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Original Research: Asthma |

Inhaled Corticosteroid Dose Response Using Domiciliary Exhaled Nitric Oxide in Persistent AsthmaThe Fenotype Trial: The Fenotype Trial FREE TO VIEW

William J. Anderson, MBChB; Philip M. Short, MBChB; Peter A. Williamson, MBBCh; Brian J. Lipworth, MD
Author and Funding Information

From the Asthma and Allergy Research Group, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, The University of Dundee, Dundee, Scotland.

Correspondence to: Brian J. Lipworth, MD, Asthma and Allergy Research Group, Division of Cardiovascular and Diabetes Medicine, The University of Dundee, Dundee, DD1 9SY, Scotland; e-mail: brianlipworth@gmail.com


Funding/Support: This study was funded by a departmental grant from the University of Dundee as part of an unrestricted research grant from Teva Pharmaceuticals USA.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(6):1553-1561. doi:10.1378/chest.12-1310
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Background:  International guidelines advocate a standard approach to asthma management for all, despite its heterogeneity. “Personalized” treatment of inflammatory asthma phenotypes confers superior benefits. We wished to evaluate dose response to inhaled corticosteroids (ICSs) in patients with asthma with an elevated fractional exhaled nitric oxide (Feno) phenotype using domiciliary measurements.

Methods:  We performed a randomized, crossover trial in 21 patients with mild to moderate persistent asthma receiving ICSs with elevated Feno (>30 parts per billion [ppb]) that increased further (>10 ppb) after ICS washout. Patients were randomized to 2 weeks of either fluticasone propionate 50 μg bid (FP100) or 250 μg bid (FP500). The primary outcome was response in diurnal domiciliary Feno levels. Secondary outcomes included mannitol challenge, serum eosinophilic cationic protein (ECP), blood eosinophil count, and asthma control questionnaire.

Results:  We found significant dose-related reductions of diurnal Feno compared with baseline − morning Feno: baseline = 71 ppb (95% CI, 61-83 ppb); FP100 = 34 ppb (95% CI, 29-40 ppb), P < .001; FP500 = 27 ppb (95% CI, 22-33 ppb), P < .001; and significant dose separation for morning, P < .05, and evening, P < .001. Time-series Feno displayed exponential decay: FP100 R2 = 0.913, half-life = 69 h (95% CI, 50-114 h); FP500 R2 = 0.966, half-life = 55 h (95% CI, 45-69 h), as well as diurnal variation. The Asthma Control Questionnaire showed significant improvements exceeding the minimal important difference (>0.5) with values in keeping with controlled asthma (<0.75) after each dose: FP100 = 0.48 (95% CI, 0.24-0.71), P = .004; FP500 = 0.37 (95% CI, 0.18-0.57), P = .001. All other secondary inflammatory related outcomes (mannitol, ECP, and eosinophils) showed significant improvements from baseline but no dose separation.

Conclusions:  There is a significant dose response of diurnal Feno to ICS in patients with asthma with an elevated Feno phenotype, which translates into well-controlled asthma. Further interventional studies are warranted using domiciliary Feno in this specific phenotype.

Trial registry:  ClinicalTrials.gov; No.: NCT00995657; URL: clinicaltrials.gov

Figures in this Article

Asthma is a common pulmonary disease, increasing in prevalence worldwide.1 It is characterized by intermittent, reversible airflow obstruction following bronchoconstriction to a variety of stimuli, which can progress to exacerbations, hospitalizations, and mortality. Inhaled corticosteroids (ICSs) are widely recognized as the “gold-standard” asthma control treatment. However, asthma is notable for its heterogeneity of presentation, and responses to inhaled bronchodilator and ICS therapy. Pointedly, there is no “gold-standard” diagnostic test for asthma; rather, it is necessary to combine investigations, symptoms, and signs to improve diagnostic accuracy.2

Asthma heterogeneity is not reflected well in current national2 and international3 asthma guidelines which are based on symptoms and spirometry. Variability of asthma outcomes also exists, and can depend on the type and/or dose of ICS,4 or parameters such as BMI5,6 and smoking status.7 A variety of inflammatory phenotypes8 in asthma are recognized including eosinophilic, neutrophilic, and noneosinophilic asthma.9 Several landmark studies have examined “personalizing” asthma treatment based on clinical hallmarks of asthma—airway hyperresponsiveness (AHR)10 and airway inflammation11,12—revealing that phenotype-driven asthma treatment confers benefits over standard care.

Fractional exhaled nitric oxide (Feno) can now be measured both simply and reliably, with recent publication of guidelines13 from the American Thoracic Society. Smith et al14 evaluated titrating ICSs against a specific Feno threshold (<15 parts per billion [ppb]), demonstrating that ICS doses could be reduced without loss of asthma control. A separate study15 found ICS doses increased when using Feno in addition to standard care, with no difference in asthma control. However, Feno levels vary significantly between patients.16

We wished to evaluate the dose response to ICSs in a phenotype-enriched sample of patients with persistent asthma all displaying elevated levels of Feno when stepped off ICSs, along with how these responses related to other inflammatory outcomes and, most importantly, asthma control. Pointedly, no studies to date have used domiciliary, diurnal measurements of Feno for this purpose. We hypothesized that by using these stringent phenotypic criteria, any dose response to ICS would be more predictable.

Patients

Male and female patients, aged 18 to 65 years, with mild-moderate persistent asthma receiving 200 to 1,000 μg/d ICS (beclometasone dipropionate [BDP] equivalent), were screened (Fig 1). Recruited patients had Feno > 30 ppb with a further rise (>10 ppb) following a 2-week washout from ICS. Exclusion criteria: recent respiratory tract infection or oral corticosteroid use (<3 months), smoking within the previous year or > 10 pack-years.

Figure Jump LinkFigure 1. Consolidated Standards of Reporting Trials diagram. FeNO = fractional exhaled nitric oxide; ppb = parts per billion.Grahic Jump Location
Study Design

We performed a randomized, double-blind, cross-over study of inhaled fluticasone propionate 50 μg one puff bid (FP100) and 250 μg one puff bid (FP500) each for 2 weeks via pressurized metered-dose inhaler (Flixotide Evohaler; Allen and Hanburys) (Fig 2). After screening, patients were stepped off second-line medications (long-acting β-agonists, theophyllines, leukotriene receptor antagonists) and converted to a fluticasone propionate equivalent of their usual ICS dose—stepping off this over 2 weeks followed by a 2-week ICS-free washout period. There was also a 2-week ICS washout between treatments. The primary outcome was change in daily morning and evening Feno from post-washout baseline. Secondary outcomes were domiciliary spirometry, laboratory-based spirometry, impulse oscillometry (IOS), mannitol challenge, Asthma Control Questionnaire (ACQ) and mini-Asthma Quality-of-Life Questionnaire (mini-AQLQ) scores, blood eosinophil counts, and serum eosinophilic cationic protein (ECP).

Figure Jump LinkFigure 2. Study flow diagram. ACQ = Asthma Control Questionnaire; AQLQ = mini-Asthma Quality of Life Questionnaire; FEV6 = forced expiratory volume in 6 s; FP = fluticasone propionate; ICS = inhaled corticosteroid; Mannitol = mannitol bronchial challenge; S1, S2 = screening visits; V0 = prewashout visit; washout periods are sequential (ie, irrespective of FP dose); V1-4 = study visits. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Measurements

Domiciliary Feno was performed morning and evening in the patient’s home, in duplicate, using a handheld NIOX MINO (Aerocrine) according to the manufacturer’s instructions and as previously described17 at a standard flow rate (50 mL/s). Domiciliary forced expiratory volume in 1 s and 6 s (FEV1, FEV6) were performed in triplicate morning and evening using a handheld PiKo-6 (nSpire Health, Inc) according to the manufacturer’s instructions and after Feno to avoid exaggerated Feno measurements. Impulse oscillometry (Masterscreen IOS) was performed in triplicate according to the manufacturer’s guidelines. A SuperSpiro spirometer (Micro Medical Ltd) was used for spirometry in triplicate in accordance with European Respiratory Society guidelines.18 Mannitol challenge was performed as previously described19 with a dry powder inhaler (Aridol; Pharmaxis Ltd) using cumulative dose increments up to 635 mg. The cumulative provocative dose (of mannitol) that causes 15% fall in FEV1 (PD15) was then calculated. Patients unresponsive to 635 mg had a value imputed to 1270 mg for statistical purposes. The ACQ20 and mini-AQLQ21 were completed at study visits. Serum ECP was analyzed in duplicate using a UniCAP system (Thermo Fisher Scientific Inc), coefficient of variation = 3%. Peripheral blood eosinophils were measured using the Sysmex XE2100 Hematology autoanalyzer.

Statistical Analysis

A power calculation determined 20 patients completing in a cross-over fashion would ensure 90% power (two-tailed, α error = 0.05) to detect a 5-ppb difference in Feno between treatments (within-patient SD = 5.4 ppb). All data were examined for normality, with non-Gaussian distributions logarithmically transformed. All baselines were pooled as no significant differences were demonstrated comparing washouts (e-Table 1). Baseline and posttreatment values for domiciliary measures were the mean of days 12 to 14 from each period. Differences between group means were analyzed using repeated measures analysis of variance with Bonferroni correction. Paired Student t tests were used for differences within or between groups as change from baseline. Time-series plots were created for domiciliary measures (Feno, FEV1, FEV6). Nonlinear regression was used to describe Feno response in both treatments, with best-fit curves compared using the extra sum-of-squares F test. Estimates of time to 25%, 50%, 75%, and 90% reduction in Feno from baseline were calculated from the exponential curve half-lives. Linear regression was used for time-series domiciliary FEV1 and FEV6. Harmonic analysis using a Cosinor model over 24 h (similarly described for peak expiratory flow rate22) was applied to the plateau (week 2) phases of each of the pooled baseline and treatment-group time series to assess for diurnal variation of domiciliary measures, with amplitudes derived from geometric mean fold differences in diurnal Feno.

Ethics

The Tayside Committee on Medical Research Ethics approved the study (09/S0501/52). All participants gave written informed consent.

Twenty-one patients completed per protocol. Screening demographics were are follows: mean age, 36.7 years (95% CI, 31.0-42.5 years); 15 male; mean BDP equivalent dose, 441 μg/d (95% CI, 332-549 μg/d); mean spirometry (FEV1, FVC, FEF25-75) as % predicted was 94.5% (95% CI, 89.5%-99.4%), 108.7% (95% CI, 104.7%-112.6%), and 61.3% (95% CI, 54.1%-68.6%), respectively; 17 patients had one or more positive skin prick test; and seven, one, and eight patients were receiving long-acting β agonists, leukotriene receptor antagonists, and antihistamines, respectively.

For the primary outcome of domiciliary Feno, significant reductions after 2 weeks of treatment were demonstrated within both FP100 and FP500 groups from pooled baseline, for both morning and evening values (Table 1), with significantly greater reduction in Feno after the higher dose. Time-series plots of all mean morning and evening Feno values were created for both washout periods (e-Fig 1) and both FP100 and FP500 treatments (Fig 3). Nonlinear regression demonstrated that an exponential one-phase decay curve was the best-fit model for each of the FP100 and FP500 time-series Feno plots (Fig 3, Table 2). For FP100, the fit-of-curve coefficient of determination was R2 = 0.913, with a half-life (t1/2) = 69.8 h (95% CI, 50.3-114 h); for FP500: R2 = 0.966; t1/2 = 54.8 h (95% CI, 45.4-68.9 h). The exponential curves were significantly different (P < .001), confirming the dose-response effect. There was significant diurnal variation of Feno during each of the second (plateau) weeks (days 8-14) as follows: pooled washout (amplitude = 15.6%; R2 = 0.521, P = .004); FP100 (amplitude = 24.3%; R2 = 0.412, P = .01); and FP500 (amplitude = 28.9%; R2 = 0.439, P = .01). Mean domiciliary Feno measurements were almost exclusively higher in the morning.

Table Graphic Jump Location
Table 1 —Domiciliary and Visit Outcome Measurements

Domiciliary data are means of days 12 to 14 from washout (baseline), and each treatment period for morning or evening. Visit data are fixed time-point measurements. Data are presented as arithmetic means (95% CIs) unless stated. ACQ = Asthma Control Questionnaire; AQLQ = Asthma Quality-of-Life Questionnaire; ECP = eosinophilic cationic protein; FEF25-75 = forced expiratory volume between 25% and 75% of FVC; Feno = fractional exhaled nitric oxide; FEV6 = forced expiratory volume in 6 s; FP = fluticasone propionate; FP100 = flucticasone propionate 50 μg bid; FP500 = flucticasone propionate 250 μg bid; Fres = frequency of resonance; IOS = impulse oscillometry; PD15 = provocative dose (of mannitol) that causes 15% fall in FEV1; ppb = parts per billion; pred = predicted; R5 = resistance at 5 Hz; RDR = response-dose ratio for mannitol as percentage fall in FEV1 per mg of mannitol used (ie, maximum fall in FEV1 divided by total cumulative dose of mannitol given).

a 

Geometric mean (95% CIs).

Significance levels are given for within groups (FP100 and FP500 columns): bP < .001, cP < .01, dP < .05; and between groups in the rightmost column (repeated measures analysis of variance with Bonferroni correction).

Table Graphic Jump Location
Table 2 —Exponential One-Phase Decay Time for Domiciliary Feno

One-phase exponential decay curves for Feno significantly different between doses of FP each administered over 2 weeks (P < .0001). Data presented as time to percentage fall in Feno from pooled baseline (estimated 95% CIs). t1/2 = half-life of one-phase exponential decay. See Table 1 legend for expansion of other abbreviations.

a 

P < .001.

Figure Jump LinkFigure 3. Time-series morning and evening FeNO values and one-phase exponential decay curves. FeNO values displayed as geometric means at each sequential time point for each group. R2 = coefficient of determination (goodness of fit) of exponential decay curves to each data set; t1/2 = half-life of exponential decay. See Figure 1 and 2 legends for expansions of other abbreviations.Grahic Jump Location

Domiciliary spirometry demonstrated significant improvements in morning FEV1 as change from baseline within both FP100 (0.18 L [95% CI, 0.1-0.26 L], P < .001) and FP500 (0.18 L [95% CI, 0.08-0.29L], P = .004), but no significant differences in evening FEV1 at either dose, nor between groups for either morning or evening FEV1 (Table 1). Time-series morning and evening FEV1 (Fig 4) demonstrated significant linear patterns during pooled washout (FEV1 reduction = 0.21 L, R2 = 0.577, P < .001) and both FP100 (FEV1 increase = 0.08 L, R2 = 0.157, P = .04) and FP500 (FEV1 increase = 0.08 L, R2 = 0.262, P = .006). Results for domiciliary FEV6 are presented in Table 1. There was no significant diurnal variability of domiciliary spirometry.

Figure Jump LinkFigure 4. Time series for diurnal domiciliary FEV1. Sequential morning/evening mean FEV1 over 2 weeks for pooled washout, FP 100 μg/d, and FP 500 μg/d. Superimposed solid lines represent linear regression slopes. FP100 = FP 50 μg bid; FP500 = FP 250 μg bid. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

Mannitol PD15 demonstrated significant improvements with both FP100 and FP500 as doubling-dose shifts from baseline, with no difference between doses (Fig 5A, Table 1). This was mirrored by mannitol response-dose ratios (Table 1). There was significant reduction in serum ECP after FP500 but not FP100 (Fig 5B, Table 1). Blood eosinophils were significantly reduced by both doses as change from baseline, with no difference between doses (Fig 5C). For IOS outcomes, there were no significant changes for any variable at either dose. For laboratory visit-based spirometry outcomes, both FEV1 and FEF25-75 demonstrated significant improvements from baseline, with no differences between doses (Table 1, (e-Fig 2). FVC did not change significantly at either dose.

Figure Jump LinkFigure 5. Secondary inflammatory outcomes. A, Mean DD shift from baseline within groups for PD15. B, Percentage changes within groups from baseline for serum ECP. C, Percentage changes within groups from baseline for peripheral blood eosinophil counts. Error bars represent 95% CIs. DD = doubling dose; ECP = eosinophilic cationic protein; PD15 = provocative dose (of mannitol) that causes 15% fall in FEV1. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

ACQ score reduced significantly after 2 weeks in both groups from baseline with mean change exceeding the minimal important difference (>0.5), with absolute values after both FP100 and FP500 in keeping with well-controlled asthma (<0.75) (Fig 6A, Table 1). Mini-AQLQ overall score also improved significantly with both fluticasone doses from baseline (Fig 6C, Table 1). By separating the mini-AQLQ components, the same significant pattern was demonstrated for “symptoms” (Fig 6B, Table 1).

Figure Jump LinkFigure 6. Asthma control and quality-of-life outcomes. A, Mean ACQ score at baseline, 100 μg/d, and 500 μg/d FP. B, Mean AQLQ symptom score at baseline, FP100 μg/d, and FP500 μg/d. C, Mean AQLQ overall score at baseline, FP100 μg/d, and FP500 μg/d. Error bars represent 95% CIs. See Figure 2 and 4 legends for expansion of abbreviations.Grahic Jump Location

The present study has shown a significant dose-response relationship between diurnal Feno and incremental ICS dosing (fluticasone propionate 100 μg/d vs 500 μg/d) in patients with asthma expressing an elevated Feno inflammatory phenotype. Feno responses to both doses demonstrate predictable one-phase exponential decay, with significantly faster decline, and greater suppression of Feno at plateau, with the higher ICS dose. Indeed, early rapid improvements in Feno were seen even with low-dose ICS. Furthermore, we have demonstrated significant diurnal variability of Feno levels (higher in the morning) with or without ICS therapy.

To our knowledge, this is the first study to have evaluated response of serial domiciliary diurnal Feno in a dose-ranging manner with ICS. A previous study by Silkoff et al23 demonstrated a dose-response effect in patients with asthma with high baseline Feno levels using three separate doses of BDP, showing dose separation on Feno between only the lowest (100 μg) and highest (800 μg) doses, albeit each treatment period was only for 1 week. However, that study did not examine the effect of Feno reduction on asthma control, did not use domiciliary Feno, and moreover used methacholine rather than mannitol challenge. Other studies have examined Feno either in “all-comers” with asthma,24 or patients with asthma with near-normal baseline Feno,25 thus reducing any signal from this as an outcome; despite patients with asthma with high Feno (> 50 ppb) being more likely to respond to ICS than those with low Feno (< 25 ppb).4,26 In one study27 with extra-fine hydrofluoroalkane beclometasone, there was a plateau response at 100 μg/d, although mean baseline levels were only 33 ppb, compared with 71 ppb in this study. Around 30% of patients we screened demonstrated high Feno levels, even with ICS prescription; that is, this phenotype may represent a moderately large proportion of asthma overall. Our Feno response quantification was augmented by portable analyzers in the community, an approach used in children to monitor home Feno,17 but never before in adult patients with asthma or for the prospective assessment of treatment response.

We already know that personalizing asthma treatment according to phenotypes has proven benefits on symptoms, exacerbations, and asthma control over-and-above standard care. The Asthma Management Project University Leiden study10 demonstrated that by guiding asthma treatment using methacholine AHR, added to symptoms and lung function, greater asthma control could be achieved. Green et al11 investigated using sputum eosinophil counts to guide antiinflammatory therapy, demonstrating an overall reduction in exacerbations. We have used mannitol AHR to guide ICS therapy,12 showing a reduction in mild exacerbations over 12 months, along with significant improvements in methacholine AHR, salivary ECP, Feno, symptoms, and reliever use.

Our domiciliary Feno findings are supported by secondary (inflammatory) outcomes. Mannitol PD15 significantly improved with both doses of ICS in line with improvement in Feno as previously described.28 However, mannitol could not discriminate between ICS doses; that is, mannitol displays “assay sensitivity” for ICS treatment response, with a 1.84 doubling-dose shift at the lower dose, but no evidence of dose-response sensitivity. However, stratifying patients by severity of AHR to mannitol rather than Feno at study entry may alter this. For example, in a study powered on methacholine AHR there was a significant difference in response comparing 500 μg vs 100 μg daily of hydrofluoroalkane fluticasone over 2 weeks.29 Blood eosinophils and ECP also reduced with ICS but only at higher dose for ECP, suggesting this does not exhibit sufficient assay sensitivity. We chose our doses of fluticasone for this study based on previous dose-response data30,31 and the systemic safety of no significant cortisol suppression at the higher dose (500 μg/d).32,33 Interestingly, in a meta-analysis of studies with fluticasone, a plateau response was seen at 200 μg/d for various outcomes, although no inflammatory outcomes were evaluated.31

We also demonstrated significant diurnal variability of domiciliary Feno levels, with or without ICS, suggesting that Feno may be additionally controlled by factors other than local airway inflammation. Pointedly, we are the first to show that diurnal variability of Feno persists following incremental ICS dosing.

In terms of potential clinical relevance, the dose response of Feno to incremental ICS mirrored improvements in both asthma control and symptoms. Indeed, the baseline ACQ score demonstrated borderline asthma control with the 95% CI lower bound > 0.75, below which delineates good asthma control.34 The ACQ score improved significantly with both doses of ICS to mean scores that were below the 0.75 level (including upper 95% CI), while the mean change exceeded the minimum important difference of 0.5.35 Similarly, significant improvements were seen in the mini-AQLQ symptom component and overall score with both ICS doses. These are strong, clinically relevant signals for such a short study.

Significant but clinically unimportant changes were seen in all measurements of pulmonary function (domiciliary and laboratory). This is unsurprising given that baseline lung function (spirometry; IOS) was relatively well preserved in these patients, and has reduced sensitivity to change over short time periods.36

One limitation of this study was the short duration of ICS treatment, albeit this was a proof-of-concept study. However, there was still a significant and clinically important signal from the primary outcome of domiciliary Feno, along with clinically significant improvements in symptoms and asthma control. Moreover, previous data show that with AHR, a plateau response occurs after 2 weeks of treatment with fluticasone.31 There will be bias in phenotype-driven analyses, but we designed this a priori, given the demands for personalized treatment. One of the strengths of the present study was the novel use of diurnal domiciliary Feno to increase the signal-to-noise ratio, which may also have had a serendipitous effect on bolstering compliance to ICS. Pointedly, a rapid increase in Feno was seen during both washouts, demonstrating the speed at which disease activity returns without ICS. Furthermore, we used additional inflammatory markers to validate this phenotype. While presently, the cost of domiciliary Feno is prohibitive, it is possible that with developing technologies this cost will come down.

In conclusion, we have demonstrated a significant dose-response relationship to ICS using diurnal domiciliary Feno measurement in patients with asthma with elevated Feno as a common inflammatory phenotype. These responses follow predictable exponential decay that is significantly greater with higher ICS dosing. These findings translated into significant improvements in symptoms and asthma control in this selected phenotype despite the short study duration. Further studies are warranted in this specific asthma phenotype using longer-term outcome measures of asthma (eg, exacerbations) following treatment based on monitoring domiciliary Feno levels.

Author contributions: Dr Lipworth guarantees the study.

Dr Anderson: contributed to study management and data analysis and wrote all versions of the manuscript.

Dr Short: contributed to trial management and data analysis and critically appraised and gave final approval of the manuscript.

Dr Williamson: contributed to study design and trial management and critically appraised and gave final approval of the manuscript.

Dr Lipworth: contributed to study design and data analysis and critically appraised and gave final approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Anderson has received support to attend international meetings from Boehringer Ingelheim GmbH and GlaxoSmithKline plc. Dr Williamson has given paid lectures for Teva Pharmaceuticals USA, GlaxoSmithKline plc, Chiesi Ltd, and Pfizer, Inc; and has received support to attend international meetings from Teva Pharmaceuticals USA and GlaxoSmithKline plc. Dr Lipworth has received unrestricted educational grants from Teva Pharmaceuticals USA, Pharmaxis Ltd, Chiesi Ltd, and Takeda Pharmaceuticals International GmbH; has performed consultancy work for Chiesi Ltd, Sandoz, Takeda Pharmaceuticals International GmbH, Fannin, Neolab Ltd, and Meda Pharmaceuticals Inc; and has received support to attend international meetings from GlaxoSmithKline plc, Teva Pharmaceuticals USA, Chiesi Ltd, Pharmaxis Ltd, and Takeda Pharmaceuticals International GmbH. Dr Short has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Additional information: The e-Figures and e-Table can be found in the “Supplemental Materials” area of the online article.

ACQ

Asthma Control Questionnaire

AHR

airway hyperresponsiveness

AQLQ

Asthma Quality-of-Life Questionnaire

BDP

beclometasone dipropionate

ECP

eosinophilic cationic protein

FEF25-75

forced expiratory flow between 25% and 75% of FVC

Feno

fractional exhaled nitric oxide

FEV6

forced expiratory volume in 6 s

FP

fluticasone propionate

FP100

fluticasone propionate 50 μg bid

FP500

fluticasone propionate 250 μg bid

ICS

inhaled corticosteroid

IOS

impulse oscillometry

PD15

provocative dose (of mannitol) that causes 15% fall in FEV1

ppb

parts per billion

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Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-907. [CrossRef] [PubMed]
 
Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the Mini Asthma Quality of Life Questionnaire. Eur Respir J. 1999;14(1):32-38. [CrossRef] [PubMed]
 
Moore VC, Parsons NR, Jaakkola MS, et al. Serial lung function variability using four portable logging meters. J Asthma. 2009;46(9):961-966. [CrossRef] [PubMed]
 
Silkoff PE, McClean P, Spino M, Erlich L, Slutsky AS, Zamel N. Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest. 2001;119(5):1322-1328. [CrossRef] [PubMed]
 
Shaw DE, Berry MA, Thomas M, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med. 2007;176(3):231-237. [CrossRef] [PubMed]
 
Jones SL, Herbison P, Cowan JO, et al. Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship. Eur Respir J. 2002;20(3):601-608. [CrossRef] [PubMed]
 
Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med. 2005;172(4):453-459. [CrossRef] [PubMed]
 
Fardon TC, Burns P, Barnes ML, Lipworth BJ. A comparison of 2 extrafine hydrofluoroalkane-134a-beclomethasone formulations on methacholine hyperresponsiveness. Ann Allergy Asthma Immunol. 2006;96(3):422-430. [CrossRef] [PubMed]
 
Porsbjerg C, Lund TK, Pedersen L, Backer V. Inflammatory subtypes in asthma are related to airway hyperresponsiveness to mannitol and exhaled NO. J Asthma. 2009;46(6):606-612. [CrossRef] [PubMed]
 
Nair A, Vaidyanathan S, Clearie K, Williamson P, Meldrum K, Lipworth BJ. Steroid sparing effects of intranasal corticosteroids in asthma and allergic rhinitis. Allergy. 2010;65(3):359-367. [CrossRef] [PubMed]
 
Sovijärvi AR, Haahtela T, Ekroos HJ, et al. Sustained reduction in bronchial hyperresponsiveness with inhaled fluticasone propionate within three days in mild asthma: time course after onset and cessation of treatment. Thorax. 2003;58(6):500-504. [CrossRef] [PubMed]
 
Masoli M, Weatherall M, Holt S, Beasley R. Clinical dose-response relationship of fluticasone propionate in adults with asthma. Thorax. 2004;59(1):16-20. [PubMed]
 
Fowler SJ, Orr LC, Wilson AM, Sims EJ, Lipworth BJ. Dose-response for adrenal suppression with hydrofluoroalkane formulations of fluticasone propionate and beclomethasone dipropionate. Br J Clin Pharmacol. 2001;52(1):93-95. [CrossRef] [PubMed]
 
Fowler SJ, Orr LC, Sims EJ, et al. Therapeutic ratio of hydrofluoroalkane and chlorofluorocarbon formulations of fluticasone propionate. Chest. 2002;122(2):618-623. [CrossRef] [PubMed]
 
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee GOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006;100(4):616-621. [CrossRef] [PubMed]
 
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5):553-558. [CrossRef] [PubMed]
 
Zhang J, Yu C, Holgate ST, Reiss TF. Variability and lack of predictive ability of asthma end-points in clinical trials. Eur Respir J. 2002;20(5):1102-1109. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Consolidated Standards of Reporting Trials diagram. FeNO = fractional exhaled nitric oxide; ppb = parts per billion.Grahic Jump Location
Figure Jump LinkFigure 2. Study flow diagram. ACQ = Asthma Control Questionnaire; AQLQ = mini-Asthma Quality of Life Questionnaire; FEV6 = forced expiratory volume in 6 s; FP = fluticasone propionate; ICS = inhaled corticosteroid; Mannitol = mannitol bronchial challenge; S1, S2 = screening visits; V0 = prewashout visit; washout periods are sequential (ie, irrespective of FP dose); V1-4 = study visits. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Time-series morning and evening FeNO values and one-phase exponential decay curves. FeNO values displayed as geometric means at each sequential time point for each group. R2 = coefficient of determination (goodness of fit) of exponential decay curves to each data set; t1/2 = half-life of exponential decay. See Figure 1 and 2 legends for expansions of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Time series for diurnal domiciliary FEV1. Sequential morning/evening mean FEV1 over 2 weeks for pooled washout, FP 100 μg/d, and FP 500 μg/d. Superimposed solid lines represent linear regression slopes. FP100 = FP 50 μg bid; FP500 = FP 250 μg bid. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Secondary inflammatory outcomes. A, Mean DD shift from baseline within groups for PD15. B, Percentage changes within groups from baseline for serum ECP. C, Percentage changes within groups from baseline for peripheral blood eosinophil counts. Error bars represent 95% CIs. DD = doubling dose; ECP = eosinophilic cationic protein; PD15 = provocative dose (of mannitol) that causes 15% fall in FEV1. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6. Asthma control and quality-of-life outcomes. A, Mean ACQ score at baseline, 100 μg/d, and 500 μg/d FP. B, Mean AQLQ symptom score at baseline, FP100 μg/d, and FP500 μg/d. C, Mean AQLQ overall score at baseline, FP100 μg/d, and FP500 μg/d. Error bars represent 95% CIs. See Figure 2 and 4 legends for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Domiciliary and Visit Outcome Measurements

Domiciliary data are means of days 12 to 14 from washout (baseline), and each treatment period for morning or evening. Visit data are fixed time-point measurements. Data are presented as arithmetic means (95% CIs) unless stated. ACQ = Asthma Control Questionnaire; AQLQ = Asthma Quality-of-Life Questionnaire; ECP = eosinophilic cationic protein; FEF25-75 = forced expiratory volume between 25% and 75% of FVC; Feno = fractional exhaled nitric oxide; FEV6 = forced expiratory volume in 6 s; FP = fluticasone propionate; FP100 = flucticasone propionate 50 μg bid; FP500 = flucticasone propionate 250 μg bid; Fres = frequency of resonance; IOS = impulse oscillometry; PD15 = provocative dose (of mannitol) that causes 15% fall in FEV1; ppb = parts per billion; pred = predicted; R5 = resistance at 5 Hz; RDR = response-dose ratio for mannitol as percentage fall in FEV1 per mg of mannitol used (ie, maximum fall in FEV1 divided by total cumulative dose of mannitol given).

a 

Geometric mean (95% CIs).

Significance levels are given for within groups (FP100 and FP500 columns): bP < .001, cP < .01, dP < .05; and between groups in the rightmost column (repeated measures analysis of variance with Bonferroni correction).

Table Graphic Jump Location
Table 2 —Exponential One-Phase Decay Time for Domiciliary Feno

One-phase exponential decay curves for Feno significantly different between doses of FP each administered over 2 weeks (P < .0001). Data presented as time to percentage fall in Feno from pooled baseline (estimated 95% CIs). t1/2 = half-life of one-phase exponential decay. See Table 1 legend for expansion of other abbreviations.

a 

P < .001.

References

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Lipworth BJ, Short PM, Williamson PA, Clearie KL, Fardon TC, Jackson CM. A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial. Chest. 2012;141(3):607-615. [CrossRef] [PubMed]
 
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Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005;352(21):2163-2173. [CrossRef] [PubMed]
 
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Olin AC, Rosengren A, Thelle DS, Lissner L, Bake B, Torén K. Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample. Chest. 2006;130(5):1319-1325. [CrossRef] [PubMed]
 
Vahlkvist S, Sinding M, Skamstrup K, Bisgaard H. Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure. J Allergy Clin Immunol. 2006;117(6):1272-1276. [CrossRef] [PubMed]
 
Miller MR, Hankinson J, Brusasco V, et al;; ATS/ERS Task Force ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. [CrossRef] [PubMed]
 
Currie GP, Haggart K, Brannan JD, Lee DK, Anderson SD, Lipworth BJ. Relationship between airway hyperresponsiveness to mannitol and adenosine monophosphate. Allergy. 2003;58(8):762-766. [CrossRef] [PubMed]
 
Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-907. [CrossRef] [PubMed]
 
Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the Mini Asthma Quality of Life Questionnaire. Eur Respir J. 1999;14(1):32-38. [CrossRef] [PubMed]
 
Moore VC, Parsons NR, Jaakkola MS, et al. Serial lung function variability using four portable logging meters. J Asthma. 2009;46(9):961-966. [CrossRef] [PubMed]
 
Silkoff PE, McClean P, Spino M, Erlich L, Slutsky AS, Zamel N. Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest. 2001;119(5):1322-1328. [CrossRef] [PubMed]
 
Shaw DE, Berry MA, Thomas M, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med. 2007;176(3):231-237. [CrossRef] [PubMed]
 
Jones SL, Herbison P, Cowan JO, et al. Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship. Eur Respir J. 2002;20(3):601-608. [CrossRef] [PubMed]
 
Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med. 2005;172(4):453-459. [CrossRef] [PubMed]
 
Fardon TC, Burns P, Barnes ML, Lipworth BJ. A comparison of 2 extrafine hydrofluoroalkane-134a-beclomethasone formulations on methacholine hyperresponsiveness. Ann Allergy Asthma Immunol. 2006;96(3):422-430. [CrossRef] [PubMed]
 
Porsbjerg C, Lund TK, Pedersen L, Backer V. Inflammatory subtypes in asthma are related to airway hyperresponsiveness to mannitol and exhaled NO. J Asthma. 2009;46(6):606-612. [CrossRef] [PubMed]
 
Nair A, Vaidyanathan S, Clearie K, Williamson P, Meldrum K, Lipworth BJ. Steroid sparing effects of intranasal corticosteroids in asthma and allergic rhinitis. Allergy. 2010;65(3):359-367. [CrossRef] [PubMed]
 
Sovijärvi AR, Haahtela T, Ekroos HJ, et al. Sustained reduction in bronchial hyperresponsiveness with inhaled fluticasone propionate within three days in mild asthma: time course after onset and cessation of treatment. Thorax. 2003;58(6):500-504. [CrossRef] [PubMed]
 
Masoli M, Weatherall M, Holt S, Beasley R. Clinical dose-response relationship of fluticasone propionate in adults with asthma. Thorax. 2004;59(1):16-20. [PubMed]
 
Fowler SJ, Orr LC, Wilson AM, Sims EJ, Lipworth BJ. Dose-response for adrenal suppression with hydrofluoroalkane formulations of fluticasone propionate and beclomethasone dipropionate. Br J Clin Pharmacol. 2001;52(1):93-95. [CrossRef] [PubMed]
 
Fowler SJ, Orr LC, Sims EJ, et al. Therapeutic ratio of hydrofluoroalkane and chlorofluorocarbon formulations of fluticasone propionate. Chest. 2002;122(2):618-623. [CrossRef] [PubMed]
 
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee GOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006;100(4):616-621. [CrossRef] [PubMed]
 
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5):553-558. [CrossRef] [PubMed]
 
Zhang J, Yu C, Holgate ST, Reiss TF. Variability and lack of predictive ability of asthma end-points in clinical trials. Eur Respir J. 2002;20(5):1102-1109. [CrossRef] [PubMed]
 
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