Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

October 3, 2012 updated by: Vertex Pharmaceuticals Incorporated

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

39

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • 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 Names:
  • 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 Names:
  • 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Subjects With Adverse Events (Combined Part 1 and Part 2)
Time Frame: Baseline to Follow-up
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.
Baseline to Follow-up
Number of Adverse Events (Combined Part 1 and Part 2)
Time Frame: Baseline to Follow-up
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.
Baseline to Follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)
Time Frame: 14 days and 28 days
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.
14 days and 28 days
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

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.
14 days and 28 days
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
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).
14 days and 28 days
Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)
Time Frame: 14 days and 28 days
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.
14 days and 28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vertex Pharmaceuticals Incorporated

Collaborators

Cystic Fibrosis Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2007

Primary Completion (Actual)

August 1, 2008

Study Completion (Actual)

August 1, 2008

Study Registration Dates

First Submitted

April 5, 2007

First Submitted That Met QC Criteria

April 5, 2007

First Posted (Estimate)

April 9, 2007

Study Record Updates

Last Update Posted (Estimate)

October 5, 2012

Last Update Submitted That Met QC Criteria

October 3, 2012

Last Verified

October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • VX06-770-101

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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