Clinical trial NCT03227471: A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis
Official title: A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cystic Fibrosis
Lead sponsor: Vertex Pharmaceuticals Incorporated
Sponsor class: INDUSTRY
First posted: 2017-07-24
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: Key Inclusion Criteria:

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 Exclusion Criteria:

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.

Primary outcomes:
measure: Parts A, B and C: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug in treatment period up to safety follow-up (up to 28 days)
measure: Parts D, E and F: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug in TC treatment period up to 28 days after last dose of study drug (up to 5 weeks)
measure: Part D: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
timeFrame: From Baseline through Day 29
measure: Part E: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
timeFrame: From Baseline through Day 29
measure: Part F: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
timeFrame: From Baseline through Day 29
Secondary outcomes:
measure: Part A: Maximum Observed Concentration (Cmax) of VX-445
timeFrame: Cohort A1-A5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose
measure: Part A: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445
timeFrame: Cohort A1-5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose
measure: Part B: Maximum Observed Concentration (Cmax) of VX-445
timeFrame: Pre-dose to 96 hours post-dose on Day 1 and Day 10
measure: Part B: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445
timeFrame: Pre-dose to 96 hours post-dose on Day 1 and Day 10
measure: Part B: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445
timeFrame: Pre-dose on Day 10
measure: Part C: Maximum Observed Concentration (Cmax) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ)
timeFrame: Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14
measure: 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)
timeFrame: Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14
measure: Part C: Maximum Observed Concentration (Cmax) of IVA and Its Metabolites (M1-IVA and M6-IVA)
timeFrame: Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14
measure: 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)
timeFrame: Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14
measure: Part C: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ)
timeFrame: Pre-dose on Day 7 and Day 14
measure: Part C: Observed Pre-dose Concentration (Ctrough) of IVA and Its Metabolites (M1-IVA and M6-IVA)
timeFrame: Pre-dose on Day 7 and Day 14
measure: Part D: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ), IVA and Its Metabolite (M1-IVA)
timeFrame: Pre-dose on Day 15 and Day 29
measure: Part E: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and IVA and Its Metabolite (M1-IVA)
timeFrame: Pre-dose on Day 15 and Day 29
measure: Part F: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and VX-561
timeFrame: Pre-dose on Day 15 and Day 29
measure: Part D: Absolute Change in Sweat Chloride Concentration
timeFrame: From Baseline through Day 29
measure: Part E: Absolute Change in Sweat Chloride Concentration
timeFrame: From Baseline through Day 29
measure: Part F: Absolute Change in Sweat Chloride Concentration
timeFrame: From Baseline through Day 29
measure: Part D: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
timeFrame: From Baseline through Day 29
measure: Part E: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
timeFrame: From Baseline through Day 29
measure: Part F: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
timeFrame: From Baseline through Day 29
measure: Part D: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
timeFrame: From Baseline through Day 29
measure: Part E: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
timeFrame: From Baseline through Day 29
measure: Part F: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
timeFrame: From Baseline through Day 29
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Banner University of Arizona Medical Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Madera
country: United States
facility: Valley Children's Healthcare
state: California
city: Oakland
country: United States
facility: (Kaiser Permanente) Oakland Medical Center
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Orlando
country: United States
facility: Central Florida Pulmonary Group
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital Cardiac and Lung Transplant Clinic
state: Florida
city: Atlanta
country: United States
facility: Children's Specialty Services at North Druid Hills
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Evansville
country: United States
facility: Covance Clinical Research Unit Inc., Evansville Clinic [Parts A, B, C only]
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Detroit
country: United States
facility: Harper University Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minn
state: Minnesota
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico School of Medicine
state: New Mexico
city: Cincinnati
country: United States
facility: UC Health Office of Clinical Research
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center/Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Austin
country: United States
facility: Austin Children's Chest Associates
state: Texas
city: Burlington
country: United States
facility: The University of Vermont
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University Hospitals
state: Virginia
city: Norfolk
country: United States
facility: Children's Hospital of the King's Daughters
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Clayton
country: Australia
facility: Monash Medical Center
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: The Royal Children's Hospital Melbourne
state: Victoria
city: Brisbane
country: Australia
facility: Mater Adult Hospital
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
city: Sydney
country: Australia
facility: Westmead Hospital
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre
city: Den Haag
country: Netherlands
facility: HagaZiekenhuis van den Haag
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
Study officials:
References:
citation: Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3.
citation: Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar JL; VX16-445-001 Study Group. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018 Oct 25;379(17):1612-1620. doi: 10.1056/NEJMoa1807120. Epub 2018 Oct 18.