Mepolizumab has clinical benefits including oral corticosteroid sparing irrespective of baseline EGPA characteristics.

Background: The Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial (GSK ID: 115921/NCT02020889) demonstrated that mepolizumab increased remission time and reduced oral corticosteroid (OCS) use compared with placebo in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). The present analysis investigated the impact of baseline characteristics on clinical outcomes and characterised the OCS-sparing effect of mepolizumab. Methods: In a phase 3, randomised controlled trial for patients with EGPA (MIRRA), patients received standard of care plus mepolizumab 300 mg or placebo every 4 weeks for 52 weeks. The accrued duration of remission, the proportion of patients in remission at weeks 36 and 48, and the proportion of patients with clinical benefit (remission, OCS or relapse-related) were assessed according to baseline EGPA characteristic subgroups (post hoc). Mepolizumab-related OCS-sparing benefits were also quantified. Results: Accrued duration of remission and the proportion of patients in remission at weeks 36 and 48 were greater with mepolizumab than placebo across the baseline subgroups of refractory disease, immunosuppressant use, EGPA duration, relapse number and OCS use ≤20 mg·day-1. The proportion of patients with clinical benefit was greater with mepolizumab versus placebo (range 76-81% versus 25-39%), irrespective of immunosuppressant use or EGPA duration. Patients treated with mepolizumab versus placebo accrued significantly more weeks on OCS ≤4 mg·day-1 (OR 5.06, 95% CI 2.47-10.38) and had a mean of 1423.1 mg less per-patient OCS exposure over 52 weeks. Conclusions: Mepolizumab treatment provided benefits to patients with EGPA across varying baseline clinical characteristics and can be considered an OCS-sparing treatment in EGPA.

Clinical Benefit of Mepolizumab in Eosinophilic Granulomatosis With Polyangiitis for Patients With and Without a Vasculitic Phenotype.

OBJECTIVE: To evaluate mepolizumab's efficacy in eosinophilic granulomatosis with polyangiitis (EGPA) with and without a vasculitic phenotype. METHODS: The MIRRA study (NCT02020889/GSK ID: 115921) included adults with relapsing/refractory EGPA and 4 or more weeks of stable oral glucocorticoids (OG). Patients received mepolizumab (300 mg subcutaneously every 4 weeks) or placebo, plus standard of care for 52 weeks. This post hoc analysis assessed EGPA vasculitic phenotype using antineutrophil cytoplasmic antibody (ANCA) history, baseline Birmingham Vasculitis Activity Score (BVAS), and Vasculitis Damage Index (VDI) score. Coprimary endpoints included accrued remission over 52 weeks and proportion in remission at Week 36 and Week 48. Remission was defined as a BVAS equal to 0 and an OG dose of 4 or more mg/day of a prednisone equivalent. Types of relapses (vasculitis, asthma, and sino-nasal) and EGPA vasculitic characteristics (by study remission status) were also assessed. RESULTS: A total of 136 patients were included (n = 68, mepolizumab and placebo). Irrespective of history of ANCA positivity status, baseline BVAS, or baseline VDI, the accrued remission duration and the proportion of patients in remission at Weeks 36 and 48 were greater with mepolizumab compared with placebo. With mepolizumab, remission at both Week 36 and Week 48 was achieved by 54% of patients with and 27% of patients without a history of ANCA positivity compared with 0% and 4%, respectively (placebo); 45% of patients with a BVAS of 0 and 22% of patients with BVAS of greater than 0 compared with 5% and 2%, respectively (placebo); and 29% of patients with a VDI score of less than 5 and 37% of patients with a VDI score of 5 or more compared with 6% and 0%, respectively (placebo). Mepolizumab reduced all types of relapses as compared with placebo. Baseline vasculitic characteristics (neuropathy, glomerulonephritis, alveolar hemorrhage, palpable purpura, and ANCA positivity) were generally similar among patients with and without remission. CONCLUSION: Mepolizumab is associated with clinical benefits for patients with and without a vasculitic EGPA phenotype.

Mepolizumab therapy improves the most bothersome symptoms in patients with hypereosinophilic syndrome.

Background: Hypereosinophilic syndrome (HES) is characterized by persistent elevated blood and/or tissue eosinophil levels and eosinophil-mediated organ damage. Presentation is highly heterogenous; patients may experience symptoms affecting multiple organ systems. Objectives: To assess the effects of mepolizumab, which targets interleukin-5, on HES-related symptom burden, based on HES daily symptoms (HES-DS) questionnaire data collected during the Phase III (ClinicalTrials.gov ID: NCT02836496) study of mepolizumab in patients with HES. Methods: Each of the six HES-related symptoms were rated (0-10) daily by patients, recalling worst symptom experience in the prior 24 hours; change from baseline at Week 32 was also calculated for mepolizumab versus placebo. Results: Mepolizumab versus placebo reduced HES-related symptom burden severity in patients with HES at Week 32. Improvements in the median change from baseline scores were seen across all symptom groups except skin for patients treated with mepolizumab; greatest improvement from baseline was observed for breathing symptoms. Conclusion: These data highlight the considerable symptom burden associated with HES and further support the clinical benefits of mepolizumab treatment for these patients.

Characterization of disease flares and impact of mepolizumab in patients with hypereosinophilic syndrome.

In patients with hypereosinophilic syndrome (HES), mepolizumab reduces the incidence of HES-related clinical signs and symptoms (flares). However, reports characterizing flare manifestations are limited. The double-blind, parallel-group 200622 trial (NCT02836496) enrolled patients ≥12 years old with HES for ≥6 months, ≥2 flares in the previous year, and screening blood eosinophil count ≥1000 cells/µL. Patients maintained ≥4 weeks stable HES therapy, before randomization (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. This post hoc analysis investigated flare manifestations and duration by re-examining the Core Assessments form and narrative recorded for each flare during the study. Flare symptoms were retrospectively categorized into constitutional, dermatological, respiratory, nasal, gastrointestinal, neurologic and other. The most frequently reported flare symptoms were constitutional (94% of flares), dermatological (82% of flares) and respiratory (72% of flares); flares reported in patients receiving mepolizumab compared with placebo were generally similar in terms of the frequency of symptoms reported. Mepolizumab was associated with a shorter median (range) duration of flares (10.0 [4, 126] days) versus placebo (26.0 [1, 154] days). In patients with HES, flares were associated with symptoms linked to multiple organ systems highlighting the challenges faced for treating flares. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02836496, identifier NCT02836496.

Safety and Efficacy of Mepolizumab in Hypereosinophilic Syndrome: An Open-Label Extension Study.

BACKGROUND: A double-blind, placebo-controlled, phase III study (200622) showed that mepolizumab reduces disease flares for patients with uncontrolled FIP1-like-1-platelet-derived growth factor receptor α-negative hypereosinophilic syndrome (HES) and two or more flares in the previous year. OBJECTIVE: To further characterize the safety, clinical benefit, and pharmacodynamics of mepolizumab. METHODS: Eligible patients from both treatment arms of the double-blind study could enter an open-label extension study (205203; NCT03306043) to receive 4-weekly mepolizumab (300 mg subcutaneously) plus background therapy for 20 weeks. Primary end points were safety-based; other end points included flare rates and changes from baseline in mean daily oral corticosteroid (OCS) dose and blood eosinophil count. RESULTS: Of 104 patients who completed the double-blind study, 98% (previous placebo, n = 52; previous mepolizumab, n = 50) enrolled in the open-label extension. Overall, 66 of patients reported adverse events (AEs) (65%), 15 reported treatment-related AEs (15%), and nine reported serious AEs (9%). No events were fatal. The annualized flare rate (95% confidence interval) in the previous placebo and previous mepolizumab groups was 0.37 (0.16-0.86) and 0.14 (0.04-0.49) events/y, respectively. Of 72 patients receiving OCS during weeks 0 to 4, 20 (28%; previous placebo, n = 14; previous mepolizumab, n = 6) achieved 50% or greater reductions in mean daily dose during weeks 16 to 20. At week 20, blood eosinophil count was reduced by 89% in patients previously receiving placebo and remained reduced for those previously receiving mepolizumab. CONCLUSIONS: Extended mepolizumab treatment was associated with a positive benefit-risk profile. Continued control of disease flares and blood eosinophil counts, plus reductions in OCS use, were observed with mepolizumab in patients with FIP1-like-1-platelet-derived growth factor receptor α-negative HES.

Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial.

BACKGROUND: Anti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear. OBJECTIVE: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES. METHODS: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/µL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed. RESULTS: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%]). CONCLUSIONS: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified.

Usability of mepolizumab single-use prefilled autoinjector for patient self-administration.

Objective: To evaluate usability of mepolizumab as a liquid drug product self-administered via a single-use prefilled autoinjector (AI) by patients with severe eosinophilic asthma (SEA), or their caregivers, in-clinic and at home.Methods: This open-label, single-arm, Phase IIIa study (NCT03099096; GSK ID: 204959) included patients aged ≥12 years with SEA who were either receiving mepolizumab (100 mg subcutaneously [SC]) every 4 weeks (Q4W) for ≥12 weeks before screening or not receiving mepolizumab but met criteria indicative of SEA. Patients/caregivers self-administered mepolizumab (100 mg SC) via an AI Q4W for 12 weeks. The first (Week 0) and third (Week 8) doses were observed in-clinic; the second dose (Week 4) was administered unobserved at home. Primary and secondary endpoints were the proportion of patients who successfully self-administered their third and second doses, respectively (determined by investigator/site staff). Patient experience, mepolizumab trough concentrations, blood eosinophil count (BEC), and safety were also assessed.Results: Of 159 patients/caregivers who self-administered ≥1 dose of mepolizumab, 157 completed the study. Nearly all patients successfully self-administered their third mepolizumab dose in-clinic and second dose at home (≥98% and ≥96%, respectively); this was further confirmed by mepolizumab trough concentrations/BEC. At study end, ≥88% of patients were "very" or "extremely" confident about using the AI correctly. Incidence of on-treatment drug-related adverse events (AEs) was low (3%); no fatal AEs occurred.Conclusions: Patients/caregivers successfully self-administered mepolizumab via the AI both in-clinic and at home; no new safety concerns were identified.

Usability of mepolizumab single-use prefilled syringe for patient self-administration.

Objective: A liquid mepolizumab formulation in a single-use prefilled syringe (PFS) is under development. We evaluated the usability of mepolizumab self-injected via PFS by patients with severe eosinophilic asthma (SEA), or their caregivers, in clinic and at home.Methods: This open-label, single-arm, Phase IIIa study included patients with SEA, aged ≥12 years, and receiving mepolizumab (100 mg subcutaneously) every 4 weeks for ≥12 weeks prior to screening. Patients with SEA not receiving mepolizumab at screening who met additional criteria were also included. Patients/caregivers self-administered mepolizumab (100 mg subcutaneously) via PFS every 4 weeks for 12 weeks. The first (Week 0) and third (Week 8) dose were observed in clinic; the second dose (Week 4) was unobserved at home. Primary and secondary endpoints were the proportion of patients who successfully self-administered their third and second doses, respectively. Injection success was determined by investigator/site staff. Patient experience, mepolizumab trough concentrations, blood eosinophil counts, and safety were also assessed.Results: Of the 56 patients/caregivers who self-administered ≥1 dose of mepolizumab, 55 completed the study. All patients were reported to have successfully self-administered their third mepolizumab dose in clinic (N = 55, 100%); this was further evidenced by trough concentrations/blood eosinophil counts. Most patients/caregivers found the PFS easy and convenient to use with 75% (n = 42) expressing little/no anxiety about using the device at home. Incidence of on-treatment drug-related adverse events was low (4%); none were fatal.Conclusions: Patients/caregivers successfully self-administered mepolizumab via the PFS both in clinic and at home, with no new safety concerns identified.

The Pharmacokinetics and Relative Bioavailability of Mepolizumab 100 mg Liquid Formulation Administered Subcutaneously to Healthy Participants: A Randomized Trial.

This study compared the pharmacokinetic (PK) profile of a new liquid formulation of mepolizumab with the established lyophilized formulation. In this open-label, parallel-group, single-dose study (NCT03014674; GSK ID: 204958), healthy participants were randomized (1:1:1) to receive a single mepolizumab dose (100 mg) administered subcutaneously as liquid in a single-use prefilled syringe or single-use prefilled autoinjector, or as a lyophilized formulation. Maximum plasma concentration, area under the plasma concentration-time curve from time zero (predose) to time of last quantifiable concentration (AUC0-t ), and AUC from time zero to infinity (AUC0-∞ ) as well as additional PK parameters, safety assessments, and blood eosinophil count were evaluated. In total, 244 participants received study drug. All PK parameters were similar across the 3 groups; 90% confidence intervals for maximum plasma concentration, AUC0-t , and AUC0-∞ treatment ratios (liquid prefilled syringe or autoinjector vs lyophilized formulation) were within conventional bioequivalence bounds (0.80-1.25), demonstrating statistical PK comparability. On-treatment adverse event incidence was 29% to 38%. Mepolizumab liquid formulation administered via prefilled syringe or autoinjector had similar PK properties to the lyophilized formulation, with no safety concerns identified.

Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study.

BACKGROUND: Idiopathic pulmonary fibrosis, a progressive and inevitably fatal disorder, has a highly variable clinical course. Biomarkers that reflect disease activity are urgently needed to inform patient management and for use as biomarkers of therapeutic response (theragnostic biomarkers) in clinical trials. We aimed to determine whether dynamic change in markers of extracellular matrix (ECM) turnover predicts progression of idiopathic pulmonary fibrosis as determined by change in forced vital capacity and death. METHODS: In this ongoing prospective, multicentre, observational cohort study (PROFILE), participants with idiopathic pulmonary fibrosis or idiopathic non-specific interstitial pneumonia diagnosed within the preceding 6 months were recruited from two coordinating centres (Nottingham, UK, and, Royal Brompton Hospital, London, UK). Serum samples were prospectively collected at baseline, 1 month, 3 months, and 6 months and were analysed for a panel of novel matrix metalloprotease (MMP)-degraded ECM proteins, by ELISA-based, neoepitope assay. 11 neoepitopes were tested in a discovery cohort of 55 patients to identify biomarkers of sufficient rigour for more detailed analyses. Eight were then further assessed in a validation cohort of 134 patients with 50 age-matched and sex-matched controls. Changes in biomarker concentrations were related to subsequent progression of idiopathic pulmonary fibrosis (defined as death or decline in forced vital capacity >10% at 12 months after study enrolment) using a repeated measures model. The PROFILE study is registered on ClinicalTrials.gov, numbers NCT01134822 and NCT01110694. FINDINGS: Of 214 eligible participants recruited between Sept 1, 2010, and March 31, 2012, 189 had a confirmed diagnosis of idiopathic pulmonary fibrosis and were included in subsequent analyses. In the discovery cohort, mean concentrations of seven neoepitopes (BGM, p=0·009; C1M, p=0·009; C3M, p=0·046; C6M, p=0·032; CRPM, p=0·008; ELM2, p=0·02; and VICM, p=0·0007) differed significantly between healthy controls and participants with idiopathic pulmonary fibrosis. Baseline concentrations of six neoepitopes (C1M, p=0·012; C3A, p=0·012; C3M, p=0·0005; C6M, p=0·0003; CRPM, p=0·021; and VICM, p=0·046) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=32) than in those with stable disease (n=23). In the validation cohort, mean concentrations of C1M (p=0·001), C3M (p=0·044), C6M (p=0·003), and CRPM (p=0·024) at baseline were higher in patients with idiopathic pulmonary fibrosis than in healthy controls. When assessed longitudinally, concentrations of six neoepitopes (BGM, C1M, C3A, C3M, C6M, and CRPM) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=71) than in patients with stable idiopathic pulmonary fibrosis (n=60) by 6 months. Baseline concentrations of two neoepitopes were associated with increased mortality (C1M: HR 1·62 [95% CI 1·14-2·31], p=0·0069; C3A: 1·91 [1·06-3·46], p=0·032). The rate of change between baseline and 3 months of six neoepitopes (BGM: HR 1·084 [95% CI 1·03-1·14], p=0·0019; C1M: 1·01 [1·003-1·017], p=0·0039; C3M: 1·106 [1·045-1·170], p=0·0005; C5M: 1·003 [1·001-1·005], p=0·0011; C6M: 1·042 [1·007-1·078], p=0·017; and CRPM: 1·38 [1·16-1·63], p=0·0002) was strongly predictive of overall survival, and the increased risk was proportional to the magnitude of change in neoepitope concentrations. The strongest association with 3-month rate of biomarker change was recorded for CRPM; greater than 0 ng/mL per month conferred a HR of 2·16 (95% CI 1·15-4·07), whereas a rate greater than 1 ng/mL per month resulted in an HR 4·08 (2·14-7·8), and a rate greater than 1·7 ng/mL per month was associated with an HR 6·61 (2·74-15·94). INTERPRETATION: Concentrations of protein fragments generated by MMP activity are increased in the serum of individuals with idiopathic pulmonary fibrosis compared with healthy controls. Increased neoepitope concentrations were associated with disease progression, and the rate of this increase predicted survival. Serial measurements of neoepitopes have potential to be used as theragnostic biomarkers in clinical trials and to guide management of idiopathic pulmonary fibrosis. FUNDING: GlaxoSmithKline R&D and the Medical Research Council.

The effect of GSK2190915, a 5-lipoxygenase-activating protein inhibitor, on exercise-induced bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) describes the condition whereby exercise causes airflow obstruction that lasts for up to 90 minutes without treatment. This double-blind, placebo-controlled, five-way crossover study investigated the dose response and duration of action of a 5-lipoxygenase-activating protein inhibitor, GSK2190915, to inhibit EIB in subjects with asthma. Forty-seven subjects with EIB were enrolled. Exercise challenge testing was scheduled at 2, 9.5, and 24 hours after receiving a single dose of GSK2190915 (10, 50, 100, and 200 mg) or placebo in randomized order. GSK2190915 at 200 and 100 mg significantly attenuated the response to exercise at 2 and 9.5 hours postdose, respectively, compared with placebo. The adjusted mean maximum percentage change from baseline forced expiratory volume at 1 second within 60 minutes postexercise challenge (FEV1 (0-60)) treatment difference for GSK2190915 at 200 mg compared with placebo at 2 hours postdose was 6.30% (95% CI, 3.06, 9.54), corresponding to a 40% attenuation of the placebo response to exercise; the treatment difference between GSK2190915 at 100 mg and placebo at 9.5 hours postdose was 3.49% (95% CI, 1.02, 5.95), corresponding to a 41% attenuation of the placebo response to exercise. No significant effect was seen at 24 hours postdose with any dose; however, investigation of statistically significant treatment-related effects at this time point was limited because of the small fall in adjusted mean FEV1 (0-60) (-7.61%; 95% CI, -10.23, -4.99) after placebo. GSK2190915 may be of benefit in EIB prevention. GSK Clinical Study LPA112025; ClinicalTrials.gov identifier number: NCT00812929.

TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis.

BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1)-expressing sensory C-fibers may play a role in the development of nasal hyper-responsiveness and symptoms of non-allergic rhinitis (NAR). OBJECTIVE: To evaluate the effects of a TRPV1-antagonist, SB-705498, on cold dry air (CDA)-induced symptoms in patients with NAR. METHODS: This randomized, double-blind, placebo-controlled, crossover study evaluated 14 days of once daily, topical intranasal SB-705498 12 mg in 40 patients with NAR using a CDA challenge experimental model in an environmental exposure chamber (EEC, Cetero Research, Mississauga, Ontario). The primary endpoint was total symptom score (TSS), expressed as weighted mean over 60 minutes (WM0-60) or maximum TSS at 1 hour and 24 hours postdosing. RESULTS: Treatment with SB-705498, relative to placebo, did not improve WM0-60 or maximum TSS at 1 hour and 24 hours post-dosing on days 1 or 14. Mean (95% CI) treatment differences (SB-705498 - placebo) on day 14 were, for WM0-60 at 1 hour: -0.12 (-0.60, 0.36); for maximum TSS at 1 hour: -0.03 (-0.58, 0.51). SB-705498 had no impact on any other efficacy parameters. SB-705498 was well tolerated and pharmacokinetics analysis supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 14 days did not alleviate the CDA-induced symptoms of NAR. Despite engagement of the TRPV1 receptor, there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Inhibition of the early asthmatic response to inhaled allergen by the 5-lipoxygenase activating protein inhibitor GSK2190915: a dose-response study.

BACKGROUND: GSK2190915, a 5-lipoxygenase activating protein inhibitor, inhibits the production of cysteinyl leukotrienes and leukotriene B4 and 5-oxo-6,8,11,14-eicosatetraenoic acid. We have previously reported that GSK2190915 100 mg daily inhibits early and late asthmatic responses to inhaled allergen; the effects of lower doses have not been reported. This study assessed the dose-response effects of GSK2190915 10 mg and 50 mg on the early asthmatic response (EAR) to inhaled allergen. METHODS: Nineteen subjects with mild asthma and an EAR were enrolled in a randomized, double-blind, three-way crossover study of GSK2190915 10 mg, 50 mg, and placebo orally once-daily for 3 days. Allergen challenge was performed 2 hours after the third dose. RESULTS: Compared with placebo, GSK2190915 10 mg and 50 mg caused significant, dose-dependent attenuation of the minimum forced expiratory volume at 1 second (FEV1) absolute change from baseline; mean treatment differences were 0.21 L (95% confidence interval [CI] 0.04 L, 0.38 L) and 0.41 L (95% CI 0.24 L, 0.58 L), respectively. GSK2190915 50 mg was more effective than 10 mg; mean difference between treatments was 0.20 L, (95% CI 0.03 L, 0.36 L). Compared with placebo, GSK2190915 50 mg, but not 10 mg, significantly inhibited the weighted mean FEV1 absolute change from baseline. CONCLUSION: GSK2190915 50 mg attenuated the EAR similarly to GSK2190915 100 mg in our previous study, suggesting 50 mg is at the top of the dose-response curve. GSK2190915 10 mg is a suboptimal dose. The EAR can be used to assess the therapeutic dose of a new treatment for asthma.

The effects of a TRPV1 antagonist, SB-705498, in the treatment of seasonal allergic rhinitis.

BACKGROUND: Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS: This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 µg (FP), FP 200 µg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS: At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Pharmacodynamics, pharmacokinetics and safety of GSK2190915, a novel oral anti-inflammatory 5-lipoxygenase-activating protein inhibitor.

AIM: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations. METHOD: Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity. RESULTS: There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85 nM and 89 nM in the Western European and Japanese studies, respectively. CONCLUSION: GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E4 at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB4.

Patient Advice and Liaison Services: strengthening the voices of individual service users in health-care organizations.

OBJECTIVE: To explore the roles of Patient Advice and Liaison Services (PALS) in their interactions with service users. CONTEXT: Every National Health Service health-care provider in England now has a PALS, which provides service users with information and help in resolving concerns and dissatisfactions with health care. DESIGN: Longitudinal qualitative study, 2002-4. This paper draws on data from 27 semi-structured interviews. SETTING AND PARTICIPANTS: PALS personnel working in six case study PALS in London. FINDINGS: PALS personnel adopt seven roles in order to support their clients in sorting out problems with health care: information provider; listener; messenger (passing on information from service users to staff); go-between (passing information forward and back); supporter (helping service users to present their own views); mediator (when two or more parties are in dispute); resource mobilizer (when the support of senior staff or other agencies is necessary to resolve a problem). CONCLUSIONS: Though these are not new functions, PALS is a universal service which is better placed than front-line health-care staff to offer such support, and increases choice for service users looking for sources of information and advice.

Early initiation of lipid-lowering therapy for acute coronary syndromes improves compliance with guideline recommendations: observations from the Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) trial.

BACKGROUND: Lipid-lowering is effective in the prevention of cardiovascular morbidity and mortality in patients with coronary artery disease, but effective strategies for improving the implementation of these therapies are needed. METHODS: In the 10,288 patients in the OPUS-TIMI 16 trial, patients were stratified by use of lipid-lowering therapy during index hospitalization and were compared for use of lipid-lowering therapy at follow-up as well as for clinical outcomes. RESULTS: Lipid-lowering therapy was used in 38% of patients during the index hospitalization, of which 94% were statins. At 10 months, 88% of patients who were discharged on lipid-lowering medications remained on these drugs. Conversely, only 34% of patients not discharged on lipid-lowering medications were receiving them at 10 months. Forty-one percent of patients with prior history of hyperlipidemia requiring treatment were not discharged on lipid-lowering therapy, and of these, only 51% were subsequently started on a lipid-lowering medication as an outpatient despite clear indications. Patients treated as inpatients with lipid-lowering therapy had a lower mortality rate at 10 months adjusted by propensity analysis (3.1% vs 5.1%, P < .0001) than patients not treated with lipid-lowering therapy. CONCLUSION: In patients with acute coronary syndromes, the initiation of lipid-lowering therapy in the inpatient setting increases the rate of its subsequent use at 10 months, making this an important method of ensuring appropriate secondary prevention.

Quality criteria for patient advice and liaison services: what do patients and the public want?

BACKGROUND: Every NHS trust and Primary Care Trust (PCT) in England now has a Patient Advice and Liaison Service (PALS) which provides an identifiable person to whom service users can turn if they have a problem or need information while using the NHS. This paper reports data from a 2-year qualitative study of London PALS. OBJECTIVE: To develop patient-centred criteria by which to assess PALS. DESIGN: Data were generated from qualitative interviews with 15 PALS service users and 15 members of local user/carer organizations, and from a workshop with representatives of 14 user/carer organizations (national and London-wide). Emergent findings were circulated to other user/carer organizations (n = 32) for critique and comment. RESULTS: Findings suggest that users and their representatives want PALS to: be responsive to the needs and wishes of individuals; be accessible to all sections of the community, including older people, ethnic minorities and groups with special needs; offer clear, accurate and comprehensive information about local health and other services; work with their NHS organization to create a more patient-centred service; collaborate effectively with other organizations; be adequately resourced. CONCLUSIONS: These criteria resemble the national standards for PALS compiled by the Department of Health, with the exception of the need for adequate resourcing. They also resemble previous work on users' and carers' criteria for service delivery. Interestingly, PALS' lack of independence was not a major concern, though clients do need access to independent advocacy when 'insider' trouble-shooting fails. Although an alternative to the adversarial approach of complaints is welcome, PALS, like complaints procedures, may be under-used by marginalized or demoralized service users.

Repeat attendance by older people at accident and emergency departments.

BACKGROUND: Older people are an increasing user group at accident and emergency departments and often have complex needs over and above the clinical cause of attendance. Few studies to date appear to have focused specifically on older people's re-attendance at such departments following direct discharge. However, these few studies conclude that incomplete staff assessment of older people's needs in this setting may play a part in reasons for re-attendance and recommend that further research is needed in this area. AIMS: The aim of this paper is to describe a 6-month study exploring re-attendance, assessment and discharge issues for people aged over 75 years at an accident and emergency department. METHODS: Documentary research was primarily used to collate data. Interviews with specialist health care professionals were also used to cross-check recorded documentary details of interest and to gain a wider perspective. In addition, illustrative cases were developed (incorporating a broader range of hospital documentation) to exemplify key issues raised relating to re-attendance by older people at the accident and emergency department concerned. FINDINGS: Professional practice related to assessment of older people's social and functional needs was inconsistent in this accident and emergency department and some staff clearly underestimated the impact of illness or injury when considering their ability to cope on discharge. An illustrative case summary is included to highlight that such issues may be significant factors in re-attendance. CONCLUSION: Improving practice in relation to social and functional assessment and raising staff awareness concerning older people's potential needs seem important in accident and emergency departments. With little research identified to date into re-attendance, further research on this issue is recommended.

Does initial and delayed heart rate predict mortality in patients with acute coronary syndromes?

BACKGROUND: Lower admission heart rate (HR) is known to predict favorable outcome in ST-elevation acute myocardial infarction. However, there are limited short-term and no long-term data available regarding the prediction value of the initial HR in patients with the full spectrum of acute coronary syndromes (ACS). In addition, it is unknown whether the HR obtained later during hospitalization for ACS (i.e., Day 2 or 3) remains prognostically valuable. HYPOTHESIS: The aim of this study was to investigate the utility of the initial and delayed HR in predicting outcome in patients with ACS. METHODS: We examined mortality at 30 days and 10 months in 10,267 patients with ACS enrolled in the oral glycoprotein IIb/IIIa inhibition with Orofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 trial. Patients were stratified by HR and day from onset of ACS into the following groups: (1) HR < 60 beats/min, (2) HR 60-80 beats/min, (3) HR 80-100 beats/min, (4) HR > 100 beats/min; and HR obtained on (1) Day 1, (2) Day 2, and (3) Day 3. RESULTS: By univariate analysis, mortality at 30 days and at 10 months increased progressively with higher HR strata (1.4 vs. 1.6 vs. 2.3 vs. 5.6%, p < 0.001, and 2.6 vs. 4.2 vs. 6.5 vs. 11.8%, p < 0.001, respectively). Elevated HR remained associated with mortality irrespective of time from onset of ACS. CONCLUSIONS: Higher initial and delayed HR is highly predictive of higher short- and long-term mortality in patients with ACS. This is a simple marker that could be easily used in risk assessment.