A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

Cystic Fibrosis Clinical Trial

Official title:

A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03227471
• Other study ID #: VX16-445-001
• Secondary ID: 2017-000797-11
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 23, 2017
• Est. completion date: March 27, 2018

Study information

• Verified date: December 2021
• Source: Vertex Pharmaceuticals Incorporated
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 225
• Est. completion date: March 27, 2018
• Est. primary completion date: March 27, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• IVA
IVA tablet for oral administration
• TEZ/IVA
TEZ/IVA fixed-dose combination for oral administration.
• VX-445
VX-445 tablet for oral administration.
• Matched Placebo
Matched placebo.
• TEZ
Tablet for oral administration.
• VX-561
Tablet for oral administration.
• VX-445
VX-445 IV injection

Locations

Country	Name	City	State
Australia	Mater Adult Hospital	Brisbane
Australia	Monash Medical Center	Clayton	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	The Royal Children's Hospital Melbourne	Parkville	Victoria
Australia	Royal Prince Alfred Hospital	Sydney
Australia	Westmead Hospital	Sydney
Belgium	Antwerp University Hospital	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent
Netherlands	Academic Medical Centre	Amsterdam
Netherlands	HagaZiekenhuis van den Haag	Den Haag
Netherlands	Radboud UMC	Nijmegen
Netherlands	Erasmus Medical Center	Rotterdam
United States	University of New Mexico School of Medicine	Albuquerque	New Mexico
United States	Children's Specialty Services at North Druid Hills	Atlanta	Georgia
United States	Austin Children's Chest Associates	Austin	Texas
United States	The University of Vermont	Burlington	Vermont
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	UC Health Office of Clinical Research	Cincinnati	Ohio
United States	University Hospitals Cleveland Medical Center/Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	National Jewish Health	Denver	Colorado
United States	Harper University Hospital	Detroit	Michigan
United States	Covance Clinical Research Unit Inc., Evansville Clinic [Parts A, B, C only]	Evansville	Indiana
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Valley Children's Healthcare	Madera	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minn	Minneapolis	Minnesota
United States	West Virginia University Hospitals	Morgantown	Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	Tulane Medical Center	New Orleans	Louisiana
United States	Children's Hospital of the King's Daughters	Norfolk	Virginia
United States	(Kaiser Permanente) Oakland Medical Center	Oakland	California
United States	Central Florida Pulmonary Group	Orlando	Florida
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Tampa General Hospital Cardiac and Lung Transplant Clinic	Tampa	Florida
United States	Banner University of Arizona Medical Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Vertex Pharmaceuticals Incorporated

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	Part D: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
Primary	Part E: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
Primary	Part F: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
Secondary	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
Secondary	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
Secondary	Part B: Maximum Observed Concentration (Cmax) of VX-445		Pre-dose to 96 hours post-dose on Day 1 and Day 10
Secondary	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
Secondary	Part B: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445		Pre-dose on Day 10
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part D: Absolute Change in Sweat Chloride Concentration	Sweat samples were collected using an approved collection device.	From Baseline through Day 29
Secondary	Part E: Absolute Change in Sweat Chloride Concentration	Sweat samples were collected using an approved collection device.	From Baseline through Day 29
Secondary	Part F: Absolute Change in Sweat Chloride Concentration	Sweat samples were collected using an approved collection device.	From Baseline through Day 29
Secondary	Part D: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
Secondary	Part E: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
Secondary	Part F: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
Secondary	Part D: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score	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.	From Baseline through Day 29
Secondary	Part E: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score	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.	From Baseline through Day 29
Secondary	Part F: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score	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.	From Baseline through Day 29