Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older With the G551D Mutation

Phase 3

Completed

• Conditions: Cystic Fibrosis
• Interventions: Drug: Placebo; Drug: Ivacaftor

• Registration Number: NCT00909532
• Lead Sponsor: Vertex Pharmaceuticals Incorporated

Brief Summary

The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 12 years and older who have the 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 phase 3 study in subjects with cystic fibrosis (CF) age 12 years and older who have a G551D-CFTR mutation and percent predicted forced expiratory volumn in 1 second (FEV1) between 40% and 90%.

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 function of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation.

This study was designed to further evaluate the efficacy of ivacaftor in subjects with CF who have a G551D-CFTR gene mutation and to evaluate safety in this population over a longer period than previously studied.

Study Timeline

• Study First Submitted: 2009-05-26
• Study First Submitted QC: 2009-05-26
• Study First Posted: 2009-05-28
• Study Start: 2009-06
• Primary Completion: 2010-07
• Disposition First Submitted: 2011-09-21
• Disposition First Submitted QC: 2011-09-21
• Disposition First Posted: 2011-09-26
• Results First Submitted: 2012-02-27
• Results First Submitted QC: 2012-07-18
• Results First Posted: 2012-08-21
• Study Completion: 2012-11
• Status Verified: 2013-01
• Last Update Submitted: 2013-01-14
• Last Update Posted: 2013-01-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 167

Inclusion Criteria

• Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele
• Forced expiratory volume in 1 second (FEV1) of 40% to 90% (inclusive) of predicted normal for age, gender, and height at Screening.
• No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator
• Willing to use highly effective birth control methods during the study

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
• History of alcohol, medication or illicit drug abuse within one year prior to Day 1
• Abnormal liver function ≥ 3x the upper limit of normal
• Abnormal renal function at Screening
• History of solid organ or hematological transplantation
• Pregnant, planning a pregnancy, breast-feeding, or unwilling to follow contraception requirements
• 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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Subjects who received placebo every 12 hours (q12h) for up to 48 weeks.
150 mg Ivacaftor q12h	Ivacaftor	Subjects who received 150 mg of ivacaftor q12h for up to 48 weeks.

Primary Outcome Measures

Name	Time	Method
Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24	baseline through 24 weeks	Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Secondary Outcome Measures

Name	Time	Method
Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48	baseline through 48 weeks	Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)	baseline through 24 weeks and 48 weeks	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).
Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48	baseline through 24 weeks and 48 weeks	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.
Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48	baseline through 24 weeks and 48 weeks	Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection.
Absolute Change From Baseline in Weight at Week 24 and Week 48	baseline to 24 weeks and 48 weeks	As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.

Trial Locations

Locations (65)

University of Alabama; 🇺🇸 Birmingham, Alabama, United States

Kaiser Permanente Medical Care Program; 🇺🇸 Oakland, California, United States

Cystic Fibrosis Research Office, Stanford University; 🇺🇸 Palo Alto, California, United States

Rady Children's Hospital; 🇺🇸 San Diego, California, United States

National Jewish Medical and Research Center; 🇺🇸 Denver, Colorado, United States

Emory Cystic Fibrosis Center; 🇺🇸 Atlanta, Georgia, United States

St. Luke's CF Clinic; 🇺🇸 Boise, Idaho, United States

Children's Memorial Hospital; 🇺🇸 Chicago, Illinois, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

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