Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

• Number of Subjects With Adverse Events (Combined Part 1 and Part 2) [ Time Frame: Baseline to Follow-up ] [ Designated as safety issue: Yes ]
  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 ] [ Designated as safety issue: Yes ]
  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.

• Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) [ Time Frame: 14 days and 28 days ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]

  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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.

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.

• 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

• 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

• 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.

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)