A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis

NCT02951182 | Completed Phase 2 Results DMC

• 2 other identifiers: VX15-440-1012016-000454-36
• Study Type: interventional
• Target: 74
• Locations: 9 countries
• Sites: 39

Brief Summary

This is a Phase 2, randomized, double-blind, placebo- and active-controlled, parallel group, multicenter study to evaluate the safety, tolerability, and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ and/or IVA therapy (F508del/MF).

Conditions

Cystic Fibrosis

Outcome Measures

Primary Outcomes (2)

• Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

  From first dose of Study Drug in the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2)

• 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 (4)

• Absolute Change in Sweat Chloride Concentrations

  From Baseline through Day 29

• Relative Change in ppFEV1

  From Baseline through Day 29

• Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

  From Baseline at Day 29

• Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA

  Predose at Day 8, Day 15 and Day 29

Study Arms (6)

Part 1: Placebo - Cohort 1A and 1B Combined

PLACEBO COMPARATOR

Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks.

Drug: Matched Placebo

Part 1 Cohort 1A: Triple Combination (TC)

EXPERIMENTAL

Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks.

Drug: TEZ; Drug: IVA; Drug: VX-440

Part 1 Cohort 1B: TC Low Dose

EXPERIMENTAL

Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks.

Drug: TEZ; Drug: IVA; Drug: VX-440

Part 1 Cohort 1B: TC High Dose

EXPERIMENTAL

Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks.

Drug: TEZ; Drug: IVA; Drug: VX-440

Part 2: TEZ/IVA

ACTIVE COMPARATOR

Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.

Drug: TEZ; Drug: IVA; Drug: Matched Placebo

Part 2: TC-2

EXPERIMENTAL

Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.

Drug: TEZ; Drug: IVA; Drug: VX-440

Interventions

TEZ DRUG

Also known as: tezacaftor, VX-661

Part 1 Cohort 1A: Triple Combination (TC); Part 1 Cohort 1B: TC High Dose; Part 1 Cohort 1B: TC Low Dose; Part 2: TC-2; Part 2: TEZ/IVA

IVA DRUG

Also known as: ivacaftor, VX-770

Part 1 Cohort 1A: Triple Combination (TC); Part 1 Cohort 1B: TC High Dose; Part 1 Cohort 1B: TC Low Dose; Part 2: TC-2; Part 2: TEZ/IVA

VX-440 DRUG

Part 1 Cohort 1A: Triple Combination (TC); Part 1 Cohort 1B: TC High Dose; Part 1 Cohort 1B: TC Low Dose; Part 2: TC-2

Matched Placebo DRUG

Part 1: Placebo - Cohort 1A and 1B Combined; Part 2: TEZ/IVA

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
• To prevent pregnancy, female participants of childbearing potential and their male partners will be required to use pre-specified, highly effective methods of non-hormonal contraception. Male participants with female partners of childbearing potential will be required to use a condom.
• Body weight ≥35 kg.
• Sweat chloride value ≥60 mmol/L from test results obtained during screening.
• Subjects must have an eligible CFTR genotype:
• Heterozygous for F508del and a minimal function (MF) mutation known or predicted not to be responsive to TEZ and/or IVA.
• Homozygous for F508del
• Subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height at the Screening Visit
• Stable CF disease as judged by the investigator.
• Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow up Visit.

You may not qualify if:

• History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
• History of cirrhosis with portal hypertension.
• Risk factors for Torsade de Pointes
• History of hemolysis.
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency assessed at Screening.
• Clinically significant abnormal laboratory values at screening
• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before the first dose of study drug.
• Lung infection with organisms associated with a more rapid decline in pulmonary status
• An acute illness not related to CF within 14 days before the first dose of study drug
• A standard digital ECG demonstrating QTc \>450 msec at screening.
• History of solid organ or hematological transplantation.
• History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period.
• History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
• Ongoing or prior participation in an investigational drug study, with certain exceptions. (e.g., ongoing participation in NCT02565914)
• Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days before screening (applies only to the Heterozygous F508del/MF cohorts; does not apply to the Homozygous F508del/F508del Cohort).

Sponsors & Collaborators

• Vertex Pharmaceuticals Incorporated: lead

Study Sites (40)

The Arizona Board of Regents on behalf of the University of Arizona

Tucson, Arizona, United States

Location

Stanford University

Palo Alto, California, United States

Location

University of California

San Francisco, California, United States

Location

National Jewish Health

Denver, Colorado, United States

Location

Joe Di Maggio Cystic Fibrosis & Pulmonary Center

Hollywood, Florida, United States

Location

Central Florida Pulmonary Group

Orlando, Florida, United States

Location

St. Luke's CF Center of Idaho

Boise, Idaho, United States

Location

Cystic Fibrosis Center of Chicago

Glenview, Illinois, United States

Location

The Johns Hopkins Hospital

Baltimore, Maryland, United States

Location

Boston Children's Hospital

Boston, Massachusetts, United States

Location

Massachusetts General Hospital Cystic Fibrosis Center

Boston, Massachusetts, United States

Location

University of Minnesota

Minneapolis, Minnesota, United States

Location

New York Medical College

Hawthorne, New York, United States

Location

Long Island Jewish Medical Center

New Hyde Park, New York, United States

Location

Columbia University Medical Center

New York, New York, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, United States

Location

Respiratory Diseases of Children and Adolescents

Oklahoma City, Oklahoma, United States

Location

UPMC OSPARS Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Location

Sanford Children's Specialty Clinic Sanford Research USD

Sioux Falls, South Dakota, United States

Location

The University of Texas Southwestern Center

Dallas, Texas, United States

Location

Children's Hospital of the Kings Daughters

Norfolk, Virginia, United States

Location

Seattle Children's Hospital

Seattle, Washington, United States

Location

Royal Adelaide Hospital

Adelaide, Australia

Location

Prince Charles Hospital

Chermside, Australia

Location

John Hunter Hospital & Hunter Medical Research Institute

New Lambton Heights, Australia

Location

Medizinische Universitat Innsbruck

Innsbruck, Austria

Location

Universitair Ziekenhuis Brussel

Brussels, Belgium

Location

Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg

Leuven, Belgium

Location

St. Paul's Hopsital

Vancouver, British Columbia, Canada

Location

St. Michael's Hospital

Toronto, Ontario, Canada

Location

Juliane Marie Center, Righospitalet

Copenhagen, Denmark

Location

University Hospital Cologne

Cologne, Germany

Location

Mukeviszidose-Zentrum am Universtitatsklinikum Jena

Jena, Germany

Location

Pneumologische Praxis Pasing

München, Germany

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Italy

Location

Hospital Universitari Vall d´Hebron Servicio de Broncoscopia

Barcelona, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Spain

Location

Heart of England NHS Foundation Trust

Birmingham, United Kingdom

Location

Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital

London, United Kingdom

Location

Southampton University Hospitals NHS Foundation Trust

Southampton, United Kingdom

Location

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

tezacaftor; ivacaftor

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
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• 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: October 26, 2016
• First Posted: November 1, 2016
• Study Start: October 1, 2016
• Primary Completion: August 1, 2017
• Study Completion: August 1, 2017
• Last Updated: August 28, 2020
• Results First Posted: August 28, 2020

Record last verified: 2020-08

Locations

AU (3); ES (2); BE (2); US (22); DK (1); DE (3); GB (3); CA (2); IT (1)