[Show abstract][Hide abstract] ABSTRACT: Real-world data on the benefit/risk profile of medicines is needed, particularly in patients who are ineligible for randomised controlled trials conducted for registration purposes. This paper describes the methodology and source data verification which enables the conduct of pre-licensing clinical trials of COPD and asthma in the community using the electronic medical record (EMR), NorthWest EHealth linked database (NWEH-LDB) and alert systems.
Dual verification of extracts into NWEH-LDB was performed using two independent data sources (Salford Integrated Record [SIR] and Apollo database) from one primary care practice in Salford (N = 3504). A feasibility study was conducted to test the reliability of the NWEH-LDB to support longitudinal data analysis and pragmatic clinical trials in asthma and COPD. This involved a retrospective extraction of data from all registered practices in Salford to identify a cohort of patients with a diagnosis of asthma (aged ≥18) and/or COPD (aged ≥40) and ≥2 prescriptions for inhaled bronchodilators during 2008. Health care resource utilisation (HRU) outcomes during 2009 were assessed. Exacerbations were defined as: prescription for oral corticosteroids (OCS) in asthma and prescription of OCS or antibiotics in COPD; and/or hospitalisation for a respiratory cause.
Dual verification demonstrated consistency between SIR and Apollo data sources: 3453 (98.6%) patients were common to both systems; 99.9% of prescription records were matched and of 29,830 diagnosis records, one record was missing from Apollo and 272 (0.9%) from SIR. Identified COPD patients were also highly concordant (Kappa coefficient = 0.98). A total of 7981 asthma patients and 4478 COPD patients were identified within the NWEH-LDB. Cohort analyses enumerated the most commonly prescribed respiratory medication classes to be: inhaled corticosteroids (ICS) (42%) and ICS plus long-acting β2-agonist (LABA) (40%) in asthma; ICS plus LABA (55%) and long-acting muscarinic antagonists (36%) in COPD. During 2009 HRU was greater in the COPD versus asthma cohorts, and exacerbation rates in 2009 were higher in patients who had ≥2 exacerbations versus ≤1 exacerbation in 2008 for both asthma (137.5 vs. 20.3 per 100 person-years, respectively) and COPD (144.6 vs. 41.0, respectively).
Apollo and SIR data extracts into NWEH-LDB showed a high level of concordance for asthma and COPD patients. Longitudinal data analysis characterized the COPD and asthma populations in Salford including medications prescribed and health care utilisation outcomes suitable for clinical trial planning.
BMC Medical Informatics and Decision Making 12/2015; 15(1). DOI:10.1186/s12911-015-0132-z · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy.
Patients with chronic obstructive pulmonary disease (COPD), ≥40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data.
The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in COPD.
Clinicaltrials.gov identifier NCT01551758 .
Respiratory research 09/2015; 16(1):101. DOI:10.1186/s12931-015-0267-6 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fluticasone furoate (FF; inhaled corticosteroid) combined with vilanterol (VI; long-acting beta2 agonist) is a once-daily therapy for asthma and chronic obstructive pulmonary disease. This 12-week phase III study compared the efficacy and safety of once-daily (evening dosing) FF/VI 100/25 mcg versus FF 100 mcg (primary objective) and FF/VI 100/25 mcg versus FF/VI 200/25 mcg (descriptive comparison only) in patients (n = 1039) ≥12 years with moderate-to-severe persistent asthma.
The primary end point was weighted mean (wm) 0-24-h serial forced expiratory volume in 1 s (FEV1) at week 12. Secondary end points (change from baseline) were trough FEV1 and the proportion (%) of rescue-free 24-h periods (both powered), the proportion (%) of symptom-free 24-h periods, and morning and evening peak expiratory flow (PEF). Safety data (adverse events, AEs) were collected throughout.
Compared with FF 100 mcg, FF/VI 100/25 mcg significantly improved wmFEV1 (p < 0.001), trough FEV1 (p = 0.014), % rescue-free (p < 0.001), % symptom-free (p = 0.002) 24-h periods, and morning and evening PEF (p < 0.001). FF/VI 200/25 mcg produced small numerical improvements versus FF/VI 100/25 mcg for all end points. Incidence of AEs was similar across groups.
FF/VI 100/25 mcg resulted in significant improvements in all primary and secondary end points versus FF 100 mcg. Numerical improvements occurred with FF/VI 200/25 mcg versus FF/VI 100/25 mcg. All treatments were well tolerated.
Journal of Asthma 08/2015; DOI:10.3109/02770903.2015.1056350 · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We created Asthma e-Lab, a secure web-based research environment to support consistent recording, description and sharing of data, computational/statistical methods and emerging findings across the five UK birth cohorts. The e-Lab serves as a data repository for our unified dataset and provides the computational resources and a scientific social network to support collaborative research. All activities are transparent, and emerging findings are shared via the e-Lab, linked to explanations of analytical methods, thus enabling knowledge transfer. eLab facilitates the iterative interdisciplinary dialogue between clinicians, statisticians, computer scientists, mathematicians, geneticists and basic scientists, capturing collective thought behind the interpretations of findings.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Introduction Chronic cough is a troublesome condition that reduces patient quality of life. Recent evidence suggests that healthy females cough more than healthy males but the mechanism underlying this in unclear.1 We hypothesise that opiate-sensitive inhibitory control mechanisms determine capsaicin-evoked cough responses in healthy subjects.
Aim To show that in healthy males the number of capsaicin-evoked coughs is increased following administration of naltrexone, an opiate receptor antagonist, compared with placebo.
Method 15 male subjects (median age 30 yrs (21–59)) were recruited in to a randomised double blind cross-over trial of single doses of naltrexone vs. placebo given 1 week apart. A capsaicin inhalational challenge (doubling doses 0.48 to 125[micro]M) was performed 60 min after ingestion of naltrexone/placebo using a dosimeter. Four inhalations 30 seconds apart were performed at each concentration and the total coughs evoked at each dose were recorded and verified using a cough monitor.
Results There was a tendency for subjects to cough more when treated with naltrexone (16.7 ± 2.7 (SEM) compared with placebo (13.7 ± 1.6), (p = 0.11, general estimating equations). See Figure 1
Conclusion This small pilot study suggest that opiate sensitive inhibitory mechanisms may have a role in controlling the cough reflex even in healthy subjects.
[Show abstract][Hide abstract] ABSTRACT: Background A recent retrospective analysis of randomised controlled trials has suggested that patients with chronic cough reporting heartburn are more likely to benefit from acid suppressive treatment than those without heartburn.1 Therefore we set out to investigate the response rate to acid suppression treatment (PPI and or H2 antagonists) in patients attending our specialist cough clinic.
Objective To determine the relationship between reported responses to acid suppression treatment and the presence or absence of heartburn.
Methods We performed a retrospective review of 59 consecutive new referrals to the clinic. The presence or absence of heartburn is collected routinely in our standard clinic proforma. Patients who were treated with acid suppression either at our clinic or previously at another centre were included, together with their reported response to treatment. A Fisher’s exact test was used to assess whether those with heartburn were more likely to report a response of their cough to acid suppression treatment than those without heartburn.
Results Of 59 new referrals (median age 58 (range 26–76), 44 female), 21 (35.6%) reported heartburn, whereas 38 (64.4%) did not. Forty-four subjects had completed a trial of acid suppression therapy; 7 (15.9%) reported either a partial or complete resolution of their cough, but 37 (84.0%) reported no response. Of those reporting heartburn, 5/21 (23.8%) also reported a response to acid suppression. Of those not reporting heartburn, 2/23 (8.7%) reported a response to acid suppression. Although a greater proportion of those with heartburn reported improvement of cough with acid suppression, this did not reach statistical significance (p = 0.23).
Conclusion This data suggests that in the setting of a specialist cough clinic few patients report a response of their cough to acid suppression therapy, even in the context of heartburn. However, a larger dataset is required to understand whether those with heartburn might be more likely to respond.
[Show abstract][Hide abstract] ABSTRACT: Background
The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β2-agonist vilanterol (VI) is under development for the treatment of asthma and chronic obstructive pulmonary disease.
To compare the efficacy and safety of FF-VI and FF in patients (≥12 years old) with persistent asthma.
In a randomized, double-blind, parallel-group study, patients (n = 609) (intent-to-treat population) received FF-VI 100-25 mcg, FF 100 mcg, or placebo once daily (evening) by using a dry powder inhaler for 12 weeks. Coprimary end points were change from baseline in trough FEV1 and serial (0-24 hours) weighted mean FEV1 (wmFEV1). Rescue-free 24-hour periods and safety also were assessed.
Placebo increased trough FEV1 (196 mL) and wmFEV1 (212 mL) versus baseline. Compared with placebo, FF-VI and FF significantly improved trough FEV1 (172 mL [P < .001] and 136 mL [P = .002]), respectively, and serial wmFEV1 (302 mL [P < .001] and 186 mL [P = .003]), respectively. Treatment differences between FF-VI and FF approached significance for serial wmFEV1 (116 mL; P = .060) but not for trough FEV1 (36 mL; P = .405). The percentage of rescue-free 24-hour periods with FF-VI was 10.6% greater than FF and 19.3% greater than placebo. Statistically significant (P = .032) urinary cortisol suppression was observed with FF-VI (ratio, 0.82) relative to placebo, but not with FF. Adverse event and safety profiles were similar across treatment groups.
Significant improvement in lung function was observed with FF-VI and FF versus placebo in patients with persistent asthma. Improvement of FEV1 when VI was added to FF was not significant. The high placebo response in evening trough FEV1 may have influenced the assessment of efficacy.
[Show abstract][Hide abstract] ABSTRACT: Background
Fluticasone furoate (FF) is a novel, once-daily inhaled corticosteroid (ICS) that has been shown to improve lung function vs. placebo in asthma patients. This study evaluated the efficacy and safety of FF 50 mcg compared with placebo in asthma patients uncontrolled by non-ICS therapy.Methods
This 12-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study randomized 248 patients (aged ¿12 years) to once-daily FF 50 mcg administered via the ELLIPTA¿a dry powder inhaler or placebo. The primary endpoint was change from baseline in pre-dose evening trough forced expiratory volume in one second (FEV1). Secondary endpoints were change from baseline in percentage of rescue-free 24-h periods (powered), evening and morning peak expiratory flow, symptom-free 24-h periods and withdrawals due to lack of efficacy. Other endpoints included Asthma Control Test¿, Asthma Quality of Life Questionnaire and ELLIPTA ease of use questions. Safety was assessed throughout the study.ResultsThere was a significant difference in evening trough FEV1 between FF 50 mcg and placebo (treatment difference: 120 mL; p¿=¿0.012). There was also a significant difference in rescue-free 24-h periods (11.6%; p¿=¿0.004) vs. placebo. There were numerically greater improvements with FF vs. placebo for all remaining secondary endpoints. The incidence of adverse events was lower with FF (31%) than with placebo (38%); few were treatment-related (FF 50 mcg: n¿=¿1, <1%; placebo: n¿=¿4, 3%).ConclusionFF 50 mcg once daily significantly improved FEV1 and percentage of rescue-free 24-h periods experienced over 12 weeks vs. placebo, and was well tolerated.Trial registration www.clinicaltrials.gov, registration number: NCT01436071.
Respiratory research 08/2014; 15(1):88. DOI:10.1186/s12931-014-0088-z · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Inhaled corticosteroids are a mainstay of therapy for persistent asthma, but suboptimal adherence with twice-daily use is widespread. Fluticasone furoate (FF) is a new inhaled corticosteroid (ICS) suitable for once-daily dosing in asthma. This study was performed to descriptively assess the efficacy and safety of two doses of FF, with no planned formal statistical hypothesis testing.
This was a 24-week double-blind, multicentre, parallel-group study (NCT01431950). Patients aged ≥ 12 years with moderate-severe persistent asthma and uncontrolled on mid-high dose ICS were stratified by baseline FEV1 and randomised (1:1) to treatment with FF 100 μg or 200 μg once daily in the evening. The primary endpoint was change from baseline trough FEV1 after 24 weeks; secondary and other endpoints included peak expiratory flow (PEF) and rescue-free and symptom-free 24-hour periods over Weeks 1–24, and Asthma Control Test™ (ACT) score at Week 24. A pre-specified subgroup analysis of patients by randomisation strata was performed for the primary and selected secondary and other endpoints. Safety assessments included adverse events, laboratory and vital sign measurements, and change from baseline in 24-hour urinary cortisol at Week 24.
With FF 100 μg and 200 μg, least squares mean trough FEV1 improved from baseline by 208 mL and 284 mL, respectively, at Week 24; treatment difference: 77 mL (95% CI: –39, 192). Similar improvements from baseline in rescue- and symptom-free periods, and morning and evening PEF were observed in both groups. Patients were 42% more likely to be well-controlled (ACT score ≥ 20) with FF 200 μg than with FF 100 μg. Slightly more patients receiving FF 200 μg vs. FF 100 μg reported adverse events (63% vs. 59%) and events deemed treatment related (5% vs. <1%). Seven serious adverse events (FF 200 μg 4; FF 100 μg 3) were reported, none of which were deemed treatment related. No clinically relevant effects of either dose on 24-hour urinary cortisol were observed.
Improvements from baseline in trough FEV1 were observed after 24 weeks of treatment with both doses of FF, with a numerically greater improvement in FEV1 observed in patients receiving FF 200 μg. Secondary endpoint findings were similar between groups. No safety concerns were identified during the study.
BMC Pulmonary Medicine 07/2014; 14(1):113. DOI:10.1186/1471-2466-14-113 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents.
We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough.
Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected.
Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P = .0049] and +0.7 doubling doses at 24 hours [95% CI, +0.0 to +1.5; P = .0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498.
This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.
The Journal of allergy and clinical immunology 07/2014; 134(1). DOI:10.1016/j.jaci.2014.01.038 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50mcg in patients with mild to moderate persistent asthma.MethodsA 24-week, multicenter, randomized, placebo- and active-controlled, double-blind, double-dummy, parallel-group, phase III study. 351 patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1:1:1) with once-daily FF 50mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1s (FEV1) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24h periods and number of withdrawals due to lack of efficacy.ResultsEvening trough FEV1 at Week 24 was not statistically significantly increased with FF 50mcg once daily (37mL [95% CI: –55, 128]; P=0.430), but was with FP 100mcg twice daily (102mL [10, 194]; P=0.030), versus placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment.ConclusionsFP 100mcg twice-daily improved evening trough FEV1 in patients with mild to moderate persistent asthma, but FF 50mcg once–daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background
Current maintenance therapies for asthma require twice-daily dosing. Vilanterol (VI) is a novel long-acting beta2 agonist, under development in combination with fluticasone furoate, a new inhaled corticosteroid (ICS). Findings from a previous 4-week study suggested that VI has inherent 24-hour activity and is therefore suitable for once-daily dosing. The study described here was a double-blind, double-dummy, randomised, placebo-controlled trial, the aim of which was to assess the efficacy of once-daily VI compared with placebo in patients with persistent asthma. The primary endpoint was change from baseline in 24-hour weighted mean forced expiratory volume in 1 second after 12 weeks of treatment vs. placebo. An active control arm received salmeterol (SAL) twice daily. All patients were maintained on a stable background dose of ICS.
Patients (n = 347) received VI, placebo or SAL (1:1:1). For the primary endpoint, substantial improvements in lung function were seen with VI (359 ml), SAL (283 ml) and placebo (289 ml). There were no statistically significant treatment differences between either the VI (70 ml, P = 0.244) or SAL (-6 ml, P = 0.926) groups and placebo. Both active treatments were well tolerated, with similarly low rates of treatment-related adverse events compared with placebo. No treatment-related serious adverse events occurred.
This study failed to show a treatment difference between VI and placebo for the primary endpoint, in the presence of a placebo response of unforeseen magnitude. Because the placebo response was so large, it is not possible to draw meaningful conclusions from the data. The reason for this magnitude of effect is unclear but it may reflect increased compliance with the anti-inflammatory therapy regimen during the treatment period.
NCT01181895 at ClinicalTrials.gov.
Journal of Negative Results in BioMedicine 06/2014; 13(1):9. DOI:10.1186/1477-5751-13-9 · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We need to assess clinical treatments in real-life settings outside of randomised controlled trials (RCTs). Pragmatic RCT (pRCT) data can supplement RCTs by providing effectiveness information to support healthcare decisions. Electronic health records can facilitate concurrent safety monitoring and data collection without direct patient contact for large randomised study populations in pRCTs. The Salford Lung Study is the world's first phase III pRCT in asthma and chronic obstructive pulmonary disease (COPD), which aims to randomise over 7000 patients. This paper describes the hurdles overcome and the enormous effort and resource required to establish this comparative effectiveness study of a prelicence intervention.
HZC115151 ASTHMA STUDY CLINICALTRIALS.GOV REGISTRATION: NCT01706198 COPD STUDY CLINICALTRIALS.GOV REGISTRATION: NCT01551758.
[Show abstract][Hide abstract] ABSTRACT: Combination therapy with an inhaled corticosteroid (ICS) and long-acting β2 agonist (LABA) is recommended for patients with asthma symptomatic on ICS alone. However, there is ongoing debate regarding the risk-benefit ratio of using LABA in asthma.
To evaluate the effect of the addition of a novel LABA, vilanterol (VI), to a once-daily ICS, fluticasone furoate (FF), on the risk of severe asthma exacerbations in patients with uncontrolled asthma.
This randomised double-blind comparative study of variable duration (≥24-78 weeks) was designed to finish after 330 events (each patient's first on-treatment severe asthma exacerbation). 2019 patients with asthma aged ≥12 years with ≥1 recorded exacerbation within 1 year were randomised and received FF/VI 100/25 μg or FF 100 μg, administered once daily in the evening. The primary endpoint was time to first severe exacerbation; secondary endpoints were rate of severe asthma exacerbations per patient per year and change in trough evening forced expiratory volume in 1 s (FEV1) from baseline.
Compared with FF, FF/VI delayed the time to first severe exacerbation (HR 0.795, 95% CI 0.642 to 0.985) and reduced the annualised rate of severe exacerbations (rate reduction 25%, 95% CI 5% to 40%). Significantly greater improvements in trough FEV1 (p<0.001) were observed with FF/VI than with FF at weeks 12, 36, 52 and at endpoint. Both treatments were well tolerated with similar rates of treatment-related adverse events and on-treatment serious adverse events.
Once-daily FF/VI reduced the risk of severe asthma exacerbations and improved lung function compared with FF alone, with good tolerability and safety profile in adolescents and adults with asthma currently receiving ICS.
[Show abstract][Hide abstract] ABSTRACT: Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 μg OD), 42% (FP250 μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 μg OD (3%) and FP250 μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 μg OD (p = 0.030) and FP250 μg BD (p = 0.036) relative to placebo. FF100 μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 μg BD with similar safety profile.
Respiratory medicine 11/2013; 108(1). DOI:10.1016/j.rmed.2013.11.009 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The inhaled corticosteroid fluticasone furoate (FF) and the long-acting β2 agonist vilanterol (VI) are in development as a combined once-daily therapy for asthma and chronic obstructive pulmonary disease. Our study objectives were to compare the efficacy and safety of once-daily FF/VI with FF alone and twice-daily fluticasone propionate (FP) in patients aged ≥12 years with moderate-to-severe persistent asthma.
Patients (n=586) received FF/VI 200/25 μg or FF 200 μg once-daily (evening dosing), or FP 500 μg twice-daily for 24 weeks. Co-primary end-points were change from baseline in trough forced expiratory volume in 1 s (FEV1) weighted mean (wm) 0–24 h serial FEV1. Secondary end-points included change from baseline in percentage of rescue-free 24-h periods, percentage of symptom-free 24-h periods and total Asthma Quality of Life Questionnaire (AQLQ). Safety assessments included adverse events, 24-h urinary cortisol excretion, vital signs and ECG.
FF/VI significantly improved trough FEV1 and wmFEV1
versus FF and FP. Significantly more rescue-free and symptom-free 24-h periods were reported with FF/VI versus FF. Treatment differences for AQLQ were not significant. Incidence of adverse events was similar across groups. No clinically significant differences were seen for 24-h urinary cortisol excretion, vital signs or ECG.
FF/VI resulted in statistically greater improvements in lung function and symptomatic end-points versus FF, and was well tolerated in this asthma population.
European Respiratory Journal 10/2013; 43(3). DOI:10.1183/09031936.00064513 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The combination of fluticasone furoate (FF), a novel inhaled corticosteroid (ICS) and vilanterol (VI), a long-acting beta2 agonist, is under development as a once-daily treatment for asthma and chronic obstructive pulmonary disease. The aim of this study was to compare the efficacy of FF/VI with fluticasone propionate (FP)/salmeterol (SAL) in patients with persistent asthma uncontrolled on medium-dose ICS.
In a randomized, double-blind, double-dummy, parallel-group study, 806 patients received FF/VI (100/25 μg, n = 403) once daily in the evening via dry powder inhaler, or FP/SAL (250/50 μg, n = 403) twice daily via Diskus™/Accuhaler™. The primary efficacy measure was 0-24 h serial weighted mean forced expiratory volume in 1 second (wmFEV1) after 24 weeks of treatment.
Improvements from baseline in 0-24 h wmFEV1 were observed with both FF/VI (341 ml) and FP/SAL (377 ml); the adjusted mean treatment difference was not statistically significant (-37 ml [95% confidence interval: -88, 15], p = 0.162). There were no differences between the 0-4 h serial wmFEV1, trough FEV1, and asthma control and quality of life questionnaire scores. There was no difference in reported exacerbations between treatments. Both treatments were well tolerated, with no clinically relevant effect on urinary cortisol excretion or vital signs, and no treatment-related serious adverse events.
The efficacy of once-daily FF/VI was similar to twice-daily FP/SAL in improving lung function in patients with persistent asthma. No safety issues were identified.
ClinicalTrials.gov; No.: NCT01147848; funded by GSK (HZA113091).
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Inhaled capsaicin elicits cough reproducibly in human subjects and is widely used in the study of cough and antitussive therapies. However, the traditional end points C2 and C5 (the concentrations of capsaicin inducing at least 2 or 5 coughs, respectively) display extensive overlap between health and disease and therefore might not best reflect clinically relevant mechanisms. OBJECTIVES: We sought to investigate capsaicin dose responses in different disease groups. METHODS: Two novel capsaicin cough challenges were compared in patients with chronic cough (CC; n = 20), asthmatic patients (n = 18), and healthy volunteers (HVs; n = 20). Increasing doubling doses of capsaicin (0.48-1000 μmol/L, 4 inhalations per dose) were administered in challenge 1, whereas the order of the doses was randomized in challenge 2. A nonlinear mixed-effects model compared dose-response parameters by disease group and sex. Parameters were also correlated with objective cough frequency. RESULTS: The model classified subjects based on maximum cough response evoked by any concentration of capsaicin (Emax) and the capsaicin dose inducing half-maximal response (ED50). HVs and asthmatic patients were not statistically different for either parameter and therefore combined for analysis (mean ED50, 38.6 μmol/L [relative SE, 28%]; mean Emax, 4.5 coughs [relative SE, 11%]). Compared with HVs/asthmatic patients, patients with CC had lower ED50 values (14.7 μmol/L [relative SE, 28%], P = .008) and higher Emax values (8.6 coughs [relative SE, 11%], P < .0001). Emax values highly correlated with 24-hour cough frequency (r = 0.71, P < .001) and were 37% higher in female compared with male subjects, regardless of disease group (P < .001). CONCLUSIONS: Nonlinear mixed-effects modeling demonstrates that maximal capsaicin cough responses better discriminate health from disease and predict spontaneous cough frequency and therefore provide important insights into the mechanisms underlying CC.
The Journal of allergy and clinical immunology 06/2013; 132(4). DOI:10.1016/j.jaci.2013.04.042 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RATIONALE: Cough is one of the principle symptoms of COPD but the potential drivers of cough are likely to be multi-factorial and poorly understood. OBJECTIVES: To quantify cough frequency in an unselected group of COPD subjects and investigate the relationships between cough, reported sputum production, smoking, pulmonary function and cellular airway inflammation. Method: We studied 68 subjects with COPD (mean age 65.6yrs(±6.7), 67.6% male, 23 smokers, 45 ex-smokers) and 24 healthy volunteers (mean age 57.5yrs(±8.9), 37.5% male, 12 smokers, 12 non-smokers). Subjects reported cough severity, cough specific quality of life and sputum expectoration and performed spirometry, sputum induction, cough reflex sensitivity to capsaicin and 24hr ambulatory cough monitoring. MEASUREMENTS AND MAIN RESULTS: COPD current smokers had the highest cough rates [median 9.0c/h (IQR 4.3-15.6), almost double that of COPD ex-smokers [4.9c/h (2.3-8.7) (p=0.018)] and healthy smokers [5.3c/h (1.2-8.3), (p=0.03)], whereas healthy volunteers coughed the least [0.7c/h (0.2-1.4)]. Cough frequency was not influenced by age or gender and only weakly correlated with cough reflex sensitivity to capsaicin (logC5 r=-0.36, p=0.004). Reported sputum production, smoking history and current cigarette consumption strongly predicted cough frequency, explaining 45.1% variance in a general linear model (p<0.001). In subjects producing a sputum sample, cough frequency was related to current cigarette consumption and percentage of sputum neutrophils (p=0.002). CONCLUSION: Ambulatory objective monitoring provides novel insights into the determinants of cough in COPD, suggesting sputum production, smoking and airway inflammation may be more important than sensitivity of the cough reflex.
American Journal of Respiratory and Critical Care Medicine 03/2013; 187(9). DOI:10.1164/rccm.201211-2000OC · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β2 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 Fridericia's formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [Tmax], 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.