Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age

A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age

This study will evaluate the pharmacokinetics (PK), safety, tolerability, efficacy, and pharmacodynamic effect of VX-445, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple combination (TC) in Cystic Fibrosis (CF) subjects 6 through 11 years of age with F/F and F/MF genotypes.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: ELX/TEZ/IVA; Drug: IVA

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • South Brisbane, Australia
    • Queensland Children's Hospital
  • Westmead, Australia
    • The Children's Hospital at Westmead
• Canada
  • Toronto, Canada
    • The Hospital for Sick Children
  • Vancouver, Canada
    • British Columbia's Children's Hospital
• Ireland
  • Dublin, Ireland
    • Children's Health Ireland at Crumlin
  • Dublin, Ireland
    • Children's Health Ireland at Temple Street
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Children's Hospital
  • London, United Kingdom
    • Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital
• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Children's Mercy Hospital
  • New York
    • New Hyde Park, New York, United States, 11040
      • Northwell Health- Long Island Jewish Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • Clinical Research of Charlotte
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital/University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Homozygous or heterozygous for F508del mutation (F/F or F/MF genotypes)
• Forced expiratory volume in 1 second (FEV1) value ≥40% of predicted mean for age, sex, and height.

Key Exclusion Criteria:

• Clinically significant cirrhosis with or without portal hypertension
• Lung infection with organisms associated with a more rapid decline in pulmonary status.
• 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: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: ELX/TEZ/IVA; Participants in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days.	Drug: ELX/TEZ/IVA; Fixed-dose combination tablet orally once daily in the morning.; Other Names: VX-445/VX-661/VX-770; elexacaftor/tezacaftor/ivacaftor; Drug: IVA; IVA tablet orally once daily in the evening.; Other Names: VX-770; ivacaftor
Experimental: Part B: ELX/TEZ/IVA; Participants in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing greater than equals to (>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.	Drug: ELX/TEZ/IVA; Fixed-dose combination tablet orally once daily in the morning.; Other Names: VX-445/VX-661/VX-770; elexacaftor/tezacaftor/ivacaftor; Drug: IVA; IVA tablet orally once daily in the evening.; Other Names: VX-770; ivacaftor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA	Part A: Day 15
Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA	Part A: Day 15
Part A: Area Under the Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24h) of ELX, TEZ, and IVA	Part A: Day 15
Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Part B: Day 1 Through Safety Follow-up Visit (up to Week 28)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)		Part A: Day 15
Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)		Part A: Day 15
Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ)		Part A: Day 15
Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA)	The AUC data was analyzed for up to 6 hours for IVA metabolite (M1-IVA). Therefore, AUC0-6h is reported for M1-IVA metabolite.	Part A: Day 15
Part A: Safety and Tolerability as Assessed by Number of Participants With TEAEs and SAEs		Part A: Day 1 Through Safety Follow-up Visit (up to Day 43)
Part B: 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.	Part B: From Baseline Through Week 24
Part B: Absolute Change in Sweat Chloride (SwCl)	Sweat samples were collected using an approved collection device.	Part B: From Baseline Through Week 24
Part B: 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.	Part B: From Baseline Through Week 24
Part B: Absolute Change in Body Mass Index (BMI)	BMI was defined as weight in kg divided by squared height in meters (m^2).	Part B: From Baseline at Week 24
Part B: Absolute Change in BMI For-Age Z-Score	BMI was defined as weight in kg divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.	Part B: From Baseline at Week 24
Part B: Absolute Change in Weight		Part B: From Baseline at Week 24
Part B: Absolute Change in Weight-for-age Z-Score	The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.	Part B: From Baseline at Week 24
Part B: Absolute Change in Height		Part B: From Baseline at Week 24
Part B: Absolute Change in Height-for-Age Z-Score	The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.	Part B: From Baseline at Week 24
Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale	The study drug acceptability (participant reaction) was assessed by a visual analog scale that incorporates a 5 point facial hedonic scale (Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much). Number of participants with the indicated categorical response in the drug acceptability assessment were reported.	Part B: At Week 24
Part B: Number of Pulmonary Exacerbations Events	Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. The total number of pulmonary exacerbations events across all participants were reported.	Part B: From Baseline Through Week 24
Part B: Number of CF Related Hospitalizations	The total number of CF related hospitalization events across all participants were reported.	Part B: From Baseline Through Week 24
Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA)		Part B: At Week 4
Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5)	LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.	Part B: From Baseline Through Week 24

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:CD010966. doi: 10.1002/14651858.CD010966.pub3.
• Zemanick ET, Taylor-Cousar JL, Davies J, Gibson RL, Mall MA, McKone EF, McNally P, Ramsey BW, Rayment JH, Rowe SM, Tullis E, Ahluwalia N, Chu C, Ho T, Moskowitz SM, Noel S, Tian S, Waltz D, Weinstock TG, Xuan F, Wainwright CE, McColley SA. A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2021 Jun 15;203(12):1522-1532. doi: 10.1164/rccm.202102-0509OC.

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2018
• Primary Completion (Actual): August 7, 2020
• Study Completion (Actual): August 7, 2020

Study Registration Dates

• First Submitted: September 28, 2018
• First Submitted That Met QC Criteria: September 28, 2018
• First Posted (Actual): October 2, 2018

Study Record Updates

• Last Update Posted (Actual): October 22, 2021
• Last Update Submitted That Met QC Criteria: September 24, 2021
• Last Verified: August 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; Elexacaftor
• Other Study ID Numbers: VX18-445-106; 2018-001695-38 (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
• product manufactured in and exported from the U.S.: No