Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study.

INTRODUCTION: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. METHODS: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. RESULTS: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. CONCLUSION: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

[Safety of umeclidinium/vilanterol in Chinese patients in a real-world setting: a prospective, multicenter, single-arm, observational study].

Objective: To evaluate the safety of umeclidinium/vilanterol in Chinese participants in a real-world setting. Methods: This was a 24-week, prospective, multicenter, single-arm, observational study that enrolled participants treated with umeclidinium/vilanterol in real-world settings from 14 sites in China from 14 December 2020 to 30 January 2022. The primary outcomes were the incidence of adverse events (AEs) and serious adverse events (SAEs) at week 24. Results: A total of 887 participants on umeclidinium/vilanterol were enrolled. The mean (±SD) age of these participants was 67.5 (±9.6) years, with more men (77.7%) enrolled. The majority of the participants (98.1%) had been diagnosed with chronic obstructive pulmonary disease, and 67.6% of them reported comorbidities. More than half of the participants (52.8%) were taking concomitant medication in addition to the study treatment. AEs were reported in 59 (6.7%) participants and were predominantly mild to moderate in severity. SAEs were reported in 21 (2.4%) participants, including 9 fatal SAEs, 10 reported non-fatal SAEs, and 2 reported both non-fatal and fatal SAEs. None of the SAEs, including the fatal events, were considered by the investigators to be related to umeclidinium/vilanterol. Adverse drug reactions (ADRs) were reported in 6 (0.7%) participants with 4 preferred terms (PTs), all of which were considered mild in severity. Of these PTs, 2 were known ADRs of umeclidinium/vilanterol. Three participants (0.3%) reported AEs that were part of serious identified/potential hazards, all of which were considered by the investigators to be unrelated to umeclidinium/vilanterol. Conclusion: The results of this study showed that umeclidinium/vilanterol was well tolerated in Chinese participants in a real-world setting and no new drug-related safety signals were observed.

Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening: a post hoc analysis of the EMAX trial.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. METHODS: The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10-30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21-24, and rescue medication use (puffs/day) over Weeks 1-24. Analyses were conducted across the full range of reversibility (-850-896 mL); however, results are presented for the range -100-400 mL because there were few participants with values outside this range. RESULTS: The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. CONCLUSIONS: FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.

Once daily combined inhaled steroid and ultra long-acting bronchodilator prescribing in pediatric asthma: a dual Center retrospective cohort study.

OBJECTIVE: A high proportion of children and adolescents who have "difficult" or therapy-resistant asthma, are found to have poor adherence to maintenance therapies. Such individuals are thus difficult asthmatics (for reasons of poor adherence) rather than being young people with true difficult asthma. In our centers, once daily ICS/ULABA (Relvar™) is considered if there is an increase in reported interval symptoms, asthma attacks requiring hospital attendance or rescue oral prednisolone, or persistently low lung function despite reported regular use of a twice daily ICS/LABA preparation. In the majority of these young people, a clinical history of overt non-adherence or a clinical suspicion of covert non-adherence will be noted. METHODS: The aim of our retrospective cohort study was to assess the clinical effectiveness of Relvar™ in a selected adolescent asthma population. RESULTS: In a pre-selected group of adolescents with likely poor prior adherence to inhaled therapies, a change to Relvar™ (once daily combined ICS/ULABA) led to improvements in asthma control, as assessed by ED attendances and oral steroid burden. CONCLUSIONS: A prospective study to verify these findings and also explore the effects on quality of life, asthma control, and adherence is warranted.

Time-to-first exacerbation, adherence, and medical costs among US patients receiving umeclidinium/vilanterol or tiotropium as initial maintenance therapy for chronic obstructive pulmonary disease: a retrospective cohort study.

BACKGROUND: Adherence to chronic obstructive pulmonary disease (COPD) maintenance medication is important for managing symptoms and exacerbation risk, and is associated with reduced mortality, hospitalizations, and costs. This study compared on-treatment exacerbations, medical costs, and medication adherence in patients with COPD initiating treatment with umeclidinium/vilanterol (UMEC/VI) or tiotropium (TIO). METHODS: This retrospective matched cohort study selected patients from Optum's de-identified Clinformatics Data Mart database who initiated maintenance treatment with UMEC/VI or TIO between 01/01/2014 and 12/31/2017 (index date defined as the first dispensing). Eligible patients were ≥ 40 years of age and had ≥ 12 months continuous health plan coverage pre- and post-index; ≥ 1 medical claim for COPD pre-index or on the index date; no moderate/severe COPD-related exacerbations on the index date; no asthma diagnosis pre- or post-index; no maintenance medication fills containing inhaled corticosteroids, long-acting ß2-agonists, or long-acting muscarinic antagonists pre-index or on the index date; and no fills for both UMEC/VI and TIO on the index date. Outcomes included time-to-first (Kaplan-Meier analysis) and rates of on-treatment COPD-related moderate/severe exacerbations, medication adherence (proportion of days covered [PDC] and proportion of adherent patients [PDC ≥ 0.8]), and COPD-related medical costs per patient per month (PPPM). Propensity score matching was used to adjust for potential confounders. RESULTS: Each cohort included 3929 matched patients. Kaplan-Meier rates of on-treatment COPD-related exacerbations were similar between cohorts (hazard ratio at 12 months; overall: 0.93, moderate: 0.92, severe: 1.07; all p > 0.05). UMEC/VI versus TIO initiators had significantly higher adherence (mean PDC: 0.44 vs 0.37; p < 0.001; proportion with PDC ≥ 0.8: 22.0% vs 16.4%; p< 0.001) and significantly lower mean on-treatment COPD-related total medical costs ($867 vs $1095 PPPM; p = 0.028), driven by lower outpatient visit costs. CONCLUSIONS: These findings provide valuable information for physicians considering UMEC/VI or TIO as initial maintenance therapy options for patients with COPD.

The effect of exacerbation history on outcomes in the IMPACT trial.

IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations.Subgroup analyses assessed whether the efficacy of FF/UMEC/VI versus FF/VI or UMEC/VI and UMEC/VI versus FF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≥2 moderate/no severe; n=4628 (45%)) and severe (≥1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc).Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI group versus FF/VI (single moderate 20% (10-29), frequent moderate 11% (2-19), severe 17% (7-26)) and versus UMEC/VI (single moderate 18% (5-29), frequent moderate 29% (21-37), severe 26% (14-35)). Moderate/severe exacerbation rates were reduced in the FF/VI group versus UMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (-12-18), frequent moderate 21% (11-29), severe 11% (-3-22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health status versus both dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung function versus FF/VI in all subgroups.Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol and umeclidinium/vilanterol in patients with COPD: results on cardiovascular safety from the IMPACT trial.

BACKGROUND: This analysis of the IMPACT study assessed the cardiovascular (CV) safety of single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI dual therapy. METHODS: IMPACT was a 52-week, randomized, double-blind, multicenter Phase III study comparing the efficacy and safety of FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg or UMEC/VI 62.5/25 mcg in patients ≥40 years of age with symptomatic chronic obstructive pulmonary disease (COPD) and ≥1 moderate/severe exacerbation in the previous year. The inclusion criteria for the study were intentionally designed to permit the enrollment of patients with significant concurrent CV disease/risk. CV safety assessments included proportion of patients with and exposure-adjusted rates of on-treatment CV adverse events of special interest (CVAESI) and major adverse cardiac events (MACE), as well as time-to-first (TTF) CVAESI, and TTF CVAESI resulting in hospitalization/prolonged hospitalization or death. RESULTS: Baseline CV risk factors were similar across treatment groups. Overall, 68% of patients (n = 7012) had ≥1 CV risk factor and 40% (n = 4127) had ≥2. At baseline, 29% of patients reported a current/past cardiac disorder and 58% reported a current/past vascular disorder. The proportion of patients with on-treatment CVAESI was 11% for both FF/UMEC/VI and UMEC/VI, and 10% for FF/VI. There was no statistical difference for FF/UMEC/VI versus FF/VI or UMEC/VI in TTF CVAESI (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.85, 1.11; p = 0.711 and HR: 0.92, 95% CI: 0.78, 1.08; p = 0.317, respectively) nor TTF CVAESI leading to hospitalization/prolonged hospitalization or death (HR: 1.19, 95% CI: 0.93, 1.51; p = 0.167 and HR: 0.96, 95% CI: 0.72, 1.27; p = 0.760, respectively). On-treatment MACE occurred in ≤3% of patients across treatment groups, with similar prevalence and rates between treatments. CONCLUSIONS: In a symptomatic COPD population with a history of exacerbations and a high rate of CV disease/risk, the proportion of patients with CVAESI and MACE was 10-11% and 1-3%, respectively, across treatment arms, and the risk of CVAESI was low and similar across treatment arms. There was no statistically significant increased CV risk associated with the use of FF/UMEC/VI versus FF/VI or UMEC/VI, and UMEC/VI versus FF/VI. TRIAL REGISTRATION: NCT02164513 (GSK study number CTT116855).

Adjudication of cardiovascular events in patients with chronic obstructive pulmonary disease: SUMMIT trial.

BACKGROUND: Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality. METHODS AND RESULTS: A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%). CONCLUSION: A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice.

BACKGROUND: Evidence for the management of chronic obstructive pulmonary disease (COPD) comes from closely monitored efficacy trials involving groups of patients who were selected on the basis of restricted entry criteria. There is a need for randomized trials to be conducted in conditions that are closer to usual clinical practice. METHODS: In a controlled effectiveness trial conducted in 75 general practices, we randomly assigned 2799 patients with COPD to a once-daily inhaled combination of fluticasone furoate at a dose of 100 µg and vilanterol at a dose of 25 µg (the fluticasone furoate-vilanterol group) or to usual care (the usual-care group). The primary outcome was the rate of moderate or severe exacerbations among patients who had had an exacerbation within 1 year before the trial. Secondary outcomes were the rates of primary care contact (contact with a general practitioner, nurse, or other health care professional) and secondary care contact (inpatient admission, outpatient visit with a specialist, or visit to the emergency department), modification of the initial trial treatment for COPD, and the rate of exacerbations among patients who had had an exacerbation within 3 years before the trial, as assessed in a time-to-event analysis. RESULTS: The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group. The numbers of other serious adverse events were similar in the two groups. CONCLUSIONS: In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events. (Funded by GlaxoSmithKline; Salford Lung Study ClinicalTrials.gov number, NCT01551758 .).

A systematic review with meta-analysis of fluticasone furoate/vilanterol combination for the treatment of stable COPD.

BACKGROUND: Current guidelines recommend the use of inhaled corticosteroids/long-acting beta2-agonists as first-line therapy for COPD patients at risk for acute exacerbations and/or severe airflow limitation. This systematic review assesses available evidence on the efficacy and safety of fluticasone furoate/vilanterol (FF/VI) combination versus each alone, for the treatment of patients with severe to very severe stable COPD. METHODS: Randomized, placebo-controlled trials of >8 weeks of duration were included. Primary end points were pulmonary function, COPD exacerbations and serious adverse events. FF/VI was compared with its mono-components. RESULTS: Five reports with six trials (n = 15,515 patients) met the entry criteria. FF/VI was associated with significant increases in trough FEV1 compared with vilanterol (VI) and fluticasone furoate (FF) (45 mL and 90 mL respectively). FF/VI significantly reduced the number of subjects with at least one moderate to severe exacerbation compared with VI (number needed to treat for benefit [NNTB] = 21) and with FF (NNTB = 26). There were no statistical differences in the rates of serious adverse events, cardiac events and all-cause mortality. On the contrary, FF/VI showed a significant 52% increase in the rate of pneumonia compared with VI monotherapy (5.3% vs. 3.5%). However, there was no difference in the rate of pneumonia when FF/VI was compared with FF alone. CONCLUSIONS: FF/VI combination was associated with a decrease of the rate of COPD exacerbations, without affecting mortality or cardiovascular outcomes in patients with moderate to severe stable COPD. Also, the use of FF was associated with an increased risk of pneumonia.

Monitoring safety in a phase III real-world effectiveness trial: use of novel methodology in the Salford Lung Study.

BACKGROUND: The Salford Lung Study (SLS) programme, encompassing two phase III pragmatic randomised controlled trials, was designed to generate evidence on the effectiveness of a once-daily treatment for asthma and chronic obstructive pulmonary disease in routine primary care using electronic health records. OBJECTIVE: The objective of this study was to describe and discuss the safety monitoring methodology and the challenges associated with ensuring patient safety in the SLS. Refinements to safety monitoring processes and infrastructure are also discussed. The study results are outside the remit of this paper. The results of the COPD study were published recently and a more in-depth exploration of the safety results will be the subject of future publications. ACHIEVEMENTS: The SLS used a linked database system to capture relevant data from primary care practices in Salford and South Manchester, two university hospitals and other national databases. Patient data were collated and analysed to create daily summaries that were used to alert a specialist safety team to potential safety events. Clinical research teams at participating general practitioner sites and pharmacies also captured safety events during routine consultations. Confidence in the safety monitoring processes over time allowed the methodology to be refined and streamlined without compromising patient safety or the timely collection of data. The information technology infrastructure also allowed additional details of safety information to be collected. CONCLUSION: Integration of multiple data sources in the SLS may provide more comprehensive safety information than usually collected in standard randomised controlled trials. Application of the principles of safety monitoring methodology from the SLS could facilitate safety monitoring processes for future pragmatic randomised controlled trials and yield important complementary safety and effectiveness data. © 2016 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Dual Bronchodilation with Indacaterol Maleate/Glycopyrronium Bromide Compared with Umeclidinium Bromide/Vilanterol in Patients with Moderate-to-Severe COPD: Results from Two Randomized, Controlled, Cross-over Studies.

PURPOSE: To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI). METHODS: Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 µg and once-daily UMEC/VI 62.5/25 µg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV1 AUC0-24). Rescue medication use, symptom control, and safety were assessed throughout. RESULTS: Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV1 AUC0-24h at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of -20 mL in both studies: -26.9 and -34.2 mL, respectively (LS mean between-treatment differences: -11.5 and -18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information. CONCLUSIONS: IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).

Randomised trial of once-daily vilanterol in children with asthma on inhaled corticosteroid therapy.

BACKGROUND: Inhaled corticosteroids (ICS) are effective maintenance treatments for childhood asthma; however, many children remain uncontrolled. Vilanterol (VI) is an inhaled long-acting beta-2 agonist which, in combination with the ICS fluticasone furoate, is being explored as a once-daily treatment for asthma in children. We evaluated the dose-response, efficacy, and safety of once-daily VI (6.25 µg, 12.5 µg and 25 µg) administered in the evening over 4 weeks, on background fluticasone propionate (FP) in children with asthma inadequately controlled on ICS. METHODS: This was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study in children ages 5-11 years with persistent asthma on ICS and as-needed short-acting beta-agonist. The study comprised a 4-week run-in, 4-week treatment period, and 1-week follow-up. From study start, children replaced their current ICS with open-label FP 100 µg twice daily. Children were randomised to receive placebo, VI 6.25 µg, VI 12.5 µg or VI 25 µg once daily. Primary endpoint was treatment difference between VI 25 and placebo groups in mean change from baseline in evening peak expiratory flow averaged over the 4-week treatment. Secondary endpoints included change from baseline in trough forced expiratory volume in one second (FEV1) at Week 4 and change from baseline in percentage of rescue-free and symptom-free 24-h periods. Safety assessments included incidence of adverse events (AEs) and asthma exacerbations. RESULTS: In total, 456 children comprised the intention-to-treat population. The adjusted treatment difference between VI 25 and placebo groups for the primary endpoint was not statistically significant (p = 0.227) so no statistical inference was made for other VI dose comparisons or other endpoints. No difference in change from baseline in trough FEV1 was observed for any VI treatments versus placebo; however, VI 25 resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week versus placebo. The incidence of AEs was slightly higher in the VI groups (28-33 %) versus placebo (22 %). Nine children experienced asthma exacerbations during the treatment period. CONCLUSION: VI plus FP did not result in significant improvements in lung function versus placebo plus FP, but was well tolerated at all doses assessed. TRIAL REGISTRATION: NCT01573767 (ClinicalTrials.gov).

Efficacy and safety evaluation of once-daily fluticasone furoate/vilanterol in Asian patients with asthma uncontrolled on a low- to mid-strength inhaled corticosteroid or low-dose inhaled corticosteroid/long-acting beta2-agonist.

BACKGROUND: Response to inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combinations varies across ethnic groups. OBJECTIVE: To investigate the efficacy and safety of the ICS/LABA combination fluticasone furoate/vilanterol (FF/VI) 100/25 µg in Asian patients with asthma. METHODS: A randomized (1:1), 12-week, double-blind, placebo-controlled, parallel group, multicenter phase III study of once-daily FF/VI 100/25 µg versus placebo in patients of Asian ancestry ages ≥12 years with asthma, uncontrolled on a low- to mid-strength ICS or low-dose ICS/LABA. The primary end point was the mean change from baseline in the daily evening peak expiratory flow. Secondary end points were the mean change from baseline in percentage rescue-free 24-hour periods, daily morning peak expiratory flow, percentage symptom-free 24-hour periods, Asthma Quality of Life Questionnaire score, adverse events, and severe exacerbations. RESULTS: The intent-to-treat population was 307 patients. There were significant (p < 0.001) improvements from baseline for FF/VI 100/25 µg versus placebo in evening peak expiratory flow (51.0 L/min [95% confidence interval {CI}, 42.2-59.7 L/min]) and all secondary end points (percentage rescue-free 24-hour periods 21.8% [95% CI, 14.6-29.1%]; morning peak expiratory flow 52.9 L/min [95% CI, 44.2-61.6 L/min]; percentage symptom-free 24-hour periods 15.8% [95% CI, 9.4-22.3%]; Asthma Quality of Life Questionnaire score 0.52 [95% CI, 0.28, 0.75]). On-treatment adverse events were 35% with FF/VI (n = 2 [serious]), 31% with placebo; severe exacerbations were FF/VI (n = 1), placebo (n = 7). CONCLUSIONS: In patients of Asian ancestry, once-daily FF/VI 100/25 µg produced statistically and clinically significant improvements in efficacy end points versus placebo, with a generally similar safety profile. Results were consistent with a global phase III study of FF/VI 100/25 µg. Clinicaltrials.gov NCT01498679.

The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in chronic obstructive pulmonary disease.

BACKGROUND: New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy. METHODS: 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. CONCLUSIONS: The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in COPD. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01551758.

Once-daily fluticasone furoate/vilanterol 100/25 mcg versus twice daily combination therapies in COPD - mixed treatment comparisons of clinical efficacy.

BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) treatment approved in the United States, Canada and Europe for the long-term maintenance therapy of COPD. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes. METHODS: Data from 33 parallel-group randomised controlled trials (RCTs) of ICS/LABAs, of ≥8 weeks' duration in patients ≥12 years of age with COPD, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for three efficacy outcomes. Lung function, assessed by change from baseline in forced expiratory volume in one second (FEV1), was the outcome of primary interest (n = 28 studies). Secondary objectives were assessment of annual rate of moderate/severe exacerbations (n = 15) and patient-reported health status, measured by change from baseline in St George's Respiratory Questionnaire (SGRQ) Total score (n = 20). Overall, 25 different treatments were included in the MTC; we report findings, including probabilities of non-inferiority, for comparisons of once-daily FF/VI 100/25 mcg with twice-daily fluticasone propionate (FP)/salmeterol (SAL) 500/50 mcg and budesonide (BUD)/formoterol (FORM) 400/12 mcg. RESULTS: For FEV1, FF/VI 100/25 mcg demonstrated >99% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg using a 50 mL margin. For annual rate of moderate/severe exacerbations, FF/VI 100/25 mcg demonstrated 73% and 77% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg, respectively, using a 10% rate ratio margin. For SGRQ Total score, the corresponding probabilities of non-inferiority were 99% and 98%, respectively, on a 2-unit margin. Significant covariate effects were identified: increased age was associated with deterioration in FEV1 and reduced exacerbation frequency; shorter study duration was associated with reduced exacerbation frequency. CONCLUSIONS: FF/VI 100/25 mcg was comparable with corresponding doses of FP/SAL and BUD/FORM on lung function and health status outcomes. Non-inferiority on moderate/severe exacerbation rate was not demonstrated to the same degree of confidence, though observed rates were similar. Model limitations include a weak treatment network for the exacerbation analysis and variability across the included studies. Our data support previous RCT findings suggesting that the efficacy of FF/VI 100/25 mcg on lung function and health status in COPD is comparable with twice-daily ICS/LABAs.

Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma.

OBJECTIVES: Fluticasone furoate (FF; inhaled corticosteroid) combined with vilanterol (VI; long-acting beta(2) 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. METHODS: The primary end point was weighted mean (wm) 0-24-h serial forced expiratory volume in 1 s (FEV(1)) at week 12. Secondary end points (change from baseline) were trough FEV(1) 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. RESULTS: Compared with FF 100 mcg, FF/VI 100/25 mcg significantly improved wmFEV(1) (p < 0.001), trough FEV(1) (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. CONCLUSIONS: 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.

Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers.

OBJECTIVE: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/ umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. METHODS: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPT® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 µg, FF/UMEC 400/500 µg, UMEC/VI 500/100 µg, or FF/VI 400/100 µg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 µg or 400/250/100 µg, FF/VI 400/100 µg, or UMEC/VI 250/100 µg. PK and PD parameters and safety were assessed. RESULTS: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. CONCLUSIONS: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies.

[Analysis on 315 cases of clinical adverse drug reaction/event induced by gastrodin].

With patients' general situation, medication use, occurrence time of adverse drug reaction/event (ADR/ADE), clinical manifestations and prognosis as reference items, a retrospective study was made for 315 cases with ADR/ADE induced by Gastrodin in Chongqing from January 2008 to June 2014, in order to analyze the characteristics of ADR/ADE and provide reference for rational clinical medication. The results showed that among the 315 cases with ADR/ADE, 143 cases (45.4%) were males and 172 cases (54.6%) were females, most of them (74.9%) were aged above 45; 60 cases (19.0%) with ADE were caused by off-label indications and 66 cases (21.0%) with ADE were caused by over dosage; ADR/ADE cases induced by intravenous drip mainly happened within 30 min (85.5%), ADR/ADE cases induced by oral administration mainly happened within 2 h (74.4%), and all of ADR/ ADE cases induced by intramuscular injection happened within 10 min. Totally 593 ADR/ADE cases were reported, which were mainly damages in gastrointestinal system, skin and its adnexa; And 61.9% of ADR/ADE cases were newly reported. It is suggested that medical workers shall learn about the regularity and characteristics of ADR/ADE induced by gastrodin, apply it in clinic with standards, pay close attention to changes of patients' situations and attach importance to the monitoring of ADR/ADE, so as to enhance the safety of medication.

Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone.

BACKGROUND: Combination therapy with an inhaled corticosteroid (ICS) and long-acting ß2 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICALTRIALSGOV NO: NCT01086384.