Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

Cystic Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00457821
• Other study ID #: VX06-770-101
• Status: Completed
• Phase: Phase 2
• First received: April 5, 2007
• Last updated: October 3, 2012
• Start date: May 2007
• Est. completion date: August 2008

Study information

• Verified date: October 2012
• Source: Vertex Pharmaceuticals Incorporated
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 39
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• Ivacaftor 25 mg/75 mg
25 mg or 75 mg q12h for a total of 28 days (Part 1)
• Ivacaftor 75 mg/150 mg
75 mg or 150 mg q12h for a total of 28 days (Part 1)
• Ivacaftor 150 mg or 250 mg
150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2)
• Placebo
Given q12h for 28 days each in Part 1 and Part 2 of the study

Locations

Country	Name	City	State
Canada	Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children	Toronto	Ontario
Germany	CF Clinic, Pediatric Pulmonology and Neonatology, Medical School of Hannover	Strasse	Hannover
United States	The Children's Hospital	Aurora	Colorado
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama Hospital	Birmingham	Alabama
United States	Children's Hospital of Boston	Boston	Massachusetts
United States	Pulmonary and Critical Care Medicine, Massachusetts General Hospital	Boston	Massachusetts
United States	Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Roy J. and Lucille A. Carver College of Medicine, The University of Iowa	Iowa City	Iowa
United States	Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota	Minneapolis	Minnesota
United States	Stanford University Medical Center	Palo Alto	California
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Pulmonary Critical Care, University of Washington	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Vertex Pharmaceuticals Incorporated	Cystic Fibrosis Foundation Therapeutics

Countries where clinical trial is conducted

United States,  Canada,  Germany, 

References & Publications (1)

Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With Adverse Events (Combined Part 1 and Part 2)	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	Yes
Primary	Number of Adverse Events (Combined Part 1 and Part 2)	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	Yes
Secondary	Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)	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	No
Secondary	Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)	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	No
Secondary	Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)	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	No
Secondary	Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)	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	No

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