A Study Evaluating the Safety and Efficacy of VX-659 Combination Therapy in Subjects With Cystic Fibrosis

A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-659 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis

This is a Phase 2, randomized, double-blind, placebo- and tezacaftor/ivacaftor (TEZ/IVA)-controlled, parallel-group, 3-part, multicenter study designed to evaluate the safety and efficacy of VX-659 in triple combination (TC) with TEZ and IVA 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: TEZ; Drug: VX-561; Drug: IVA; Drug: Placebo (matched to VX-659/TEZ/IVA); Drug: VX-659; Drug: TEZ/IVA; Drug: Placebo (matched to VX-659/TEZ/VX-561)

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Contacts and Locations

Study Locations

• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland
    • St. Vincent's University Hosptial
  • Galway, Ireland
    • Galway University Hospitals
  • Limerick, Ireland
    • University Hospital Limerick
• Israel
  • Haifa, Israel
    • Carmel Medical Center
  • Haifa, Israel
    • Ruth Children's Hospital Rambam Health Care Campus
  • Jerusalem, Israel
    • Hadassah Medical Organization
  • Ramat Gan, Israel
    • The Chaim Sheba Medical Center
  • Tikvah, Israel
    • Schneider Children's Medical Center
• United Kingdom
  • Birmingham, United Kingdom, B95SS
    • Birmingham Heartlands Hospital
  • Cambridge, United Kingdom
    • Papworth Hospital NHS Foundation Trust, Papworth Everard
  • Cardiff, United Kingdom
    • University Hospital Llandough in Cardiff
  • Devon, United Kingdom
    • Royal Devon and Exeter NHS Foundation Trust, Royal Devon and Exeter Hospital
  • Fulham, United Kingdom
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust, The Royal Victoria Infirmary
  • Glasgow, United Kingdom
    • Greater Glasgow and Clyde NHS Board, Glasgow Clinical Research Facility
  • Hampshire, United Kingdom
    • Southampton University Hospitals NHS Foundation Trust
  • London, United Kingdom
    • Regional Respiratory Centre Belfast City Hospital
  • London, United Kingdom
    • Royal Brompton & Harefied NHS Foundation Trust
  • Manchester, United Kingdom
    • University Hospital of South Manchester NHS Trust, North West Lung Centre
  • Merseyside, United Kingdom
    • Liverpool Heart and Chest Hospital
  • Nottingham, United Kingdom
    • Nottingham University Hospitals NHS Trust
  • Nottingham, United Kingdom
    • Ruth Children's Hospital Rambam Health Care Campus
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami/Miller School of Medicine
  • Illinois
    • Morton Grove, Illinois, United States, 60053
      • Advocate Children's Hospital - Park Ridge / North Suburban Pulmonary and Critical Care Consultants
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • The University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Hospital/ Johns Hopkins Hospital, David Rubenstein Child Health Building
  • Massachusetts
    • Boston, Massachusetts, United States, 02155
      • Boston Children's Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital CF Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Jersey
    • New Brunswick, New Jersey, United States, 08902
      • Rutgers-Robert Wood Johnson Medical School/ Rutgers-Robert Wood Johnson Medical School, Clinical Research Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • New Hyde Park, New York, United States, 11040
      • Northwell Health, Long Island Jewish Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Respiratory Diseases of Children & Adolescents
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Research / USD
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center-Adult Cystic Fibrosis Clinic
    • Memphis, Tennessee, United States, 38103
      • Children's Foundation Research Center / Le Bonheur Children's Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84014
      • University of Utah / Primary Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Pediatric Pulmonary & Allergy/Immunology Clinic

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:

• Body weight ≥35 kg.

• Subjects must have an eligibleCFTR genotype.

  • Part 1 and Part 3: Heterozygous for F508del and an MF mutation (F/MF)
  • Part 2: Homozygous for F508del (F/F)
• FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height

Key Exclusion Criteria:

• 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
• Masking: QUADRUPLE

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Part 1: Placebo; Participants received placebo matched to VX-659/TEZ/IVA in TC treatment period for 4 weeks and placebo matched TEZ/IVA in washout period for 4 days.	Drug: Placebo (matched to VX-659/TEZ/IVA); Placebo matched to VX-659 and TEZ/IVA.
EXPERIMENTAL: Part 1: VX-659/TEZ/IVA TC - Low Dose; Participants received VX-659 80 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.	Drug: IVA; Tablet for oral administration.; Other Names: VX-770; Ivacaftor; Drug: VX-659; Tablet for oral administration.; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination tablet for oral administration.; Other Names: VX-661/VX-770; Tezacaftor/Ivacaftor
EXPERIMENTAL: Part 1: VX-659/TEZ/IVA TC - Medium Dose; Participants received VX-659 240 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.	Drug: IVA; Tablet for oral administration.; Other Names: VX-770; Ivacaftor; Drug: VX-659; Tablet for oral administration.; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination tablet for oral administration.; Other Names: VX-661/VX-770; Tezacaftor/Ivacaftor
EXPERIMENTAL: Part 1: VX-659/TEZ/IVA TC - High Dose; Participants received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.	Drug: IVA; Tablet for oral administration.; Other Names: VX-770; Ivacaftor; Drug: VX-659; Tablet for oral administration.; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination tablet for oral administration.; Other Names: VX-661/VX-770; Tezacaftor/Ivacaftor
ACTIVE_COMPARATOR: Part 2: TEZ/IVA; Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.	Drug: IVA; Tablet for oral administration.; Other Names: VX-770; Ivacaftor; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination tablet for oral administration.; Other Names: VX-661/VX-770; Tezacaftor/Ivacaftor
EXPERIMENTAL: Part 2: VX-659/TEZ/IVA TC; Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.	Drug: IVA; Tablet for oral administration.; Other Names: VX-770; Ivacaftor; Drug: VX-659; Tablet for oral administration.; Drug: TEZ/IVA; TEZ/IVA fixed-dose combination tablet for oral administration.; Other Names: VX-661/VX-770; Tezacaftor/Ivacaftor
PLACEBO_COMPARATOR: Part 3: Placebo; Participants received placebo matched to VX-659/TEZ/VX-561 in TC treatment period for 4 weeks.	Drug: Placebo (matched to VX-659/TEZ/VX-561); Placebo matched to VX-659, TEZ and VX-561.
EXPERIMENTAL: Part 3: VX-659/TEZ/VX-561 TC; Participants received VX-659 400 mg qd/TEZ 100 mg qd/VX-561 200 mg qd in TC treatment period for 4 weeks.	Drug: TEZ; Tablet for oral administration.; Other Names: VX-661; Tezacaftor; Drug: VX-561; Tablet for oral administration.; Other Names: CTP-656; Drug: VX-659; Tablet for oral administration.

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 (TEAEs) and Serious Adverse Events (SAEs)		Day 1 Through Safety Follow-up (up to Day 61 for Part 1, Day 85 for Part 2 and Day 57 for Part 3)
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 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
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
Observed Pre-dose Concentration (Ctrough) of VX-659, TEZ, M1-TEZ, IVA, M1-IVA, and VX-561		Pre-dose at Day 15 and 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(12):CD010966. doi: 10.1002/14651858.CD010966.pub3.
• Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, Plant BJ, Prais D, Ramsey BW, Taylor-Cousar JL, Tullis E, Uluer A, McKee CM, Robertson S, Shilling RA, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Rowe SM; VX16-659-101 Study Group. VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018 Oct 25;379(17):1599-1611. doi: 10.1056/NEJMoa1807119. Epub 2018 Oct 18.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 8, 2017
• Primary Completion (ACTUAL): February 28, 2018
• Study Completion (ACTUAL): February 28, 2018

Study Registration Dates

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

Study Record Updates

• Last Update Posted (ACTUAL): April 22, 2021
• Last Update Submitted That Met QC Criteria: March 29, 2021
• Last Verified: February 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; VX-659
• Other Study ID Numbers: VX16-659-101; 2016-003585-11 (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