Memorials to Dr WG Grace - general practitioner and cricketing legend.

Dr WG Grace was a general practitioner in Bristol, in the late nineteenth century, but is better remembered as 'the father of cricket'. He showed early promise as a skilled cricket player and was already playing for Gloucester County, by the age of fifteen. However, coming from a well-established medical family, his father wanted him to become a doctor. He trained in Bristol and after qualifying he set up his own practice in the same environs. By this time, he was a superb cricketer with a glittering county and England career, combined with his clinical duties. He has several memorials where he lived and practised in Bristol, which are described and illustrated in this review. These include commemorative plaques in the local church, and near his later residence in Clifton, as well as a large mural at a train station and another at a shopping centre. These are all tributes to one of the most famous sons of Bristol. He is also celebrated at Lord's Cricket Ground, the home of cricket, with eponymous memorial gates and a full-size statue inside the ground. A fine example of a doctor who also had other talents, these memorials reflect his widespread appeal and his long-lasting legacy.

Memorials to John Snow - Pioneer in anaesthesia and epidemiology.

John Snow was an English physician and a founding father of epidemiology, whose name is inextricably linked with tracing the source of the 1854 cholera outbreak in Soho, which killed over 600 people. Despite his recommendation to remove the water pump handle and thus reduce the spread of cholera, his theory of faecal-oral transmission was not widely believed until after his death. Furthermore, he also pioneered substantial achievements in the development of anaesthesia. He studied both chloroform and ether, improving the accuracy of their delivery. In his obstetric practice, he achieved the feat of obtaining satisfactory analgesia with a safer technique and is remembered for administering chloroform to Queen Victoria, during the delivery of her last two children. There are several interesting and unusual memorials to Snow, ranging from replica water pumps, blue plaques and a public house named after him. The most recent new memorial was erected in 2017, in his home town of York, which commemorates his origins and his subsequent contribution to curbing the cholera outbreak. All the memorials commemorate his achievements, which remain relevant today. Public health and epidemiology expertise is required in the current world of the COVID-19 pandemic, where his legacy remains as important as ever.

Comparative Adherence and Persistence of Single- and Multiple-Inhaler Triple Therapies Among Patients with Chronic Obstructive Pulmonary Disease in an English Real-World Primary Care Setting.

Purpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting ß2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England. Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥35 years and had a forced expiratory volume in 1 second/forced vital capacity <0.7, linkage to HES and continuous registration with a general practitioner for 12 months pre- and 6 months post-initiation. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured using the proportion of days covered by days' supply of SITT or MITT prescriptions. Persistence was measured with a gap of >30 days between the end of a prescription and the following refill used to determine non-persistence. Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference <10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p<0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months). Conclusion: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation.

Pragmatic randomised controlled trials in COPD and asthma: how to guide clinical practice.

The use of real-world evidence (RWE) studies, including pragmatic randomised controlled trials (RCTs; randomised RWE studies), to aid the development of treatment guidelines, is gradually becoming a mainstay within clinical practice. RWE is an integral part of patient-driven decision-making and offers important value to add complimentary evidence to traditional RCTs; these provide a more well-rounded view of the benefits to patient-reported outcomes and improve the external validity of a given treatment versus findings from traditional RCTs alone. Discussions in recent scientific workshops explored the importance of pragmatic RCTs in optimising guideline development and patient care in chronic obstructive pulmonary disease (COPD) and asthma. The Salford Lung Study in patients with COPD (NCT01551758) and asthma (NCT01706198) were the world's first prelicence pragmatic RCTs that compared novel investigational treatments with existing COPD and asthma treatments and, more recently (2021), RWE studies have been used by the American Thoracic Society and the US Food and Drug Administration to support the approval of an immunosuppressant drug in patients receiving lung transplants. This highlights the importance of RWE data in supporting clinical guideline development and emphasises the advantages for the use of pragmatic RCTs in guiding clinical practice.

INTREPID: single- versus multiple-inhaler triple therapy for COPD in usual clinical practice.

INTRODUCTION: Real-world trial data comparing single- with multiple-inhaler triple therapy (MITT) in COPD patients are currently lacking. The effectiveness of once-daily single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) and MITT were compared in usual clinical care. METHODS: INTREPID was a multicentre, randomised, open-label, phase IV effectiveness study comparing FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA inhaler with a clinician's choice of any approved non-ELLIPTA MITT in usual COPD clinical practice in five European countries. Primary end-point was proportion of COPD Assessment Test (CAT) responders (≥2-unit decrease in CAT score from baseline) at week 24. Secondary end-points in a subpopulation included change from baseline in forced expiratory volume in 1 s (FEV1) and percentage of patients making at least one critical error in inhalation technique at week 24. Safety was also assessed. RESULTS: 3092 patients were included (FF/UMEC/VI n=1545; MITT n=1547). The proportion of CAT responders at week 24 was significantly greater with FF/UMEC/VI versus non-ELLIPTA MITT (OR 1.31, 95% CI 1.13-1.51; p<0.001) and mean change from baseline in FEV1 was significantly greater with FF/UMEC/VI (77 mL versus 28 mL; treatment difference 50 mL, 95% CI 26-73 mL; p<0.001). The percentage of patients with at least one critical error in inhalation technique was low in both groups (FF/UMEC/VI 6%; non-ELLIPTA MITT 3%). Safety profiles, including incidence of pneumonia serious adverse events, were similar between treatments. CONCLUSIONS: In a usual clinical care setting, treatment with once-daily single-inhaler FF/UMEC/VI resulted in significantly more patients gaining health status improvement and greater lung function improvement versus non-ELLIPTA MITT.

Clinical effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol in usual practice: the COPD INTREPID study design.

Effectiveness studies complement conventional randomised controlled trials by providing a holistic view of treatments in the setting of usual clinical practice. We present the protocol for the ongoing INTREPID (INvestigation of TRelegy Effectiveness: usual PractIce Design; ClinicalTrials.gov identifier: NCT03467425) study, a randomised, open-label, 24-week effectiveness study of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; Trelegy) delivered by the ELLIPTA inhaler versus non-ELLIPTA multiple-inhaler triple therapy in patients with chronic obstructive pulmonary disease (COPD) in usual practice settings. INTREPID was designed to provide evidence of FF/UMEC/VI effectiveness in patients with COPD managed in routine healthcare systems across multiple European countries. Between study initiation and end-of-study visits, patients will receive their medication and care as they would ordinarily receive it, from their usual healthcare provider at their usual healthcare centre. Study-specific intervention will be minimal. The primary end-point will be the proportion of COPD assessment test (CAT) responders, defined as a clinically meaningful improvement from baseline of ≥2 units, at week 24. The CAT was chosen as it provides health status information relevant to patients, physicians, health technology agencies and payers. Lung function (forced expiratory volume in 1 s) and critical inhaler errors will also be assessed in a subgroup of patients. The strengths and weaknesses of the protocol and some of the challenges associated with conducting this multicountry study, such as differences in healthcare systems and treatment practices across sites, will also be discussed.

Addition of a 5-lipoxygenase-activating protein inhibitor to an inhaled corticosteroid (ICS) or an ICS/long-acting beta-2-agonist combination in subjects with asthma.

OBJECTIVE: To investigate the clinical benefits of 'add-on' therapy with GSK2190915 in combination with the inhaled corticosteroid (ICS) fluticasone propionate (FP) and the ICS/long-acting beta 2 agonist (LABA) combination FP/salmeterol in asthmatic subjects. METHODS: Both studies were cross-over, randomized, double-blind, double-dummy and placebo-controlled in subjects with a forced expiratory volume in 1 second (FEV1) best of >50 and ≤80% of predicted. Add-on to ICS: Subjects (n = 162) aged ≥12 years received FP 100 µg twice daily (BID) plus GSK2190915 100 mg once daily (QD); GSK2190915 300 mg QD; montelukast 10 mg QD; salmeterol 50 µg BID or placebo. Add-on to ICS/LABA: Female subjects (n = 145) aged ≥18 years received FP/salmeterol 250/50 µg BID plus GSK2190915 300 mg QD, montelukast 10 mg QD or placebo. In both studies, the primary endpoint was trough FEV1 at the end of the treatment period. Secondary endpoints included a range of objective and patient-reported measures of efficacy. RESULTS: Add-on to ICS: There was no statistically significant difference in the primary endpoint between either dose of GSK2190915 (add-on to FP) and placebo. Nominally statistically significant increases were demonstrated for GSK2190915 300 mg add-on relative to placebo for mean morning peak expiratory flow (p = 0.049), percentage of symptom-free days (p = 0.035) and percentage of symptom-free 24 h periods (p = 0.030). Add-on to ICS/LABA: There were no statistically significant differences on the primary endpoint between treatment regimens. Nominally statistically significant decreases were demonstrated in daytime (p = 0.023), night-time (p = 0.041) and 24 h (p = 0.019) short-acting beta 2 agonist usage with FP/salmeterol + GSK2190915 300 mg vs. FP/salmeterol + placebo. CONCLUSION: There was no clinically significant improvement in the primary endpoint following GSK2190915 add-on treatment; however, improvements in a range of secondary endpoints and biomarker data provided evidence of pharmacological activity. Improvements in response to background treatment may have been a limitation in both studies. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT01156792 and NCT01248975.

Efficacy, safety and tolerability of GSK2190915, a 5-lipoxygenase activating protein inhibitor, in adults and adolescents with persistent asthma: a randomised dose-ranging study.

BACKGROUND: GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose-response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only. METHODS: Eight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged ≥12 years with a forced expiratory volume in 1 second (FEV1) of 50-85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10-300 mg), twice-daily inhaled fluticasone propionate 100 µg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. RESULTS: For the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p ≤ 0.05). No dose-response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10 mg dose appeared to be sub-optimal. GSK2190915 was associated with a dose-dependent reduction in urinary leukotriene E4. The profile and incidence of adverse events were similar between treatment groups. CONCLUSION: Efficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use. No additional improvement on efficacy endpoints was gained by administration of GSK2190915 doses greater than 30 mg. GSK2190915 was well-tolerated. These results may support further studies with GSK2190915 30 mg. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01147744.

Efficacy and optimal dosing interval of the long-acting beta2 agonist, vilanterol, in persistent asthma: a randomised trial.

BACKGROUND: Vilanterol (VI) is a novel once-daily long-acting beta2 agonist with inherent 24-h activity. The aim of this study was to evaluate the efficacy of three once-daily doses and one twice-daily dose of VI used concurrently with ICS in adult patients (≥18 years) with persistent asthma. Safety was also assessed. METHODS: Multicentre, randomised, double-blind, placebo-controlled, five-period crossover study consisting of 7-day treatment periods separated by 7-day wash-out periods. Seventy-five patients, maintained on ICS, received VI 6.25, 12.5 and 25 mcg once-daily (evening), VI 6.25 mcg twice-daily (morning/evening), and placebo. The primary endpoint was trough forced expiratory volume in 1 s (FEV(1)) (mean of 23 h and 24 h post evening dose) on Day 7; secondary endpoint was weighted mean 24-h serial FEV(1) on Day 7. RESULTS: All VI groups demonstrated statistically significant increases in trough FEV(1) versus placebo (p < 0.001). There was a statistically significant increase in weighted mean 24-h FEV(1) for each VI group versus placebo (p < 0.001). The effects of once-daily VI on trough FEV(1) and weighted mean 24-h FEV(1) were dose dependent. The incidence of adverse events (AEs) was low in each VI treatment group and was not dose dependent (5-9%; placebo = 18%); no drug-related AEs or serious AEs were reported. CONCLUSION: Once-daily treatment with VI was well tolerated and associated with improvements in lung function. The VI 6.25 mcg twice-daily dose showed the greatest change in trough FEV(1), however, similar changes in weighted mean 24-h FEV(1) with VI 12.5 mcg once-daily were observed. Although our study was not powered to demonstrate non-inferiority of once- versus twice-daily dosing of VI, the data suggest no advantage over a 24-h period of twice-daily over once-daily dosing for the same total daily dose. ClinicalTrials.gov: NCT00980200.

Fluticasone furoate: once-daily evening treatment versus twice-daily treatment in moderate asthma.

BACKGROUND: Inhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD) evening and twice-daily (BD) regimens of the novel inhaled corticosteroid fluticasone furoate (FF) in asthma patients. METHODS: Patients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1) 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml) were randomized to FF or fluticasone propionate (FP) regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 µg OD, FF or FP 100 µg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough) FEV1; non-inferiority of FF 200 µg OD and FF 100 µg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs) and 24-hour urinary cortisol excretion were assessed. RESULTS: The intent-to-treat population comprised 147 (FF) and 43 (FP) patients. On Day 28, pre-dose FEV1 showed FF 200 µg OD to be non-inferior (pre-defined limit -110 ml) to FF 100 µg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml); all FF and FP regimens were significantly superior to placebo (p ≤ 0.02). AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 µg OD, 0.75; 100 µg BD, 0.84; p ≤ 0.02). CONCLUSIONS: FF 200 µg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose. TRIAL REGISTRATION: Clinicaltrials.gov; NCT00766090.

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized, placebo-controlled trial.

BACKGROUND: Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma. METHODS: Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV(1)) 50-80% of predicted normal value and FEV(1) reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV(1) at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV(1). RESULTS: A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV(1) compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV(1) at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV(1) than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups. CONCLUSIONS: FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma. TRIAL REGISTRATION: NCT00398645.

Fluticasone furoate nasal spray is effective and well tolerated for perennial allergic rhinitis in adolescents and adults.

BACKGROUND: Fluticasone furoate nasal spray (FFNS), an intranasal corticosteroid, has been shown to be effective in perennial allergic rhinitis in randomized, double-blind, placebo-controlled studies but has been less extensively studied in perennial allergic rhinitis than seasonal allergic rhinitis. This study was designed to evaluate the efficacy and safety of FFNS in perennial allergic rhinitis in adolescents and adults ≥12 years of age. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study (FFU111439), patients ≥12 years old with perennial allergic rhinitis received FFNS, 110 micrograms (n = 160), or placebo (n = 155) q.d. for 4 weeks. RESULTS: Over the entire treatment period, FFNS was significantly (p < 0.05) more effective than placebo with respect to mean changes from baseline in daily reflective total nasal symptoms (primary end point), morning and evening reflective total nasal symptoms, daily reflective individual nasal symptoms, morning predose instantaneous total and individual nasal symptoms, and morning and evening peak nasal inspiratory flow. FFNS did not show a statistically significant difference from placebo in comparisons of ocular symptom measures. Clinically meaningful improvement versus placebo was observed on the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities overall score. Adverse events reported in >3% of patients in a treatment group and reported more frequently with FFNS than placebo were epistaxis (15% FFNS, 8% placebo) and nasopharyngitis (5% FFNS, 1% placebo). CONCLUSION: Once-daily FFNS was well tolerated and more effective than placebo at improving nasal symptoms of perennial allergic rhinitis in adolescents and adults ≥12 years of age.