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

A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis

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).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: IVA; Drug: Matched Placebo; Drug: TEZ; Drug: VX-440

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
  • Chermside, Australia
    • Prince Charles Hospital
  • New Lambton Heights, Australia
    • John Hunter Hospital & Hunter Medical Research Institute
• Austria
  • Innsbruck, Austria
    • Medizinische Universität Innsbruck
• Belgium
  • Brussels, Belgium
    • Universitair Ziekenhuis Brussel
  • Leuven, Belgium
    • Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • St. Paul's Hopsital
  • Ontario
    • Toronto, Ontario, Canada
      • St. Michael's Hospital
• Denmark
  • Copenhagen, Denmark
    • Juliane Marie Center, Righospitalet
• Germany
  • Jena, Germany
    • Mukeviszidose-Zentrum am Universtitatsklinikum Jena
  • Koeln, Germany
    • University Hospital Cologne
  • Muenchen, Germany
    • Pneumologische Praxis Pasing
• Italy
  • Milano, Italy
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
• Spain
  • Barcelona, Spain
    • Hospital Universitari Vall d´Hebron Servicio de Broncoscopia
  • Seville, Spain
    • Hospital Universitario Virgen del Rocío
• United Kingdom
  • Birmingham, United Kingdom
    • Heart of England NHS Foundation Trust
  • London, United Kingdom
    • Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital
  • Southampton, United Kingdom
    • Southampton University Hospitals NHS Foundation Trust
• United States
  • Arizona
    • Tucson, Arizona, United States
      • The Arizona Board of Regents on behalf of the University of Arizona
  • California
    • Palo Alto, California, United States
      • Stanford University
    • San Francisco, California, United States
      • University of California
  • Colorado
    • Denver, Colorado, United States
      • National Jewish Health
  • Florida
    • Hollywood, Florida, United States
      • Joe Di Maggio Cystic Fibrosis & Pulmonary Center
    • Orlando, Florida, United States
      • Central Florida Pulmonary Group
  • Idaho
    • Boise, Idaho, United States
      • St. Luke's CF Center of Idaho
  • Illinois
    • Glenview, Illinois, United States
      • Cystic Fibrosis Center of Chicago
  • Maryland
    • Baltimore, Maryland, United States
      • The Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States
      • Boston Children's Hospital
    • Boston, Massachusetts, United States
      • Massachusetts General Hospital Cystic Fibrosis Center
  • Minnesota
    • Minneapolis, Minnesota, United States
      • University of Minnesota
  • New York
    • Hawthorne, New York, United States
      • New York Medical College
    • New Hyde Park, New York, United States
      • Long Island Jewish Medical Center
    • New York, New York, United States
      • Columbia University Medical Center
  • Ohio
    • Columbus, Ohio, United States
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Respiratory Diseases of Children and Adolescents
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States
      • UPMC OSPARS Children's Hospital of Pittsburgh
  • South Dakota
    • Sioux Falls, South Dakota, United States
      • Sanford Children's Specialty Clinic Sanford Research USD
  • Texas
    • Dallas, Texas, United States
      • The University of Texas Southwestern Center
  • Virginia
    • Norfolk, Virginia, United States
      • Children's Hospital of the Kings Daughters
  • Washington
    • Seattle, Washington, United States
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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).
• Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part 1: Placebo - Cohort 1A and 1B Combined; Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks.	Drug: Matched Placebo
Experimental: Part 1 Cohort 1A: Triple Combination (TC); 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: IVA; Other Names: VX-770; ivacaftor; Drug: TEZ; Other Names: VX-661; tezacaftor; Drug: VX-440
Experimental: Part 1 Cohort 1B: TC Low Dose; Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks.	Drug: IVA; Other Names: VX-770; ivacaftor; Drug: TEZ; Other Names: VX-661; tezacaftor; Drug: VX-440
Experimental: Part 1 Cohort 1B: TC High Dose; Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks.	Drug: IVA; Other Names: VX-770; ivacaftor; Drug: TEZ; Other Names: VX-661; tezacaftor; Drug: VX-440
Active Comparator: Part 2: TEZ/IVA; 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: IVA; Other Names: VX-770; ivacaftor; Drug: Matched Placebo; Drug: TEZ; Other Names: VX-661; tezacaftor
Experimental: Part 2: TC-2; 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: IVA; Other Names: VX-770; ivacaftor; Drug: TEZ; Other Names: VX-661; tezacaftor; Drug: VX-440

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in Sweat Chloride Concentrations	Sweat samples were collected using an approved collection device.	From Baseline through Day 29
Relative Change in ppFEV1	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Day 29
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 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

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: October 26, 2016
• First Submitted That Met QC Criteria: October 28, 2016
• First Posted (Estimate): November 1, 2016

Study Record Updates

• Last Update Posted (Actual): August 28, 2020
• Last Update Submitted That Met QC Criteria: August 27, 2020
• Last Verified: August 1, 2020

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
• Other Study ID Numbers: VX15-440-101; 2016-000454-36 (EudraCT Number)