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

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

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).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Matched Placebo; Drug: VX-445; Drug: VX-445; Drug: IVA; Drug: TEZ/IVA; Drug: TEZ; Drug: VX-561

• Study Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia
    • Mater Adult Hospital
  • Sydney, Australia
    • Royal Prince Alfred Hospital
  • Sydney, Australia
    • Westmead Hospital
  • Victoria
    • Clayton, Victoria, Australia
      • Monash Medical Center
    • Melbourne, Victoria, Australia
      • The Alfred Hospital
    • Parkville, Victoria, Australia
      • The Royal Children's Hospital Melbourne
• Belgium
  • Edegem, Belgium
    • Antwerp University Hospital
  • Gent, Belgium
    • Universitair Ziekenhuis Gent
• Netherlands
  • Amsterdam, Netherlands
    • Academic Medical Centre
  • Den Haag, Netherlands
    • HagaZiekenhuis van Den Haag
  • Nijmegen, Netherlands
    • Radboud UMC
  • Rotterdam, Netherlands
    • Erasmus Medical Center
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Banner University of Arizona Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Madera, California, United States, 93636
      • Valley Children's Healthcare
    • Oakland, California, United States, 96411
      • (Kaiser Permanente) Oakland Medical Center
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Florida
    • Orlando, Florida, United States, 32803
      • Central Florida Pulmonary Group
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital Cardiac and Lung Transplant Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30324
      • Children's Specialty Services at North Druid Hills
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Indiana
    • Evansville, Indiana, United States, 47710
      • Covance Clinical Research Unit Inc., Evansville Clinic [Parts A, B, C only]
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Harper University Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minn
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • UC Health Office of Clinical Research
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center/Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Texas
    • Austin, Texas, United States, 78723
      • Austin Children's Chest Associates
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Morgantown, Virginia, United States, 26506
      • West Virginia University Hospitals
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

15

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part A: Pooled Placebo (Except Cohort A7); Participants without CF who received single dose of placebo matched to VX-445 in Cohort A1 to A5.	Drug: Matched Placebo; Matched placebo.
Experimental: Part A: VX-445 (Except Cohort A7); 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor
Experimental: Part A: VX-445 (Cohort A7); 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor
Placebo Comparator: Part B: Pooled Placebo (Cohort B1 to B4); Participants without CF who received multiple doses of placebo matched to VX-445 once daily (qd) for 10 days in Cohort B1 to B4.	Drug: Matched Placebo; Matched placebo.
Experimental: Part B: VX-445 (Cohort B1 to B4); 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).	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor
Placebo Comparator: Part C: Pooled Placebo (Cohort C1 to C3); 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.	Drug: Matched Placebo; Matched placebo.
Experimental: Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3); 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor; Drug: IVA; IVA tablet for oral administration; Other Names: VX-770; ivacaftor; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination for oral administration.; Other Names: VX-661/VX-770; tezacaftor/ivacaftor
Placebo Comparator: Part D: 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.	Drug: Matched Placebo; Matched placebo.
Experimental: Part D: VX-445/TEZ/IVA TC - Low Dose; 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor; Drug: IVA; IVA tablet for oral administration; Other Names: VX-770; ivacaftor; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination for oral administration.; Other Names: VX-661/VX-770; tezacaftor/ivacaftor
Experimental: Part D: VX-445/TEZ/IVA TC - Medium Dose; 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor; Drug: IVA; IVA tablet for oral administration; Other Names: VX-770; ivacaftor; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination for oral administration.; Other Names: VX-661/VX-770; tezacaftor/ivacaftor
Experimental: Part D: VX-445/TEZ/IVA TC - High Dose; 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor; Drug: IVA; IVA tablet for oral administration; Other Names: VX-770; ivacaftor; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination for oral administration.; Other Names: VX-661/VX-770; tezacaftor/ivacaftor
Active Comparator: Part E: 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.	Drug: TEZ/IVA; TEZ/IVA fixed-dose combination for oral administration.; Other Names: VX-661/VX-770; tezacaftor/ivacaftor
Experimental: Part E: VX-445/TEZ/IVA TC; 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor; Drug: IVA; IVA tablet for oral administration; Other Names: VX-770; ivacaftor; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination for oral administration.; Other Names: VX-661/VX-770; tezacaftor/ivacaftor
Placebo Comparator: Part F: 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.	Drug: Matched Placebo; Matched placebo.
Experimental: Part F: VX-445/TEZ/VX-561 TC; 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.	Drug: VX-445; VX-445 tablet for oral administration.; Other Names: ELX; elexacaftor; Drug: VX-445; VX-445 IV injection; Other Names: ELX; elexacaftor; Drug: TEZ; Tablet for oral administration.; Other Names: VX-661; tezacaftor; Drug: VX-561; Tablet for oral administration.; Other Names: CTP-656

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Sweat samples were collected using an approved collection device.	From Baseline through Day 29
Part E: Absolute Change in Sweat Chloride Concentration	Sweat samples were collected using an approved collection device.	From Baseline through Day 29
Part F: Absolute Change in Sweat Chloride Concentration	Sweat samples were collected using an approved collection device.	From Baseline through Day 29
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated

Publications and helpful links

General Publications

• 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:CD010966. doi: 10.1002/14651858.CD010966.pub3.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2017
• Primary Completion (Actual): March 27, 2018
• Study Completion (Actual): March 27, 2018

Study Registration Dates

• First Submitted: July 18, 2017
• First Submitted That Met QC Criteria: July 21, 2017
• First Posted (Actual): July 24, 2017

Study Record Updates

• Last Update Posted (Actual): January 18, 2022
• Last Update Submitted That Met QC Criteria: December 16, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor; Elexacaftor
• Other Study ID Numbers: VX16-445-001; 2017-000797-11 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No