Maximum Observed Concentration (Cmax) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 Part C: Maximum Observed Concentration (Cmax) of IVA and Its Metabolites (M1-IVA and M6-IVA) Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of IVA and Its Metabolites (M1-IVA and M6-IVA) Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 Part C: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) Pre-dose on Day 7 and Day 14 Part C: Observed Pre-dose Concentration (Ctrough) of IVA and Its Metabolites (M1-IVA and M6-IVA) Pre-dose on Day 7 and Day 14 Part D: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ), IVA and Its Metabolite (M1-IVA) Pre-dose on Day 15 and Day 29 Part E: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and IVA and Its Metabolite (M1-IVA) Pre-dose on Day 15 and Day 29 Part F: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and VX-561 Pre-dose on Day 15 and Day 29 Part D: Absolute Change in Sweat Chloride Concentration From Baseline through Day 29 Sweat samples were collected using an approved collection device.
Part E: Absolute Change in Sweat Chloride Concentration From Baseline through Day 29 Sweat samples were collected using an approved collection device.
Part F: Absolute Change in Sweat Chloride Concentration From Baseline through Day 29 Sweat samples were collected using an approved collection device.
Part D: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part E: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part F: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part D: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline through Day 29 The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Part E: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline through Day 29 The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Part F: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline through Day 29 The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Related Research Topics
Explore scientific publications, clinical data analysis, treatment approaches, and expert-compiled information related to the mechanisms and outcomes of this trial. Click any topic for comprehensive research insights.
Trial Locations
- Locations (38)
Banner University of Arizona Medical Center
🇺🇸Tucson, Arizona, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
Valley Children's Healthcare
🇺🇸Madera, California, United States
(Kaiser Permanente) Oakland Medical Center
🇺🇸Oakland, California, United States
National Jewish Health
🇺🇸Denver, Colorado, United States
Central Florida Pulmonary Group
🇺🇸Orlando, Florida, United States
Tampa General Hospital Cardiac and Lung Transplant Clinic
🇺🇸Tampa, Florida, United States
Children's Specialty Services at North Druid Hills
🇺🇸Atlanta, Georgia, United States
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Covance Clinical Research Unit Inc., Evansville Clinic [Parts A, B, C only]
🇺🇸Evansville, Indiana, United States
Scroll for more (28 remaining)Banner University of Arizona Medical Center🇺🇸Tucson, Arizona, United States