Clinical trial NCT00457821: Safety Study of Ivacaftor in Subjects With Cystic Fibrosis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: G551D mutation
Fibrosis
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Pathologic Processes
Lead sponsor: Vertex Pharmaceuticals Incorporated
Sponsor class: INDUSTRY
Collaborators: name: Cystic Fibrosis Foundation
First posted: 2007-04-09
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

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 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)

Primary outcomes:
measure: Number of Subjects With Adverse Events (Combined Part 1 and Part 2)
timeFrame: Baseline to Follow-up
measure: Number of Adverse Events (Combined Part 1 and Part 2)
timeFrame: Baseline to Follow-up
Secondary outcomes:
measure: Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)
timeFrame: 14 days and 28 days
measure: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)
timeFrame: 14 days and 28 days
measure: Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)
timeFrame: 14 days and 28 days
measure: Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)
timeFrame: 14 days and 28 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Hospital
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Aurora
country: United States
facility: The Children's Hospital
state: Colorado
city: Iowa City
country: United States
facility: Roy J. and Lucille A. Carver College of Medicine, The University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Pulmonary and Critical Care Medicine, Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital of Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota
state: Minnesota
city: Chapel Hill
country: United States
facility: Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Seattle
country: United States
facility: Pulmonary Critical Care, University of Washington
state: Washington
city: Toronto
country: Canada
facility: Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children
state: Ontario
city: Strasse
country: Germany
facility: CF Clinic, Pediatric Pulmonology and Neonatology, Medical School of Hannover
state: Hannover
Study officials:
affiliation: Vertex Pharmaceuticals Incorporated
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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, Ordonez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003. doi: 10.1056/NEJMoa0909825.
citation: Accurso FJ, Van Goor F, Zha J, Stone AJ, Dong Q, Ordonez CL, Rowe SM, Clancy JP, Konstan MW, Hoch HE, Heltshe SL, Ramsey BW, Campbell PW, Ashlock MA. Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data. J Cyst Fibros. 2014 Mar;13(2):139-47. doi: 10.1016/j.jcf.2013.09.007.