Showing papers by "William W. Busse published in 2013"

Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study.

Abstract: Rationale: For many patients with asthma, allergic airway inflammation is primarily a Th2-weighted process; however, heterogeneity in patterns of inflammation suggests phenotypic distinctions exist that influence disease presentation and treatment effects.Objectives: To assess the potential of fractional exhaled nitric oxide (FeNO), peripheral blood eosinophil count, and serum periostin as biomarkers of Th2 inflammation and predictors of treatment effects of omalizumab.Methods: The EXTRA omalizumab study enrolled patients (aged 12–75 yr) with uncontrolled severe persistent allergic asthma. Analyses were performed evaluating treatment effects in relation to FeNO, blood eosinophils, and serum periostin at baseline. Patients were divided into low- and high-biomarker subgroups. Treatment effects were evaluated as number of protocol-defined asthma exacerbations during the 48-week treatment period (primary endpoint).Measurements and Main Results: A total of 850 patients were enrolled. Data were available from 3...

Randomized, Double-Blind, Placebo-controlled Study of Brodalumab, a Human Anti–IL-17 Receptor Monoclonal Antibody, in Moderate to Severe Asthma

Abstract: Rationale: IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment.Objectives: To determine efficacy and safety of brodalumab, a human anti–IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids.Methods: Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation.Measurements and Main Results: Demographics and baseline characteristics were generally balanced among ...

Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia

Abstract: Background Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity. Objectives We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood. Methods In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive. Results The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 + 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts. Conclusion Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients.

An Association between l-Arginine/Asymmetric Dimethyl Arginine Balance, Obesity, and the Age of Asthma Onset Phenotype

Abstract: Rationale: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (FeNO). This may be explained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to l-arginine, which can lead to greater nitric oxide synthase uncoupling. Objectives: To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function. Methods: Cross-sectional study of participants from the Severe Asthma Research Program, across early- ( 12 yr) onset asthma phenotypes. Measurements and Main Results: Subjects with late-onset asthma had a higher median plasma ADMA level (0.48 μM, [interquartile range (IQR), 0.35–0.7] compared with early onset, 0.37 μM [IQR, 0.29–0.59], P = 0.01) and lower median plasma l-arginine (late onset, 52.3 [IQR, 43–61] compared with early onset, 51 μM [IQR 39–66]; P = 0.02). The log of plasma l-arginine/ADMA was inversely correlated with BMI in the late- (r = −0.4, P = 0.0006) in contrast to the early-onset phenotype (r = −0.2, P = 0.07). Although FeNO was inversely associated with BMI in the late-onset phenotype (P = 0.02), the relationship was lost after adjusting for l-arginine/ADMA. Also in this phenotype, a reduced l-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. Conclusions: In late-onset asthma phenotype, plasma ratios of l-arginine to ADMA may explain the inverse relationship of BMI to FeNO. In addition, these lower l-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.

High eosinophil count: A potential biomarker for assessing successful omalizumab treatment effects

Abstract: High No. of protocol-defined asthma exacerbations, n (%) 0 41 (80.4) 25 (62.5) 1 9 (17.6) 9 (22.5) >_2 1 (2.0) 6 (15.0) Unadjusted exacerbation rate* 0.25 0.59 Poisson regression§ Ratio of exacerbation rates (95% CI) 0.41 (0.20-0.82) P value .0125 Low (n 5 56) (n 5 70) No. of protocol-defined asthma exacerbations, n (%) 0 48 (85.7) 60 (85.7) 1 7 (12.5) 9 (12.9) >_2 1 (1.8) 1 (1.4) Unadjusted exacerbation rate* 0.17 0.16 Poisson regression Ratio of exacerbation rates§ (95% CI) 1.07 (0.45-2.53) P value .8807

Glucocorticoid-induced osteoporosis: An update on effects and management

Abstract: Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures

Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients

Abstract: Background Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. Objective We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. Methods Genome-wide association studies of lung function (percent predicted FEV 1 [ppFEV 1 ], percent predicted forced vital capacity, and FEV 1 /forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses. Results Seven of 28 previously identified lung function loci ( HHIP , FAM13A , THSD4 , GSTCD , NOTCH4-AGER , RARB , and ZNF323 ) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels ( P IL12A , IL12RB1 , STAT4 , and IRF2 ) associated with ppFEV 1 ( P −4 ) belong to the T H 1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 T H 1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV 1 values in 4 populations ( P = 3 × 10 −11 ). Genetic scores of these 4 SNPs were associated with ppFEV 1 values ( P = 2 × 10 −7 ) and the American Thoracic Society severe asthma classification ( P = .005) in the Severe Asthma Research Program population. T H 2 pathway genes ( IL13 , TSLP , IL33 , and IL1RL1 ) conferring asthma susceptibility were not associated with lung function. Conclusion Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. T H 1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.

Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients

Abstract: Background The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on T H 2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2. Objective We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma. Methods Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting β-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting β-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV 1 , symptom scores, rescue short-acting β-agonist use, and exacerbations. Results Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, −0.492; range for AMG 853 groups [n = 317], −0.444 to −0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator. Conclusion AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma.

Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β2 agonist vilanterol administered once daily for 52 weeks in patients ≥12 years old with asthma: a randomised trial

Abstract: Background The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β 2 agonist vilanterol (VI) is in development for asthma and chronic obstructive pulmonary disease. Objective To assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma. Methods Patients (aged ≥12 years; on inhaled corticosteroid) were randomised (2:2:1) to FF/VI 100/25 µg or FF/VI 200/25 µg once daily in the evening, or fluticasone propionate (FP) 500 µg twice daily. Safety evaluations included adverse events (AEs), non-fasting glucose, potassium, 24-h urinary cortisol excretion, ophthalmic assessments, heart rate and pulse rate. Results On-treatment AEs were similar across groups (FF/VI 66–69%; 73% FP). Oral candidiasis/oropharyngeal candidiasis was more common with FF/VI (6–7%) than FP (3%). Twelve serious AEs were reported; one (worsening hepatitis B on FP) was considered drug related. Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 (ratios [95% CI] to FP ranged from 1.43 [1.11 to 1.84] to 1.67 [1.34 to 2.08]; p≤0.006), but not at Week 52 (ratios to FP were 1.05 [0.83 to 1.33] for FF/VI 100/25 µg and 1.09 [0.87 to 1.38] for FF/VI 200/25 µg). No clinically important changes in non-fasting glucose, potassium, QT interval corrected using Fridericia9s formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [T max ], Week 52) was significantly increased with FF/VI versus FP (3.4 bpm, 95% CI 1.3 to 5.6; p=0.002 [FF/VI 100/25 µg]; 3.4 bpm, 95% CI 1.2 to 5.6; p=0.003 [FF/VI 200/25 µg]). Mean heart rate (24-h Holter monitoring) decreased from screening values in all groups (0.2–1.1 bpm FF/VI vs 5 bpm FP; Week 52). Conclusions FF/VI (100/25 µg or 200/25 µg) administered once daily over 52 weeks was well tolerated by patients aged ≥12 years with asthma. The overall safety profile of FF/VI did not reveal any findings of significant clinical concern. ClinicalTrials.gov NCT01018186

Budesonide and formoterol effects on rhinovirus replication and epithelial cell cytokine responses

Abstract: Background Combination therapy with budesonide and formoterol reduces exacerbations of asthma, which are closely associated with human rhinovirus (RV) infections in both children and adults. These data suggest that budesonide and formoterol inhibit virus-induced inflammatory responses of airway epithelial cells.

Markers of vascular perturbation correlate with airway structural change in asthma

Abstract: Rationale: Air trapping and ventilation defects on imaging are characteristics of asthma. Airway wall thickening occurs in asthma and is associated with increased bronchial vascularity and vascular permeability. Vascular endothelial cell products have not been explored as a surrogate to mark structural airway changes in asthma. Objectives: Determine whether reporters of vascular endothelial cell perturbation correlate with airway imaging metrics in patients with asthma of varying severity. Methods: Plasma from Severe Asthma Research Program subjects was analyzed by ELISAs for soluble von Willebrand factor mature protein (VWF:Ag) and propeptide (VWFpp), P-selectin, and platelet factor 4. Additional subjects were analyzed over 48 hours after whole-lung antigen challenge. We calculated ventilation defect volume by hyperpolarized helium-3 magnetic resonance imaging and areas of low signal density by multidetector computed tomography (less than −856 Hounsfield units [HU] at functional residual capacity and −950 HU at total lung capacity [TLC]). Measurements and Main Results: VWFpp and VWFpp/Ag ratio correlated with and predicted greater percentage defect volume on hyperpolarized helium-3 magnetic resonance imaging. P-selectin correlated with and predicted greater area of low density on chest multidetector computed tomography less than −950 HU at TLC. Platelet factor 4 did not correlate. Following whole-lung antigen challenge, variation in VWFpp, VWFpp/Ag, and P-selectin among time-points was less than that among subjects, indicating stability and repeatability of the measurements. Conclusions: Plasma VWFpp and P-selectin may be useful as surrogates of functional and structural defects that are evident on imaging. The results raise important questions about why VWFpp and P-selectin are associated specifically with different imaging abnormalities.

Middleton's Allergy: Principles and Practice: Eighth Edition

Abstract: 30여 년 전에 Elliott Middleton Jr, Charles E. Reed, Elliot F. Ellis가 천식과 알레르기 질환들과 관련된 새롭고 포괄적인 교과서의 편찬에 대한 생각을 착안하였고, Allergy: Principles and Practice의 첫 판을 발간하였다. 이 Middleton’s Allergy: Principles and Practice의 7번째 판은 위의 원년 저자들의 결실이며, 혁신적이고 탁월한 시각과 선견을 담은, 현재도 그 발전 을 진행하고 있는 기념물적인 저서이다. 이 책의 일부 chapter는 여러 저서나 논문들에 실린 중요한 내용을 가장 이해하기 쉽 게 요약하였다고 생각한다. 따라서, Allergy: Principles and Practice는 교과서로써 뿐만 아니라, 참고문헌집으로써의 역할 을 한다. 따라서 이 책은 allergy를 공부하는 모든 학생, 임상의, 임상연구자, 또는 기초 연구자들, 알레르기 검사를 위한 훈련 생, 의과대학생에게 매우 유익하다. 매번의 개정을 통해 알레르기 염증반응과 그와 관련된 알레르기 질환에 대한 가장 최신 의 권위적인 정보를 제공하고 있다. 이를 위해 이 책은 Allergy라는 기초 과학의 토대(PRINCIPLES)에 관한 정보를 제공하 고, 이러한 정보를 임상적인 적용에 접목(PRACTICE)하는 초판부터 고집해온 방법을 고수하고 있다. 이러한 접근은 기초과 학연구의 발견 또는 지식을 임상의학에 적용하는 중계연구라는 최근의 노력들과 그 맥을 같이 한다고 할 수 있다. 이 책은 총 2권으로 구성되어 있는데, 제 1권은 allergic inflammation의 기초적인 ‘PRINCIPLE’과 그 기원에 대해 기술하 고 있다. 제 1권은 세 개의 섹션으로 구성되어 있는데, 주로 면역세포들의 biology와 그와 관련된 알레르기 반응과정들이 기술 되어 있는 ‘IMMUNOLOGY’, ‘AEROBIOLOGY AND ALLERGENS’, 주위환경에 감작된 개체의 기능적 상호작용을 나타 내는 ‘PHYSIOLOGY’로 구성되어 있다. 제 2권은 ‘PRACTICE’와 관련된 내용이다. 역시 세 개의 섹션으로 구성되며, 기초과학 적인 측면을 임상과학으로 중계한 ‘CLINICAL SCIENCE’, ‘DIAGNOSIS AND APPROACH TO THE PATIENT’, 그리고 마지막으로 ‘THERAPEUTICS’에 대해 기술하고 있다. 이 책은 ELSEVIER 출판사를 통해 출간되었고 “expertconsult.com”을 통해 책을 등록하면 어디서든 온라인으로 책을 읽 을 수 있다. 이 책을 통해 알레르기 염증반응과 알레르기 질환을 공부하고 싶은 모든 사람에게 기초적인 면역학적 지식뿐만 아니라, 최 신의 연구경향과 결과를 쉽게 접할 수 있게 하며, 임상질환에서의 응용을 모색하는 모든 연구자에게 귀중한 정보를 제공할 것으로 기대한다.

A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, Tolerability, and Efficacy of Brodalumab (AMG 827) in Subjects with Moderate to Severe Asthma

Abstract: T U E S D A Y 816 Effect of Inhaled Corticosteroids (ICS) Vs. Inhaled Corticosteroid with Long-Acting Beta2 Agonists (ICS/LABA) On Asthma Control: Results From National Asthma Survey Neetu Talreja, MD, Dennis K. Ledford, MD, FAAAAI, Richard F. Lockey, MD; Morsani College of Medicine University of South Florida and James A. Haley Veteran Hospital. RATIONALE: There is limited evidence for the comparative efficacy of ICS vs. ICS/LABA to treat asthma in children under 12 years. METHODS: Data from the 2003 National Asthma Survey were analyzed to compare asthma control in children (5 to 11 yrs) using ICS vs. ICS/LABA. Both short term (symptoms within last 2 weeks, day and night symptoms in last 30 days and use of systemic glucocorticoids in last 3 months) and long term (asthma exacerbation, emergency department visits, hospitalizations and activity limitations in the prior year) outcomes were compared. Demographics, availability of health insurance, indoor allergen exposure and asthma education were compared between the two groups. Asthma control in adult (18 to 44 years) and older population (>565 years) was also assessed for the same parameters. RESULTS: 134 children on ICS and 69 on ICS/LABA were identified. Baseline characteristics were similar in both groups. There were no differences in short and long term asthma outcomes between the two groups (p>0.05 for all outcome measures). Similar results were obtained with the adult and older population (p>0.05 for all outcome measures). ICS/LABAwas used for more than 6 months in 58% of children, 81% of adults and 46% of the older population. CONCLUSIONS: Asthma control in children using ICS vs. ICS/LABA was similar. So was asthma control using similar medications in the adult and older populations. LABA tolerance or the use of ICS/LABA in subjects with more severe asthma could explain these findings.

Efficacy and safety of once-daily (OD) fluticasone furoate (FF) 50mcg over 24 weeks in adults and adolescents with persistent asthma

Abstract: Introduction: The OD FF 50mcg dose showed effectiveness in asthma patients (pts) uncontrolled by short-acting β2 agonists (SABAs) in a 12-week dose-ranging study. Objective: To assess efficacy/safety of FF 50mcg OD compared with placebo (PBO) in pts with asthma uncontrolled by non-corticosteroid therapies and/or SABA. Methods: Randomised, double-blind, double-dummy, parallel-group study (N=347;ITT) of FF 50mcg in the PM via dry powder inhaler, FP (active control) 100mcg BD via DISKUS or PBO for 24 weeks. Endpoints (all Δ baseline): primary–trough (pre-bronch.) FEV1; secondary–%rescue-free 24-h periods (powered; %RF), PM and AM PEF, %symptom-free 24-h periods (%SF). Safety was assessed throughout. Results: FF (126mL), FP (191mL) and PBO (89mL) increased trough FEV1 at 24 weeks vs baseline. %RF: FF 28.9, FP 31.7, PBO 21.1. PM PEF (L/min): FF 24.9, FP 12.0, PBO 7.6. AM PEF (L/min): FF 30.0, FP 21.4, PBO 10.8. %SF: FF 25.1, FP 24.3, PBO 16.8. See Table for treatment differences. AE profile was broadly similar across groups; AEs of special interest: FP and PBO both 10%; FF 3%. ![Figure][1] Conclusions: This study showed a small statistically significant improvement in trough FEV1 with FP, but not FF, vs PBO in pts with persistent asthma uncontrolled by non-ICS therapy. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP. Funded by GSK (FFA115285;[NCT01436110][2]). [1]: pending:yes [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01436110&atom=%2Ferj%2F42%2FSuppl_57%2FP3397.atom

Efficacy and safety of once-daily (OD) fluticasone furoate (FF) in adults and adolescents with moderate-to-severe persistent asthma

Abstract: Introduction: FF OD is effective in asthma patients (pts) uncontrolled by low-dose ICS (100mcg, 200mcg) or mid-dose ICS (200mcg). Objective: To assess efficacy/safety of two strengths of FF in pts (aged ≥12 years) with moderate-to-severe persistent asthma uncontrolled on a total daily dose of FP >250–1000mcg (or equivalent). Methods: Randomised, double-blind, parallel-group, descriptive (no formal inference was planned) study (N=219; ITT) of FF 100mcg or FF 200mcg OD in the PM via dry powder inhaler for 24 weeks. Endpoints (all Δ baseline [BL]): primary – trough (pre-bronch.) FEV1; secondary/other – %rescue-free 24-h periods (%RF), PM/AM PEF, %symptom-free 24-h periods (%SF), Asthma Control Test (ACT) scores. Safety: AEs, 24-h urine cortisol (UC) excretion, laboratory tests. Results: Data are for FF 100, FF 200. FF increased trough FEV1 (208mL, 284mL), %RF (21.3, 23.1), PM PEF (5.9L/min, 7.2L/min), AM PEF (13.4L/min, 13.2L/min), %SF (17.5, 19.6), ACT score (4.5, 4.9) and %pts ACT score ≥20 (53%, 59%). See Figure for treatment differences. AE profile was broadly similar across groups, except treatment-related AEs (<1%, 5%). No clinically relevant Δ 24-h UC (ratio vs BL: 1.15, 1.09) or laboratory tests. Conclusions: Relative to baseline, FF showed consistent improvements in efficacy (often numerically greater with FF 200mcg) and no safety concerns. Funded by GSK (FFA114496;[NCT01431950][1]). ![Figure][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01431950&atom=%2Ferj%2F42%2FSuppl_57%2FP3398.atom [2]: pending:yes

Authors’ reply to ‘Safety and tolerability of fluticasone furoate/vilanterol’

Abstract: We thank Dr Lipworth for his response to our article on the safety and tolerability of fluticasone furoate/vilanterol (FF/VI) combination in asthma,1 in which he specifically discusses effects on urinary cortisol. We acknowledge the limitations of urinary cortisol assessment; however, as outlined in the online supplement, the urinary cortisol population in our study specifically excluded subjects with an incomplete urine collection and/or 24-h urinary creatinine levels below the lower limit of the threshold range. Thus, our data are not confounded …