Glenn Crater

Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study.

BACKGROUNDnCombination long-acting bronchodilator therapy may be more effective than long-acting bronchodilator monotherapy in chronic obstructive pulmonary disease (COPD).nnnOBJECTIVESnTo compare the efficacy and safety of once-daily umeclidinium/vilanterol (UMEC/VI) 125/25 mcg with placebo and UMEC or VI monotherapy in COPD.nnnMETHODSnThis was a double-blind, placebo-controlled, parallel-group study. A total of 1493 patients were randomized (3:3:3:2) to 24 weeks of treatment with UMEC/VI 125/25 mcg, UMEC 125 mcg, VI 25 mcg, or placebo once-daily via dry powder inhaler.nnnRESULTSnPrimary efficacy endpoint was trough forced expiratory volume in one second (FEV1) on Day 169 (23-24 h post-dose). Additional lung-function, symptomatic and health-related quality of life endpoints were also assessed. Safety evaluations included: adverse events, vital signs, electrocardiography and clinical laboratory measurements. All active treatments significantly improved trough FEV1 vs placebo (0.124-0.238 L, all p<0.001). Improvements with UMEC/VI 125/25 mcg were significantly greater than for UMEC 125 mcg or VI 25 mcg (0.079 L and 0.114 L; both p≤0.001). Improvements for UMEC/VI 125/25 mcg vs placebo were observed for the transition dyspnea index (1.0 unit; p<0.001), rescue albuterol use at Weeks 1-24 (-1.5 puffs/day) and St. Georges Respiratory Questionnaire (-3.60 units, p<0.001). No safety signals were observed.nnnCONCLUSIONSnOnce-daily UMEC/VI 125/25 mcg was well tolerated and provided greater improvements in lung function, health status, and dyspnea scores compared with monotherapy components and placebo over 24 weeks. This study supports the use of UMEC/VI 125/25 mcg for the maintenance treatment of COPD.nnnCLINICAL TRIAL REGISTRATIONnprotocol number: DB2113361; ClinicalTrials.gov identifier: NCT01313637.

A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD.

BACKGROUNDnThis study evaluated the dose-response and dosing interval of the novel long-acting muscarinic receptor antagonist (LAMA) GSK573719 in patients with COPD.nnnMETHODSnThis randomized, double-blind, placebo-controlled, 3-way cross-over, incomplete block study evaluated 5 once-daily doses of GSK573719 (62.5-1000 μg), 3 twice-daily doses (62.5-250 μg), and open-label tiotropium for 14 days in patients (N = 176) with COPD (FEV(1) of 35-70% predicted). The primary endpoint was morning trough FEV(1) at Day 15. Secondary endpoints included 0-24 h weighted mean FEV(1) and serial FEV(1) values over 28 h. Safety measures and pharmacokinetics were assessed.nnnRESULTSnAll once-daily doses of GSK573719 significantly increased trough FEV(1) at Day 15 with improvements ranging from 95 to 186 mL over placebo (p ≤ 0.006), from 79 to 172 mL with twice-daily dosing (p ≤ 0.03), and 105 mL with tiotropium (p = 0.003). No clear dose ordering was observed. Once-daily doses significantly (p < 0.001) increased 0-24 h weighted mean FEV(1) at Day 14 by 131-143 mL over placebo, comparable to increases with the twice-daily doses (120-142 mL) and tiotropium (127 mL). Significant reductions in rescue albuterol use and improvements in FVC were also observed with once-daily dosing. Plasma C(max) occurred within 5-15 min of dosing after which the drug was rapidly cleared and eliminated. GSK573719 was well tolerated, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters.nnnCONCLUSIONnOnce-daily dosing with GSK573719 in COPD provides clinically significant and sustained improvement in lung function over 24 h with similar efficacy to twice-daily dosing.

Lung function and symptom improvement with fluticasone propionate/salmeterol and ipratropium bromide/albuterol in COPD: Response by beta-agonist reversibility ☆

This retrospective analysis of data from two multi-center, randomized, double-blind, parallel group studies compared the efficacy of fluticasone propionate/salmeterol (FSC) 250/50 mcg twice daily with ipratropium bromide/albuterol (IB/ALB) 36/206 mcg four times daily in albuterol-reversible (n=320 [44%]) and non-reversible (n=399 [56%]) patients with COPD. In reversible and non-reversible patients, both treatments significantly increased FEV(1)AUC(0-6h) from baseline and the magnitude of improvement was larger in reversible patients. FSC increased FEV(1)AUC(0-6h) by 1.46+/-0.08 and 1.98+/-0.13 l-h at Day 1 and Week 8, respectively, in reversible patients, compared with 0.71+/-0.06 and 0.94+/-0.10 l-h in non-reversible patients (p<0.001). With IB/ALB, increases were 1.46+/-0.08 and 1.19+/-0.11 l-h at Day 1 in reversible patients and Week 8, respectively, and 0.89+/-0.06 and 0.74+/-0.09 l-h (p < or = 0.041) in non-reversible patients. After 8 weeks, in both the reversible and non-reversible populations, the FEV(1) AUC(0-6h) significantly increased with FSC treatment (p < or = 0.002) and significantly decreased with IB/ALB (p < or = 0.010). In both reversibility groups, improvement in Transition Dyspnea Index (TDI) scores, overall daytime diary symptom scores and nocturnal symptom measures were significantly greater with FSC treatment compared with IB/ALB (p < or = 0.044). Reversibility status was not predictive of the magnitude of reduction in symptom scores. We conclude that both reversible and non-reversible patients receive greater clinical benefit with FSC compared with IB/ALB and acute bronchodilator reversibility is not useful for differentiating patients based on symptomatic responses to FSC compared with IB/ALB.

Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD

BACKGROUNDnCombining maintenance medications with different mechanisms of action may improve outcomes in COPD. In this study we evaluated the efficacy and safety of fluticasone/salmeterol (FSC) (250/50xa0mcg twice daily) when added to tiotropium (18xa0mcg once daily) (TIO) in subjects with symptomatic moderate to severe COPD.nnnMETHODSnThis was a 24-week, randomized, double-blind, parallel group, multi-center study. Subjects 40 years or older with cigarette smoking history ≥10 pack-years and with the diagnosis of COPD and post-bronchodilator FEV(1) ≥40 to ≤ 80% of predicted normal and FEV(1)/FVC of ≤0.70 were enrolled. Following a 4-week treatment with open-label TIO 18xa0mcg once daily, subjects were randomized in a double-blind fashion to either the addition of FSC 250/50 DISKUS twice daily or matching placebo. The primary efficacy endpoint was AM pre-dose FEV(1) and secondary endpoints included other measures of lung function, rescue albuterol use, health status and exacerbations.nnnRESULTSnThe addition of FSC to TIO significantly improved lung function indices including AM pre-dose FEV(1), 2xa0h post-dose FEV(1), AM pre-dose FVC, 2xa0h post-dose FVC and AM pre-dose IC compared with TIO alone. Furthermore, this combination was superior to TIO alone in reducing rescue albuterol use. However, there were no significant differences between the treatment groups in health status or COPD exacerbations. The incidence of adverse events was similar in both groups.nnnCONCLUSIONSnThe addition of FSC to subjects with COPD treated with TIO significantly improves lung function without increasing the risk of adverse events. NCT00784550.

28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial.

BACKGROUNDnUmeclidinium (UMEC; GSK573719) is a new long-acting muscarinic antagonist (LAMA) currently in development in combination with vilanterol (VI), an inhaled, long-acting beta₂ agonist for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to evaluate the safety and tolerability of repeat dosing of UMEC and VI in combination once daily for 28 days in patients with COPD.nnnMETHODSnThis was a multicenter, double-blind, placebo-controlled, parallel group study. Patients aged ≥40 years with post-bronchodilator FEV₁ ≤80% of predicted normal values and FEV₁/FVC ratio ≤0.70, and a smoking history of ≥10 pack-years, were randomized 4:1 to once-daily UMEC/VI (500/25 mcg; n = 42) or placebo (n = 9).nnnRESULTSnUMEC/VI was non-inferior to placebo in weighted mean pulse rate over 0-6 h at Day 28 (primary endpoint: difference of -0.5 bpm, 95% CI: -5.5 to 4.5). There was no evidence of a difference between UMEC/VI compared with placebo in blood pressure, minimum and maximum pulse rate, or QTcF assessments. Adverse events (AEs) were reported by 11 (26%) patients in the UMEC/VI group and one (11%) patient in the placebo group. No serious AEs were reported. Both UMEC and VI showed rapid absorption (median t(max) ∼6 min for both drugs) with no evidence of accumulation for AUC or C(max) on Day 28 compared with Day 1 for UMEC or VI. There was no correlation between individual steady-state C(max) and pulse rate on Day 28. Change from baseline in trough FEV₁ on Day 29 showed numerically greater improvements with UMEC/VI compared with placebo.nnnCONCLUSIONnOnce-daily dosing with UMEC in combination with VI in patients with moderate-to-very-severe COPD was well tolerated over 28 days.

Prevalence of COPD among symptomatic patients in a primary care setting

Abstract Objective: Spirometry is recognized as the gold standard assessment for the diagnosis of COPD. However, spirometry continues to be underused, perpetuating the underdiagnosis of COPD. The aim of this study was to evaluate the prevalence of COPD in a primary care setting in patients with a smoking history and self-reported chronic bronchitis symptoms. Research design and methods: This was a multi-center, cross-sectional study. The primary assessment was the percentage of patients with airway obstruction (post-bronchodilator FEV1/FVC ratiou2009≤u20090.70) compared to those without obstruction (post-bronchodilator FEV1/FVC ratiou2009>u20090.70). Results: Airflow obstruction consistent with COPD was confirmed in 26% of patients (mean age 52.9 years, FEV1 81.4% predicted and smoking history 39.8 pack-years) that reported chronic bronchitis symptoms. Airflow obstruction increased with age and smoking history. Slight or moderate dyspnea was reported by 68% of patients and the majority had not talked to their doctor about cough and continued to smoke. Limitations: Patients were evaluated at a single visit. The definition of airway obstruction used may have lead to overdiagnosis in patients aged 70 and older. Conclusion: This study confirms that many patients with COPD remain undiagnosed in the primary care setting. Evaluation of spirometry in patients with a smoking history and chronic bronchitis symptoms can aid in the diagnosis of COPD, allowing earlier treatment thereby reducing the burden of this debilitating disease. Clinical trial registration: Study code ADC109043; clinicaltrials.gov #NCT00442468.

Effect of fluticasone propionate/salmeterol on arterial stiffness in patients with COPD

BACKGROUNDnCOPD is associated with increased arterial stiffness which may in part explain the cardiovascular morbidity observed in the disease. A causal relationship between arterial stiffness and cardiovascular events has not been established, though their strong association raises the possibility that therapies that reduce arterial stiffness may improve cardiovascular outcomes. Prior studies suggest that fluticasone propionate/salmeterol (FSC) may improve cardiovascular outcomes in COPD and we hypothesized that FSC would reduce arterial stiffness in these patients.nnnMETHODSnThis multicenter, randomized, double-blind, placebo-controlled study compared the effects of FSC 250/50 μg twice-daily and placebo on aortic pulse wave velocity (aPWV) as determined by ECG-gated carotid and femoral artery waveforms. The primary endpoint was aPWV change from baseline at 12-weeks (last measure for each patient).nnnRESULTSn249 patients were randomized; the mean FEV(1) in each group was similar (55% predicted) and 60% of patients reported a cardiovascular disorder. At 12-weeks, aPWV between FSC and placebo was -0.42 m/s (95%CI -0.88, 0.03; p = 0.065). A statistically significant reduction in aPWV between FSC and placebo was observed in those who remained on study drug throughout the treatment period [-0.49 m/s (95%CI -0.98, -0.01; p = 0.045)]. A post hoc analysis suggested the effect of FSC was greater in patients with higher baseline aPWV.nnnCONCLUSIONnFSC does not reduce aPWV in all patients with moderate to severe COPD, but may have effects in those with elevated arterial stiffness. Additional studies are required to determine if aPWV could serve as a surrogate for cardiovascular events in COPD.

Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease

BackgroundThis retrospective cohort study compared the risks of exacerbations and COPD-related healthcare costs between patients with chronic obstructive pulmonary disease (COPD) initiating tiotropium (TIO) alone and patients initiating triple therapy with fluticasone-salmeterol combination (FSC) added to TIO.MethodsManaged-care enrollees who had an index event of ≥ 1 pharmacy claim for TIO during the study period (January 1, 2003-April 30, 2008) and met other eligibility criteria were categorized into one of two cohorts depending on their medication use. Patients in the TIO+FSC cohort had combination therapy with TIO and FSC, defined as having an FSC claim on the same date as the TIO claim. Patients in the TIO cohort had no such FSC use. The risks of COPD exacerbations and healthcare costs were compared between cohorts during 1 year of follow-up.ResultsThe sample comprised 3333 patients (n = 852 TIO+FSC cohort, n = 2481 TIO cohort). Triple therapy with FSC added to TIO compared with TIO monotherapy was associated with significant reductions in the adjusted risks of moderate exacerbation (hazard ratio 0.772; 95% confidence interval [CI] 0.641, 0.930) and any exacerbation (hazard ratio 0.763; 95% CI 0.646, 0.949) and a nonsignificant reduction in COPD-related adjusted monthly medical costs.ConclusionsTriple therapy with FSC added to TIO compared with TIO monotherapy was associated with significant reductions in the adjusted risks of moderate exacerbation and any exacerbation over a follow-up period of up to 1 year. These improvements were gained with triple therapy at roughly equal cost of that of TIO alone.

Prevalence of Airway Obstruction Assessed by Lung Function Questionnaire

OBJECTIVEnTo estimate the prevalence of unidentified chronic obstructive pulmonary disease (COPD) and determine the screening accuracy of the Lung Function Questionnaire (LFQ).nnnPATIENTS AND METHODSnCigarette smokers who had a smoking history of 10 or more pack-years and were aged 30 years or older were recruited from 36 centers from February 18, 2009, to May 29, 2009. A total of 1575 patients completed a Web-based survey including the 5-item LFQ. Spirometry was performed on patients with an LFQ total score of 18 or less and on a subset scoring more than 18. The primary outcome was the proportion of patients at risk of airflow obstruction as measured by the LFQ (score, ≤ 18) in whom an airflow obstruction was confirmed by spirometry.nnnRESULTSnOf the patients who completed the LFQ, 849 (54%) had standardized spirometry data available. On the basis of LFQ and spirometry results, the estimated prevalence of possible COPD was 17.9% (95% confidence interval, 15.3%-20.6%). At a cut point of 18 or less, sensitivity, specificity, positive predictive value, and negative predictive value of the LFQ were 88%, 25%, 21%, and 90%, respectively. Approximately 1 in 5 patients (21%) aged 30 years or older and 1 in 4 (26%) aged 50 years or older scored 18 or less on the LFQ and had a ratio of forced expiratory volume in the first second of expiration to forced vital capacity less than 0.70.nnnCONCLUSIONnOn the basis of postbronchodilator spirometry results using weighted estimates, approximately 1 in 5 patients (21%) aged 30 years or older with a smoking history of 10 or more pack-years seen in a primary care setting is likely to have COPD. The LFQ could be a helpful COPD case-finding tool for clinicians to identify patients who need further evaluation.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT01013948.

Fluticasone propionate/salmeterol 250/50 μg versus salmeterol 50 μg after chronic obstructive pulmonary disease exacerbation

BackgroundInhaled long-acting beta2agonists used alone and in combination with an inhaled corticosteroid reduce the risk of exacerbations in patients with stable COPD. However, the relative efficacy of these agents in preventing recurrent exacerbations in those recovering from an initial episode is not known. This study compared the rate of COPD exacerbations over the 26 weeks after an initial exacerbation in patients receiving the combination of fluticasone propionate and salmeterol (FP/SAL) or SAL alone.MethodsPatients (n = 639) aged ≥40 years were randomized to either twice-daily inhaled FP/SAL 250/50 μg or SAL 50 μg. Primary, and secondary, endpoints were rates of recurrent severe, and moderate/severe, exacerbations of COPD. Lung function, health outcomes and levels of biomarkers of systemic inflammation were also assessed.ResultsThere was no statistically significant treatment difference in rates of recurrent severe exacerbations (treatment ratio 0.92 [95% CI: 0.58, 1.45]) and moderate/severe exacerbations (0.82 [0.64, 1.06]) between FP/SAL and SAL in the intent-to-treat population. Pre-dose morning FEV1change from baseline was greater (0.10 L [0.04, 0.16]) with FP/SAL than SAL. No treatment difference was seen for other endpoints including patient-reported health outcomes and biomarker levels for the full cohort.ConclusionsNo significant treatment difference between FP/SAL and SAL was seen in COPD exacerbation recurrence for the complete cohort. Treatment benefit with FP/SAL over SAL (treatment ratio 0.68 [0.47, 0.97]) was seen in patients having FEV1≥ 30% and prior exposure to ICS. No unexpected safety issues were identified with either treatment. Patients with the most severe COPD may be more refractory to treatment.Trial registrationClinicalTrials.gov (identifier http://clinicaltrials.gov/show/NCT01110200). This study was funded by GlaxoSmithKline (study number ADC113874).