Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

Tracking Information
First Submitted Date ICMJE	April 5, 2007
First Posted Date ICMJE	April 9, 2007
Results First Submitted Date	February 27, 2012
Results First Posted Date	October 5, 2012
Last Update Posted Date	October 5, 2012
Study Start Date ICMJE	May 2007
Actual Primary Completion Date	August 2008 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 3, 2012)	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.; 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.
Original Primary Outcome Measures ICMJE; (submitted: April 5, 2007)	Safety and tolerability assessments based on clinical evaluations, laboratory assessments, and adverse events during administration of VX-770
Change History	Complete list of historical versions of study NCT00457821 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: October 3, 2012)	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.; 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.; 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).; 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.
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Safety Study of Ivacaftor in Subjects With Cystic Fibrosis
Official Title ICMJE	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
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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Cystic Fibrosis
Intervention ICMJE	Drug: Ivacaftor 25 mg/75 mg 25 mg or 75 mg q12h for a total of 28 days (Part 1) Other Name: VX-770; Drug: Ivacaftor 75 mg/150 mg 75 mg or 150 mg q12h for a total of 28 days (Part 1) Other Name: VX-770; Drug: Ivacaftor 150 mg or 250 mg 150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2) Other Name: VX-770; Drug: Placebo Given q12h for 28 days each in Part 1 and Part 2 of the study
Study Arms	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. Intervention: Drug: Ivacaftor 25 mg/75 mg; 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. Intervention: Drug: Ivacaftor 75 mg/150 mg; Experimental: Ivacaftor Group C Subjects in Part 2 who received 150 mg or 250 mg of ivacaftor q12h for 28 days. Intervention: Drug: Ivacaftor 150 mg or 250 mg; Placebo Comparator: Placebo Subjects who received placebo in Part 1 and subjects who received placebo in Part 2. Intervention: Drug: Placebo
Publications *	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, 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.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: October 3, 2012)	39
Original Enrollment ICMJE; (submitted: April 5, 2007)	36
Actual Study Completion Date	August 2008
Actual Primary Completion Date	August 2008 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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)
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Canada, Germany, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00457821
Other Study ID Numbers ICMJE	VX06-770-101
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Vertex Pharmaceuticals Incorporated
Study Sponsor ICMJE	Vertex Pharmaceuticals Incorporated
Collaborators ICMJE	Cystic Fibrosis Foundation Therapeutics
Investigators ICMJE	Study Director: Medical Monitor Vertex Pharmaceuticals Incorporated
PRS Account	Vertex Pharmaceuticals Incorporated
Verification Date	October 2012
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP