Clinical trial NCT00909727: Study of Ivacaftor in Cystic Fibrosis Subjects Aged 6 to 11 Years With the G551D Mutation
Official title: A Phase 3, 2-Part, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Pharmacokinetics, Efficacy and Safety of VX-770 in Subjects Aged 6 to 11 Years With Cystic Fibrosis and the G551D Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis
Keywords: 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: 2009-05-28
Enrollment: 52
Sex: ALL
Minimum age (years): 6
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective 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.

Detailed description: This is a Phase 3, 2-part, randomized, double-blind, placebo-controlled, parallel group multicenter study of orally administered ivacaftor in subjects with cystic fibrosis (CF) 6 to 11 years of age who have the G551D-CFTR mutation and a forced expiratory volume in 1 second (FEV1) between 90% and 105% predicted (using Knudson standards).

Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, ivacaftor was selected for clinical development as a possible treatment for patients with CF. Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating effect of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation.

This study was conducted in 2 parts. Part A was conducted to analyze the PK properties of ivacaftor and to determine the most appropriate dose to administer to subjects in Part B of this study. Part B explored the safety and efficacy of ivacaftor over long-term treatment in subjects 6 to 11 years of age.

Eligibility criteria: Inclusion Criteria:

* Weighing at least 15 kg
* Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele
* Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening
* Able to swallow tablets
* As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned
* Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject
* Willing to use at least 1 highly effective birth control method during 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
* Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study
* Abnormal liver function ≥ 3x the upper limit of normal
* Abnormal renal function at Screening
* History of solid organ or hematological transplantation
* Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening
* Use of inhaled hypertonic saline treatment
* Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4)

Primary outcomes:
measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24
timeFrame: baseline through 24 weeks
Secondary outcomes:
measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 48
timeFrame: baseline through 48 weeks
measure: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children)
timeFrame: baseline through 24 weeks and 48 weeks
measure: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48
timeFrame: baseline through 24 weeks and 48 weeks
measure: Absolute Change From Baseline in Weight at Week 24 and Week 48
timeFrame: baseline to 24 weeks and 48 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Atlanta
country: United States
facility: Emory Cystic Fibrosis Center
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Glenview
country: United States
facility: The Cystic Fibrosis Center of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Department of Pediatrics
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital Spectrum Health Hospitals
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: The Children's Mercy Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center Pediatric Pulmonary/ CF
state: Nebraska
city: Knoxville
country: United States
facility: East Tennessee Children's Hospital Pediatric Pulmonary and Respiratory Care
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah Pediatric Pulmonology
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Pediatric Respiratory Medicine
state: Virginia
city: Westmead
country: Australia
facility: The Children's Hospital Westmead
state: New South Wales
city: Herston
country: Australia
facility: Royal Children's Hospital Brisbane
state: Queensland
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
state: Victoria
city: Subiaco
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Hospital for Sick Children CF Center
state: Ontario
city: Paris
country: France
facility: Hôpital Robert Debré - Service de gastro-entérologiemucoviscidose et nutrition
city: Erlangen
country: Germany
facility: Kinder- und Jugendklinik Universitätsklinikum Erlangen
city: Jena
country: Germany
facility: Mukoviszidose-Zentrum am Klinikum der Friedrich-Schiller-Universität Jena, Klinik für Kinder- und Jugendmedizin
city: Dublin
country: Ireland
facility: Our Lady's Children's Hospital
city: Dublin
country: Ireland
facility: The National Children's Hospital
city: London
country: United Kingdom
facility: Dept of Gene Therapy, Imperial College London
Study officials:
affiliation: Roy A. & Lucille A. Carver College of Medicine
name: Richard Ahrens, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K, Ordonez CL, Ahrens R; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013 Jun 1;187(11):1219-25. doi: 10.1164/rccm.201301-0153OC.