Study of Ivacaftor in Cystic Fibrosis Subjects Aged 6 to 11 Years With the G551D Mutation (ENVISION)

A Phase 3, 2-Part, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Pharmacokinetics, Efficacy and Safety of VX-770 in Subjects Aged 6 to 11 Years With Cystic Fibrosis and the G551D Mutation

The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic adenosine monophosphate (AMP)-dependent protein kinase A (PKA) activation.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Placebo; Drug: Ivacaftor

Detailed Description

This is a Phase 3, 2-part, randomized, double-blind, placebo-controlled, parallel group multicenter study of orally administered ivacaftor in subjects with cystic fibrosis (CF) 6 to 11 years of age who have the G551D-CFTR mutation and a forced expiratory volume in 1 second (FEV1) between 90% and 105% predicted (using Knudson standards).

Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, ivacaftor was selected for clinical development as a possible treatment for patients with CF. Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating effect of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation.

This study was conducted in 2 parts. Part A was conducted to analyze the PK properties of ivacaftor and to determine the most appropriate dose to administer to subjects in Part B of this study. Part B explored the safety and efficacy of ivacaftor over long-term treatment in subjects 6 to 11 years of age.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • The Children's Hospital Westmead
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Children's Hospital Brisbane
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital Melbourne
  • Western Australia
    • Subiaco, Western Australia, Australia, 6008
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H-3V4
      • British Columbia Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children CF Center
• France
  • Paris, France, 75935
    • Hôpital Robert Debré - Service de gastro-entérologiemucoviscidose et nutrition
• Germany
  • Erlangen, Germany, 91054
    • Kinder- und Jugendklinik Universitätsklinikum Erlangen
  • Jena, Germany, 07740
    • Mukoviszidose-Zentrum am Klinikum der Friedrich-Schiller-Universität Jena, Klinik für Kinder- und Jugendmedizin
• Ireland
  • Dublin, Ireland, 12
    • Our Lady's Children's Hospital
  • Dublin, Ireland, 24
    • The National Children's Hospital
• United Kingdom
  • London, United Kingdom, SW3 6LR
    • Dept of Gene Therapy, Imperial College London
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233-1711
      • University of Alabama
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Cystic Fibrosis Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
    • Glenview, Illinois, United States, 60025
      • The Cystic Fibrosis Center of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Department of Pediatrics
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital Spectrum Health Hospitals
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Children's Mercy Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68195-5190
      • University of Nebraska Medical Center Pediatric Pulmonary/ CF
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Children's Hospital Pediatric Pulmonary and Respiratory Care
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Pediatric Pulmonology
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Pediatric Respiratory Medicine

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Weighing at least 15 kg
• Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele
• Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening
• Able to swallow tablets
• As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned
• Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject
• Willing to use at least 1 highly effective birth control method during the study
• No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator

Exclusion Criteria:

• History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject
• Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study
• Abnormal liver function ≥ 3x the upper limit of normal
• Abnormal renal function at Screening
• History of solid organ or hematological transplantation
• Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening
• Use of inhaled hypertonic saline treatment
• Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects who received placebo every 12 hours (q12h) for up to 48 weeks.	Drug: Placebo; Tablet given orally q12h for up to 48 weeks
Experimental: 150 mg Ivacaftor q12h; Subjects who received 150 mg of ivacaftor q12h for up to 48 weeks.	Drug: Ivacaftor; 150-mg tablet given orally q12h for up to 48 weeks; Other Names: VX-770

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24	Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.	baseline through 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 48	Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.	baseline through 48 weeks
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children)	The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID).	baseline through 24 weeks and 48 weeks
Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48	The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.	baseline through 24 weeks and 48 weeks
Absolute Change From Baseline in Weight at Week 24 and Week 48	As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.	baseline to 24 weeks and 48 weeks

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated
• Collaborators: Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Richard Ahrens, MD, Roy A. & Lucille A. Carver College of Medicine

Publications and helpful links

General Publications

• Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K, Ordonez CL, Ahrens R; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013 Jun 1;187(11):1219-25. doi: 10.1164/rccm.201301-0153OC.

Helpful Links

• U.S. FDA Resources
• genetics home reference
• Medline Plus

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: May 26, 2009
• First Submitted That Met QC Criteria: May 26, 2009
• First Posted (Estimate): May 28, 2009

Study Record Updates

• Last Update Posted (Estimate): August 21, 2012
• Last Update Submitted That Met QC Criteria: July 18, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Fibrosis; Respiratory Tract Diseases; Pathologic Processes; Digestive System Diseases; Infant, Newborn, Diseases; Lung Diseases; Genetic Diseases, Inborn; Pancreatic Diseases
• 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: VX08-770-103