Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older Homozygous for the F508del-CFTR Mutation (DISCOVER)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of VX-770 in Subjects Aged 12 Years and Older With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation

The purpose of this study was to evaluate the safety and efficacy of ivacaftor in participants with cystic fibrosis (CF) who were aged 12 years or older and were homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. Ivacaftor is a potent and selective CFTR 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: Terminated
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Placebo; Drug: Ivacaftor

Detailed Description

This study investigated the effects of ivacaftor in participants with cystic fibrosis (CF) >=12 years of age with a forced expiratory volume in 1 second (FEV1) >=40 percent (%) predicted. This study was conducted in 2 parts.

• Part A of this study was a randomized, double-blind, placebo-controlled, parallel-group evaluation of participants with CF who were aged 12 years or older and were homozygous for the F508del-CFTR mutation.
• Part B of this study was an open-label extension of Part A, enrolling participants who completed Part A and met pre-specified endpoint criteria, and explored the safety and efficacy of ivacaftor over long-term treatment in participants with CF aged 12 years or older who were homozygous for the F508del-CFTR mutation.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Medical Center
  • California
    • Oakland, California, United States, 94611
      • Kaiser Permanente Medical Care Program
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Orlando, Florida, United States, 32801
      • Nemours Children's Clinic
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's CF Clinic
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachussetts Medical School
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital; Spectrum Health Hospitals
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Children's Mercy Hospital
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Long Branch, New Jersey, United States, 07740
      • Monmouth Medical Center
    • Morristown, New Jersey, United States, 07962
      • Morristown Memorial Hospital
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital of Buffalo
    • Hawthorne, New York, United States, 10532
      • New York Medical College
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York City, New York, United States, 10003
      • The CF Center, Beth Israel Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Toledo, Ohio, United States, 43606
      • Toldedo Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • University of Tennessee
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Univeristy of Utah
  • Vermont
    • Colchester, Vermont, United States, 05446
      • Vermont Lung Center at the University of Vermont
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Medical College of Virginia

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:

• Confirmed diagnosis of cystic fibrosis (CF) and homozygous for F508del-CFTR mutation
• Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height
• Willing to use at least 2 highly effective birth control methods during the study
• No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator
• Able to understand and comply with protocol requirements, restrictions, and instructions and likely to complete the study as planned, 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
• History of alcohol, medication or illicit drug abuse within one year prior to Day 1
• Abnormal liver function >=3 x the upper limit of normal
• Abnormal renal function at Screening
• History of solid organ or hematological transplantation
• Pregnant or breast-feeding (for women)
• Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to screening
• Previous participation in a VX-809 study
• Used inhaled hypertonic saline treatment
• Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)

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; Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period), followed by ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).	Drug: Placebo; Tablet; Drug: Ivacaftor; Tablet; Other Names: VX-770
Experimental: Ivacaftor; Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period), followed by ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).	Drug: Ivacaftor; Tablet; Other Names: VX-770

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16	Spirometry (as measured by ppFEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Knudson method.	Part A baseline through Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A : Absolute Change From Part A Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 16	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life.	Part A baseline through Week 16
Part A : Absolute Change From Part A Baseline in Sweat Chloride Concentration Through Week 16	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.	Part A baseline through Week 16
Part A : Rate of Change From Baseline in Weight Through Week 16	As malnutrition is common in participants 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.	Part A baseline through Week 16
Part B : Absolute Change From Part A and Part B Baseline in ppFEV1 Through Week 64	ppFEV1 is defined in Outcome Measure 1.	Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
Part B : Rate of Change From Part A Baseline in ppFEV1 Through Week 64	ppFEV1 is defined in Outcome Measure 1.	Part A baseline through Week 64
Part B : Rate of Change From Part B Baseline in ppFEV1 Through Week 64	ppFEV1 is defined in Outcome Measure 1.	Part B baseline through Week 64
Part B : Absolute Change From Part A and Part B Baseline in CFQ-R Respiratory Domain Score Through Week 64	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life.	Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
Part B : Absolute Change From Part A and Part B Baseline in Sweat Chloride Concentration Through Week 64	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.	Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
Part B : Absolute Change From Part A and Part B Baseline in Weight Through Week 64	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.	Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
Part B : Number of Participants With Pulmonary Exacerbations	Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.	Part B baseline through Week 64
Part B : Number of Pulmonary Exacerbation Events	Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.	Part B baseline through Week 64
Part B : Number of Pulmonary Exacerbation Events Per Participant Per Year	Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.	Part B baseline through Week 64

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated
• Collaborators: Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Patrick A Flume, MD, Medical University of South Carolina

Publications and helpful links

General Publications

• Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordonez CL, Geller DE; VX 08-770-104 Study Group. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012 Sep;142(3):718-724. doi: 10.1378/chest.11-2672.

Helpful Links

• U.S. FDA Resources
• Medline Plus
• Genetics Home Reference

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: August 4, 2009
• First Submitted That Met QC Criteria: August 5, 2009
• First Posted (Estimate): August 6, 2009

Study Record Updates

• Last Update Posted (Estimate): September 11, 2015
• Last Update Submitted That Met QC Criteria: August 27, 2015
• Last Verified: August 1, 2015

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: VX08-770-104; 2009-010261-23 (EudraCT Number)