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Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

This study has been completed.
Sponsor:
Collaborator:
Cystic Fibrosis Foundation
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:
NCT00457821
First received: April 5, 2007
Last updated: October 3, 2012
Last verified: October 2012
  Purpose

The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. 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 AMP-dependent protein kinase A (PKA) activation.


Condition Intervention Phase
Cystic Fibrosis
Drug: Ivacaftor 25 mg/75 mg
Drug: Ivacaftor 75 mg/150 mg
Drug: Ivacaftor 150 mg or 250 mg
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D

Resource links provided by NLM:


Further study details as provided by Vertex Pharmaceuticals Incorporated:

Primary Outcome Measures:
  • Number of Subjects With Adverse Events (Combined Part 1 and Part 2) [ Time Frame: Baseline to Follow-up ] [ Designated as safety issue: Yes ]
    Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.

  • Number of Adverse Events (Combined Part 1 and Part 2) [ Time Frame: Baseline to Follow-up ] [ Designated as safety issue: Yes ]
    Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.


Secondary Outcome Measures:
  • Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) [ Time Frame: 14 days and 28 days ] [ Designated as safety issue: No ]
    The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest.

  • Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) [ Time Frame: 14 days and 28 days ] [ Designated as safety issue: No ]

    Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

    Relative change reflects the percent change from the baseline values [100% * (X-Y)/Y], where X and Y are post-baseline and baseline values, respectively.


  • Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) [ Time Frame: 14 days and 28 days ] [ Designated as safety issue: No ]
    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).

  • Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) [ Time Frame: 14 days and 28 days ] [ Designated as safety issue: No ]
    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.


Enrollment: 39
Study Start Date: May 2007
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ivacaftor Group A
Subjects in Part 1 who first received 25 mg or 75 mg of ivacaftor every 12 hours (q12h) for 14 days, then crossed over to receive the alternate dose for another 14 days.
Drug: Ivacaftor 25 mg/75 mg
25 mg or 75 mg q12h for a total of 28 days (Part 1)
Other Name: VX-770
Experimental: Ivacaftor Group B
Subjects in Part 1 who first received 75 mg or 150 mg of ivacaftor q12h for 14 days then crossed over to receive the alternate dose for another 14 days.
Drug: Ivacaftor 75 mg/150 mg
75 mg or 150 mg q12h for a total of 28 days (Part 1)
Other Name: VX-770
Experimental: Ivacaftor Group C
Subjects in Part 2 who received 150 mg or 250 mg of ivacaftor q12h for 28 days.
Drug: Ivacaftor 150 mg or 250 mg
150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2)
Other Name: VX-770
Placebo Comparator: Placebo
Subjects who received placebo in Part 1 and subjects who received placebo in Part 2.
Drug: Placebo
Given q12h for 28 days each in Part 1 and Part 2 of the study

Detailed Description:

This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. Enrollment of 39 subjects occurred at 15 centers in the US, Canada, and Germany.

The study was conducted in 2 parts:

  • Part 1 consisted of Group A and Group B. Subjects in Group A (10 subjects) were randomized to receive 25 mg of ivacaftor every 12 hours [q12h] (4 subjects), 75 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. Subjects in Group B (10 subjects) were randomized to receive 75 mg of ivacaftor q12h (4 subjects), 150 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, the subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days.
  • Part 2 consisted of Group C; these subjects did not participate in Part 1. Subjects were randomized to receive 150 mg of ivacaftor q12h (7 subjects), 250 mg of ivacaftor q12h (7 subjects), or placebo (4 subjects) for a total of 28 days. Ivacaftor doses studied in Part 2 were selected following an interim pharmacokinetic/pharmacodynamic (PK/PD) and statistical analyses of data from Part 1. The 2 doses selected for Part 2 were anticipated to enable better definition of the optimal therapeutic dose.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Weighing at least 40 kg
  • Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele
  • Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height
  • Willing to remain on stable medication regimen for the duration of study participation
  • No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of 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
  • Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study
  • History of alcohol, medication or illicit drug abuse within one year prior to Day 1
  • Abnormal liver function ≥ 3x the upper limit of normal
  • History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation)
  • History of solid organ or hematological transplantation
  • Pregnant or breast-feeding (for women)
  • Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout
  • Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00457821

Locations
United States, Alabama
University of Alabama Hospital
Birmingham, Alabama, United States, 35211
United States, California
Stanford University Medical Center
Palo Alto, California, United States, 34304
United States, Colorado
The Children's Hospital
Aurora, Colorado, United States, 80045
United States, Iowa
Roy J. and Lucille A. Carver College of Medicine, The University of Iowa
Iowa City, Iowa, United States, 52242-1083
United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Children's Hospital of Boston
Boston, Massachusetts, United States, 02215
Pulmonary and Critical Care Medicine, Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Minnesota
Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, North Carolina
Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4399
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Washington
Pulmonary Critical Care, University of Washington
Seattle, Washington, United States, 98195
Canada, Ontario
Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Germany
CF Clinic, Pediatric Pulmonology and Neonatology, Medical School of Hannover
Strasse, Hannover, Germany, D-30625
Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated
Cystic Fibrosis Foundation
Investigators
Study Director: Medical Monitor Vertex Pharmaceuticals Incorporated
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT00457821     History of Changes
Other Study ID Numbers: VX06-770-101
Study First Received: April 5, 2007
Results First Received: February 27, 2012
Last Updated: October 3, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Vertex Pharmaceuticals Incorporated:
G551D mutation
Fibrosis
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Pathologic Processes

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases
Pancreatic Diseases
Pathologic Processes
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on November 27, 2014