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

NCT ID: NCT03227471

Last Updated: 2022-01-18

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

225 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-01-23

Study Completion Date

2018-03-27

Brief Summary

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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).

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Detailed Description

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Conditions

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Cystic Fibrosis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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.

Group Type EXPERIMENTAL

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

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.

Group Type EXPERIMENTAL

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

VX-445

Intervention Type DRUG

VX-445 IV injection

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.

Group Type PLACEBO_COMPARATOR

Matched Placebo

Intervention Type DRUG

Matched placebo.

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.

Group Type PLACEBO_COMPARATOR

Matched Placebo

Intervention Type DRUG

Matched placebo.

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).

Group Type EXPERIMENTAL

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

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.

Group Type PLACEBO_COMPARATOR

Matched Placebo

Intervention Type DRUG

Matched placebo.

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.

Group Type EXPERIMENTAL

IVA

Intervention Type DRUG

IVA tablet for oral administration

TEZ/IVA

Intervention Type DRUG

TEZ/IVA fixed-dose combination for oral administration.

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

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.

Group Type PLACEBO_COMPARATOR

Matched Placebo

Intervention Type DRUG

Matched placebo.

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.

Group Type EXPERIMENTAL

IVA

Intervention Type DRUG

IVA tablet for oral administration

TEZ/IVA

Intervention Type DRUG

TEZ/IVA fixed-dose combination for oral administration.

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

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.

Group Type EXPERIMENTAL

IVA

Intervention Type DRUG

IVA tablet for oral administration

TEZ/IVA

Intervention Type DRUG

TEZ/IVA fixed-dose combination for oral administration.

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

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.

Group Type EXPERIMENTAL

IVA

Intervention Type DRUG

IVA tablet for oral administration

TEZ/IVA

Intervention Type DRUG

TEZ/IVA fixed-dose combination for oral administration.

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

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.

Group Type ACTIVE_COMPARATOR

TEZ/IVA

Intervention Type DRUG

TEZ/IVA fixed-dose combination for oral administration.

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.

Group Type EXPERIMENTAL

IVA

Intervention Type DRUG

IVA tablet for oral administration

TEZ/IVA

Intervention Type DRUG

TEZ/IVA fixed-dose combination for oral administration.

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

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.

Group Type PLACEBO_COMPARATOR

Matched Placebo

Intervention Type DRUG

Matched placebo.

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.

Group Type EXPERIMENTAL

VX-445

Intervention Type DRUG

VX-445 tablet for oral administration.

TEZ

Intervention Type DRUG

Tablet for oral administration.

VX-561

Intervention Type DRUG

Tablet for oral administration.

Interventions

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IVA

IVA tablet for oral administration

Intervention Type DRUG

TEZ/IVA

TEZ/IVA fixed-dose combination for oral administration.

Intervention Type DRUG

VX-445

VX-445 tablet for oral administration.

Intervention Type DRUG

Matched Placebo

Matched placebo.

Intervention Type DRUG

TEZ

Tablet for oral administration.

Intervention Type DRUG

VX-561

Tablet for oral administration.

Intervention Type DRUG

VX-445

VX-445 IV injection

Intervention Type DRUG

Other Intervention Names

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VX-770 ivacaftor VX-661/VX-770 tezacaftor/ivacaftor ELX elexacaftor VX-661 tezacaftor CTP-656 ELX elexacaftor

Eligibility Criteria

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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.

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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Vertex Pharmaceuticals Incorporated

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Banner University of Arizona Medical Center

Tucson, Arizona, United States

Site Status

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Site Status

Valley Children's Healthcare

Madera, California, United States

Site Status

(Kaiser Permanente) Oakland Medical Center

Oakland, California, United States

Site Status

National Jewish Health

Denver, Colorado, United States

Site Status

Central Florida Pulmonary Group

Orlando, Florida, United States

Site Status

Tampa General Hospital Cardiac and Lung Transplant Clinic

Tampa, Florida, United States

Site Status

Children's Specialty Services at North Druid Hills

Atlanta, Georgia, United States

Site Status

Northwestern Memorial Hospital

Chicago, Illinois, United States

Site Status

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

Evansville, Indiana, United States

Site Status

University of Kansas Medical Center

Kansas City, Kansas, United States

Site Status

Tulane Medical Center

New Orleans, Louisiana, United States

Site Status

Harper University Hospital

Detroit, Michigan, United States

Site Status

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

Minneapolis, Minnesota, United States

Site Status

Morristown Medical Center

Morristown, New Jersey, United States

Site Status

University of New Mexico School of Medicine

Albuquerque, New Mexico, United States

Site Status

UC Health Office of Clinical Research

Cincinnati, Ohio, United States

Site Status

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

Cleveland, Ohio, United States

Site Status

Nationwide Children's Hospital

Columbus, Ohio, United States

Site Status

Austin Children's Chest Associates

Austin, Texas, United States

Site Status

The University of Vermont

Burlington, Vermont, United States

Site Status

University of Virginia Health System

Charlottesville, Virginia, United States

Site Status

West Virginia University Hospitals

Morgantown, Virginia, United States

Site Status

Children's Hospital of the King's Daughters

Norfolk, Virginia, United States

Site Status

Virginia Commonwealth University

Richmond, Virginia, United States

Site Status

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Site Status

Monash Medical Center

Clayton, Victoria, Australia

Site Status

The Alfred Hospital

Melbourne, Victoria, Australia

Site Status

The Royal Children's Hospital Melbourne

Parkville, Victoria, Australia

Site Status

Mater Adult Hospital

Brisbane, , Australia

Site Status

Royal Prince Alfred Hospital

Sydney, , Australia

Site Status

Westmead Hospital

Sydney, , Australia

Site Status

Antwerp University Hospital

Edegem, , Belgium

Site Status

Universitair Ziekenhuis Gent

Ghent, , Belgium

Site Status

Academic Medical Centre

Amsterdam, , Netherlands

Site Status

Radboud UMC

Nijmegen, , Netherlands

Site Status

Erasmus Medical Center

Rotterdam, , Netherlands

Site Status

HagaZiekenhuis van den Haag

The Hague, , Netherlands

Site Status

Countries

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United States Australia Belgium Netherlands

References

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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.

Reference Type DERIVED
PMID: 37983082 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33331662 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30334692 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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2017-000797-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

VX16-445-001

Identifier Type: -

Identifier Source: org_study_id

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