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J Clin Pharmacol. 2018 Apr;58(4):448-456. doi: 10.1002/jcph.1043. Epub 2017 Nov 28.

Randomized, Double-Blind, Crossover, Clinical-End-Point Pilot Study to Examine the Use of Exhaled Nitric Oxide as a Bioassay for Dose Separation of Inhaled Fluticasone Propionate.

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CompleWare Corporation, Iowa City, IA, USA.
Clinical Research Program, Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin, Madison, WI, USA.
University of Florida, Gainesville, FL, USA.
Sandoz, Inc, Princeton, NJ, USA.


This was a randomized, double-blind, crossover, clinical-end-point pilot study examining the hypothesis that inhaled fluticasone propionate decreases exhaled nitric oxide (eNO) concentrations within a week of beginning treatment and shows evidence of dose separation across the marketed dose range. Subjects had a ≥6-month history of asthma and screening eNO ≥60 parts per billion. At the start of each treatment period, eNO was ≥55 parts per billion, and forced expiratory volume in 1 second was ≥50% predicted. Subjects attended a clinic visit daily on consecutive mornings during each of 3 1-week treatment periods to measure eNO and receive once-daily doses of 100/50, 250/50, or 500/50 fluticasone propionate/salmeterol combination product (Advair® Diskus). Daily eNO value recorded was the highest of 3 measurements; 1 inhalation of treatment was then administered. Procedures were repeated for 3 treatment cycles, separated by 14-day minimum washouts. A total of 105 subjects were screened; 22 were randomized; and 17 completed all treatments. Mean percentage eNO decrease (standard deviation) from day 1 baseline for each treatment period was 36.6 (±18.7), 45.3 (±16.5), and 54.6 (±12.5) with Advair® 100/50, 250/50, and 500/50, respectively. Mean percentage decrease in eNO across each treatment (dose) was modeled using a mixed-model ANOVA. Although the overall treatment was significant (P = .0015), because of the relatively small sample size and within-subject variability, only the 100/50 vs 500/50 (P = .0003) and 250/50 vs 500/50 (P = .047) treatments were significantly different.


bioassay; exhaled nitric oxide; fluticasone propionate

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