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

NCT03227471 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: VX16-445-0012017-000797-11
• Study Type: interventional
• Target: 225
• Locations: 4 countries
• Sites: 38

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).

Conditions

Cystic Fibrosis

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (23)

• 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

Study Arms (15)

Part A: Pooled Placebo (Except Cohort A7)

PLACEBO COMPARATOR

Participants without CF who received single dose of placebo matched to VX-445 in Cohort A1 to A5.

Drug: Matched Placebo

Part A: VX-445 (Except Cohort A7)

EXPERIMENTAL

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

Part A: VX-445 (Cohort A7)

EXPERIMENTAL

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

Part B: Pooled Placebo (Cohort B1 to B4)

PLACEBO COMPARATOR

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

Part B: VX-445 (Cohort B1 to B4)

EXPERIMENTAL

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

Part C: Pooled Placebo (Cohort C1 to C3)

PLACEBO COMPARATOR

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

Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)

EXPERIMENTAL

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: IVA; Drug: TEZ/IVA; Drug: VX-445

Part D: Placebo

PLACEBO COMPARATOR

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

Part D: VX-445/TEZ/IVA TC - Low Dose

EXPERIMENTAL

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: IVA; Drug: TEZ/IVA; Drug: VX-445

Part D: VX-445/TEZ/IVA TC - Medium Dose

EXPERIMENTAL

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: IVA; Drug: TEZ/IVA; Drug: VX-445

Part D: VX-445/TEZ/IVA TC - High Dose

EXPERIMENTAL

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: IVA; Drug: TEZ/IVA; Drug: VX-445

Part E: TEZ/IVA

ACTIVE COMPARATOR

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

Part E: VX-445/TEZ/IVA TC

EXPERIMENTAL

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: IVA; Drug: TEZ/IVA; Drug: VX-445

Part F: Placebo

PLACEBO COMPARATOR

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

Part F: VX-445/TEZ/VX-561 TC

EXPERIMENTAL

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; Drug: TEZ; Drug: VX-561

Interventions

IVA DRUG

IVA tablet for oral administration

Also known as: VX-770, ivacaftor

Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3); Part D: VX-445/TEZ/IVA TC - High Dose; Part D: VX-445/TEZ/IVA TC - Low Dose; Part D: VX-445/TEZ/IVA TC - Medium Dose; Part E: VX-445/TEZ/IVA TC

TEZ/IVA DRUG

TEZ/IVA fixed-dose combination for oral administration.

Also known as: VX-661/VX-770, tezacaftor/ivacaftor

Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3); Part D: VX-445/TEZ/IVA TC - High Dose; Part D: VX-445/TEZ/IVA TC - Low Dose; Part D: VX-445/TEZ/IVA TC - Medium Dose; Part E: TEZ/IVA; Part E: VX-445/TEZ/IVA TC

VX-445 DRUG

VX-445 tablet for oral administration.

Also known as: ELX, elexacaftor

Part A: VX-445 (Cohort A7); Part A: VX-445 (Except Cohort A7); Part B: VX-445 (Cohort B1 to B4); Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3); Part D: VX-445/TEZ/IVA TC - High Dose; Part D: VX-445/TEZ/IVA TC - Low Dose; Part D: VX-445/TEZ/IVA TC - Medium Dose; Part E: VX-445/TEZ/IVA TC; Part F: VX-445/TEZ/VX-561 TC

Matched Placebo DRUG

Matched placebo.

Part A: Pooled Placebo (Except Cohort A7); Part B: Pooled Placebo (Cohort B1 to B4); Part C: Pooled Placebo (Cohort C1 to C3); Part D: Placebo; Part F: Placebo

TEZ DRUG

Tablet for oral administration.

Also known as: VX-661, tezacaftor

Part F: VX-445/TEZ/VX-561 TC

VX-561 DRUG

Tablet for oral administration.

Also known as: CTP-656

Part F: VX-445/TEZ/VX-561 TC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Vertex Pharmaceuticals Incorporated: lead

Study Sites (38)

Banner University of Arizona Medical Center

Tucson, Arizona, 85724, United States

Location

University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72205, United States

Location

Valley Children's Healthcare

Madera, California, 93636, United States

Location

(Kaiser Permanente) Oakland Medical Center

Oakland, California, 96411, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

Central Florida Pulmonary Group

Orlando, Florida, 32803, United States

Location

Tampa General Hospital Cardiac and Lung Transplant Clinic

Tampa, Florida, 33606, United States

Location

Children's Specialty Services at North Druid Hills

Atlanta, Georgia, 30324, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Covance Clinical Research Unit Inc., Evansville Clinic [Parts A, B, C only]

Evansville, Indiana, 47710, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Tulane Medical Center

New Orleans, Louisiana, 70112, United States

Location

Harper University Hospital

Detroit, Michigan, 48201, United States

Location

Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minn

Minneapolis, Minnesota, 55404, United States

Location

Morristown Medical Center

Morristown, New Jersey, 07960, United States

Location

University of New Mexico School of Medicine

Albuquerque, New Mexico, 87131, United States

Location

UC Health Office of Clinical Research

Cincinnati, Ohio, 45267, United States

Location

University Hospitals Cleveland Medical Center/Rainbow Babies and Children's Hospital

Cleveland, Ohio, 44106, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Austin Children's Chest Associates

Austin, Texas, 78723, United States

Location

The University of Vermont

Burlington, Vermont, 05401, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

West Virginia University Hospitals

Morgantown, Virginia, 26506, United States

Location

Children's Hospital of the King's Daughters

Norfolk, Virginia, 23507, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Monash Medical Center

Clayton, Victoria, Australia

Location

The Alfred Hospital

Melbourne, Victoria, Australia

Location

The Royal Children's Hospital Melbourne

Parkville, Victoria, Australia

Location

Mater Adult Hospital

Brisbane, Australia

Location

Royal Prince Alfred Hospital

Sydney, Australia

Location

Westmead Hospital

Sydney, Australia

Location

Antwerp University Hospital

Edegem, Belgium

Location

Universitair Ziekenhuis Gent

Ghent, Belgium

Location

Academic Medical Centre

Amsterdam, Netherlands

Location

Radboud UMC

Nijmegen, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

HagaZiekenhuis van den Haag

The Hague, Netherlands

Location

Related Publications (3)

• Heneghan M, 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. 2023 Nov 20;11(11):CD010966. doi: 10.1002/14651858.CD010966.pub4.

  PMID: 37983082 DERIVED

• 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.

  PMID: 33331662 DERIVED

• 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.

  PMID: 30334692 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

ivacaftor; tezacaftor, ivacaftor drug combination; elexacaftor; tezacaftor

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Results Point of Contact

• Title: Medical Monitor
• Organization: Vertex Pharmaceuticals Incorporated

medicalinfo@vrtx.com

617-341-6777

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 18, 2017
• First Posted: July 24, 2017
• Study Start: January 23, 2017
• Primary Completion: March 27, 2018
• Study Completion: March 27, 2018
• Last Updated: January 18, 2022
• Results First Posted: January 18, 2022

Record last verified: 2021-12

Locations

NL (4); BE (2); AU (6); US (26)