Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes.

Prevention and treatment of COPD exacerbations are recognized as key goals in disease management. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250 mcg/50 mcg (FSC 250/50) and salmeterol 50 mcg (SAL) twice-daily on moderate/severe exacerbations. Subjects received treatment with FSC 250/50 during a one month run-in, followed by randomization to FSC 250/50 or SAL for 52 weeks. Moderate/severe exacerbations were defined as worsening symptoms of COPD requiring antibiotics, oral corticosteroids and/or hospitalization. In 797 subjects with COPD (mean FEV(1) = 0.98L, 34% predicted normal), treatment with FSC 250/50 significantly reduced the annual rate of moderate/severe exacerbations by 30.4% compared with SAL (1.10 and 1.59 per subject per year, respectively, p < 0.001), the annual rate of exacerbations requiring oral corticosteroids by 34% (p < 0.001) and the annual rate of moderate/severe exacerbations requiring hospitalization by 36% (p = 0.043). Clinical improvements observed during run-in treatment with FSC 250/50 were better maintained over 52 weeks with FSC 250/50 compared to SAL. Statistically significant reductions in albuterol use, dyspnea scores, and nighttime awakenings and numerical benefits on quality of life were seen with FSC 250/50 compared with SAL. The incidence of adverse events was similar across groups. Pneumonia was reported more frequently with FSC 250/50 compared with SAL (7% vs. 2%). FSC 250/50 is more effective than SAL at reducing the rate of moderate/severe exacerbations. These data confirm the beneficial effect of FSC on the management of COPD exacerbations and support the use of FSC in patients with COPD.

The efficacy and safety of cilomilast in COPD.

The aim of this review is to present the clinical data on the efficacy and safety of cilomilast in patients with chronic obstructive pulmonary disease (COPD). Over 6000 COPD patients received cilomilast during an extensive clinical development programme performed by GlaxoSmithKline (GSK).Five phase III randomized, double-blind, placebo-controlled, parallel-group pivotal studies were conducted in poorly reversible patients (<15% or <200 mL improvement over baseline in forced expiratory volume in 1 second (FEV(1)) after salbutamol). Patients were randomized to receive oral cilomilast 15 mg (n = 2088) or placebo (n = 1408) twice daily for 24 weeks. The co-primary efficacy variables were changes from baseline in trough (predose) FEV(1) and in total score of the St George's Respiratory Questionnaire (SGRQ).Additional studies were performed to investigate the anti-inflammatory actions of cilomilast by measuring inflammatory cells and mediators in biopsies and induced sputum; to assess the long-term effects of cilomilast; to assess the cardiac safety of cilomilast; and to assess the efficacy of cilomilast on hyperinflation. Results from one of the phase III and from one supportive study have been previously published.In the phase III pivotal studies, when averaged over 24 weeks, the mean change from baseline in FEV(1) in the cilomilast group showed improvement compared with placebo in all studies (range 24-44 mL treatment difference). When averaged over 24 weeks, there was a similar improvement in the mean total SGRQ score in both treatment groups with a decrease ranging from -1.8 to -4.2 units in the cilomilast group and 0.4 to -4.9 units in the placebo group. Only one study, however, showed both a statistically and clinically meaningful difference between the two treatment groups (treatment difference -4.1 units; p < 0.001). Although cilomilast was shown to reduce COPD exacerbations in some of these studies, there was no effect on the incidence of COPD exacerbations in a study specifically powered to detect a difference compared with placebo.No significant change was found in the primary endpoints of the anti-inflammatory studies, although some anti-inflammatory activity was detected, including a reduction in tissue CD8+ T lymphocytes and CD68+ macrophages in airway biopsies. In addition, studies did not demonstrate a consistent significant effect of cilomilast on hyperinflation.In all studies, adverse events associated with the gastrointestinal body system were reported more frequently in the cilomilast group than the placebo group and predominantly occurred within the first 2 weeks of initiating cilomilast therapy.During the cilomilast development programme a number of different endpoints were investigated to characterize the efficacy and safety of this second-generation phosphodiesterase 4 inhibitor. Safety assessments throughout the late-phase programme did not reveal any evidence of serious safety concerns with the use of cilomilast. Previous studies in phase II and early phase III had shown improvements in efficacy endpoints and some evidence of an anti-inflammatory mechanism of action. However, subsequent phase III studies failed to definitively confirm the earlier programme results, which led to termination of the development of cilomilast.

Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations.

OBJECTIVES: COPD exacerbations are associated with significant morbidity and mortality. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations. METHODS: Patients received standardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in, followed by randomization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months. Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids, antibiotics, or hospitalization. RESULTS: In 782 patients with COPD (mean FEV(1)=0.94+/-0.36 L, 33% predicted normal), treatment with fluticasone propionate/salmeterol 250/50 significantly reduced (1) the annual rate of moderate to severe exacerbations by 30.5% compared with salmeterol (1.06 and 1.53 per subject per year, respectively, p<0.001), (2) the risk of time to first exacerbation by 25% (hazard ratio=0.750, p=0.003) and (3) the annual rate of exacerbations requiring oral corticosteroids by 40% (p<0.001). Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol. Adverse events were reported for a similar percentage of subjects across groups. A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol (7% vs. 4%). CONCLUSIONS: We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year. The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered. This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD.

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.

Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline. OBJECTIVES: In a post hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg, either component alone or placebo, on the rate of post-bronchodilator FEV(1) decline in patients with moderate or severe COPD. METHODS: A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis. MEASUREMENTS AND MAIN RESULTS: Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV(1) was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV(1) decline by 16 ml/year compared with placebo (95% confidence interval [CI], 7-25; P < 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5-22; P = 0.003). Rates of decline were similar among the active treatment arms. FEV(1) declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV(1) decline. CONCLUSIONS: Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV(1) in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www.clinicaltrials.gov (NCT00268216).

Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD.

STUDY OBJECTIVE: To examine the effect of fluticasone propionate, 250 microg/salmeterol, 50 microg combination (FSC 250/50) twice daily on lung hyperinflation and associated measures of exercise performance in patients with COPD. DESIGN: This was a randomized, double-blind, parallel-group study. PATIENTS: Eligible patients were > or = 40 years old with a diagnosis of COPD, prealbuterol FEV(1) < 70% of predicted, FEV1/FVC ratio > or = 0.70, and functional residual capacity (FRC) > or = 120% of predicted normal. INTERVENTIONS: Patients were randomized to FSC 250/50; salmeterol, 50 microg; or placebo twice daily for 8 weeks. Predose and postdose spirometry, plethysmography, and constant-load cycle cardiopulmonary exercise test evaluations were compared. The primary comparison was FSC 250/50 with placebo. The salmeterol group was included for exploratory comparisons with FSC 250/50. RESULTS: A total of 185 patients (mean baseline FEV1 of 41% predicted) were enrolled. At rest, FSC 250/50 significantly reduced postdose FRC and increased inspiratory capacity (IC) compared with placebo (differences of - 0.35 +/- 0.12 L and 0.33 +/- 0.06 L [mean +/- SE], respectively, at week 8; p > or = 0.003) and increased exercise endurance time (difference, 132 +/- 45 s; p = 0.004). At a standardized time during exercise (isotime), FSC 250/50 increased postdose IC by 0.20 +/- 0.05 L over placebo with associated improvements in tidal volume and minute ventilation (p < 0.05 vs placebo at week 8). Improvement in exercise time was significantly correlated with the increase in IC (r = 0.45, p < 0.001) but not FEV1 (r = 0.23, p = 0.08). Predose comparisons of FSC 250/50 with salmeterol and placebo favored FSC 250/50. CONCLUSION: We conclude that FSC 250/50 decreases lung hyperinflation at rest and during exercise with an associated increase in exercise endurance time when compared with placebo.

Future perspectives in COPD.

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex. The development of a multidimensional index--such as the BODE index--provides a means of classifying patients with COPD that also correlates with their prognosis. The individual components of the BODE index--body mass index (B), airflow obstruction (O) dyspnoea (D) and exercise capacity (E)--incorporate the pulmonary as well as the systemic effects seen in patients with COPD. Recent research has focussed on examining these impairments (including those of metabolism and inflammation) more carefully, and determining the effects of treatment on both the systemic and physiological aspects of COPD. Ongoing research initiatives by the public and private sector will contribute to our understanding of the disease processes underlying COPD, our understanding of the benefits associated with commonly used pharmacotherapies, as well as laying the foundations for the development of new agents and therapeutic tools. Advances in the use of pharmacotherapy have been mirrored by research to better define the benefits associated with pulmonary rehabilitation. Many questions remain to be answered, but a comprehensive approach is now considered essential to the life-long management of COPD, and will undoubtedly reduce the considerable socio-economic burden of COPD.

The efficacy and safety of inhaled fluticasone propionate/salmeterol and ipratropium/albuterol for the treatment of chronic obstructive pulmonary disease: an eight-week, multicenter, randomized, double-blind, double-dummy, parallel-group study.

BACKGROUND: The pathology of chronic obstructive pulmonary disease (COPD) includes both obstructive and inflammatory components. OBJECTIVE: The aim of this study was to confirm the findings of a previous study that compared the efficacy of a combination of 2 short-acting bronchodilators with the use of an inhaled corticosteroid and a long-acting beta-agonist in the treatment of COPD. METHODS: We conducted an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group study of subjects with moderate to severe COPD to compare fluticasone propionate/salmeterol 250/50 microg BID (FSC) with ipratropium/albuterol 36/206 microg QID (IB/ALB). The primary efficacy measure was morning preadministration forced expiratory volume in 1 second (FEV(1)). Secondary measures were morning peak expiratory flow (PEF), 6-hour FEV(1) AUC, percentage of symptom-free nights, Transition Dyspnea Index (TDI) score, and overall daytime symptom score. Additional measures included sleep symptoms, supplemental albuterol use, and nighttime awakenings due to respiratory symptoms. Safety evaluations were based on clinical adverse events and COPD exacerbations. RESULTS: Baseline characteristics were similar between the FSC (n = 180) and IB/ALB (n = 181) groups, including mean age (63.7 and 65.4 years, respectively), mean body weight (81 and 79 kg, respectively), screening pulmonary function (mean [SD], 43.7% [14.2%] and 41.6% [13.4%] of predicted FEV(1)), race (82% and 91% white), and sex (64% and 62% male). FSC resulted in greater improvements in morning preadministration FEV(1), morning PEF, and 6-hour FEV(1) AUC (all, P < 0.001), TDI score (P = 0.026), overall daytime symptom score (P = 0.024), percentage of symptom-free nights (P = 0.010), nighttime awakenings due to respiratory symptoms (P = 0.002), sleep symptom score (P = 0.003), and percentage of days and nights without rescue albuterol use compared with IB/ALB (P = 0.021 and P < 0.001, respectively). Compared with day 1, the FEV(1) AUC at week 8 increased by 0.38 L-h with FSC and decreased by 0.18 L-h with IB/ALB (P < 0.001 between groups). The type and incidence of adverse events were similar between the 2 groups. One or more adverse event was reported for 81 (45%) and 85 (47%) subjects in the FSC and IB/ALB groups, respectively. CONCLUSION: In this 8-week study, subjects with moderate to severe COPD experienced greater improvements in lung function and symptom measures with FSC than with IB/ALB.

A short-term comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol for the treatment of COPD.

BACKGROUND: This is the first comparison of two combination therapies, fluticasone propionate/salmeterol and ipratropium bromide/albuterol (salbutamol), for the treatment of patients with COPD. METHODS: A randomized, double-blind, double-dummy, parallel group, multicenter evaluation of fluticasone propionate/salmeterol 250/50 microg twice daily via DISKUS and ipratropium bromide/albuterol 36/206 microg four times daily via metered-dose inhaler over 8 weeks was conducted at 41 research sites in the US. Morning pre-dose FEV(1), 6-hour serial spirometry, PEF, dyspnea, night-time awakenings, supplemental albuterol use, and patient diary evaluations of symptoms were evaluated. RESULTS: A total of 365 patients with symptomatic COPD were enrolled. The treatment groups were similar in mean age (63.3 and 63.9 years), screening pulmonary function (44.1% and 43.2% of predicted FEV(1)), race (96% and 95% White), and sex distribution (59% and 60% male). Both fluticasone propionate/salmeterol and ipratropium bromide/albuterol improved lung function, symptoms, and supplemental albuterol use compared with baseline. Fluticasone propionate/salmeterol was more effective than ipratropium bromide/albuterol for improvement in morning pre-dose FEV(1), morning PEF, 6-hour FEV(1) area under the curve (AUC(6)), Transition Dyspnea Index (TDI) focal score, daytime symptom score, night-time awakenings, sleep symptoms, and albuterol-free nights (p < or = 0.013). Compared with day 1, at week 8 the FEV(1) AUC(6) significantly increased with fluticasone propionate/salmeterol and significantly decreased with ipratropium bromide/albuterol (p < or = 0.003). The incidence of adverse events was similar between treatment groups, except for a higher incidence of oral candidiasis with fluticasone propionate/salmeterol. CONCLUSIONS: Short-term treatment with the combined inhaled corticosteroid and long-acting beta(2)-adrenoceptor agonist fluticasone propionate/salmeterol resulted in greater control of lung function and symptoms than combined ipratropium bromide/albuterol bronchodilator therapy, in patients with COPD.

Loss of response to treatment with leukotriene receptor antagonists but not inhaled corticosteroids in patients over 50 years of age.

BACKGROUND: There are limited published data describing the relative efficacy of available treatment options in younger versus older patients with persistent asthma. OBJECTIVE: To compare the efficacy of fluticasone propionate (FP) and zafirlukast (Z) in younger (12 to 49 years of age) versus older (50 years and older) patients with asthma. METHODS: A retrospective analysis of five randomized, double-blind, double-dummy studies 4 to 12 weeks in duration of 1,742 patients <50 years of age and 243 patients aged 50 years or older. Interventions were inhaled fluticasone propionate (FP) 88 microg, oral Z 20 mg, or placebo twice daily. RESULTS: Treatment with FP resulted in significantly greater improvements than Z in all efficacy measurements (except for nighttime awakenings) regardless of age. In older patients, treatment with FP significantly increased pulmonary function compared with Z: FEV (FP= +0.19 L; placebo = -0.34 L; Z = -0.06 L); AM peak expiratory flow rate [PEFR] (FP = +25 L/minute; placebo = -18 L/minute; Z = +4 L/minute); PM PEFR (FP = +24 L/minute; placebo = -24 L/minute; Z = +5 L/minute; P < or = 0.023; for all comparisons). Compared with Z, treatment with FP in older patients also resulted in significantly greater increases in the percentage of symptom-free days (25% vs 13%) and rescue-free days (35% vs 17%); and significantly greater reductions in albuterol use (-1.6 vs -0.3 puffs/day) and the percentage of patients with exacerbations (2.7% vs 14.3%; P < or = 0.031). CONCLUSIONS: Regardless of age, treatment with FP in patients with asthma significantly improved pulmonary function and overall asthma control. In contrast, treatment with Z in older patients with asthma resulted in small improvements in asthma symptoms, whereas lung function improved minimally or not at all, and exacerbations increased. These data suggest that FP effectively controls inflammation in older patients, whereas Z may mask inflammation and may not provide the level of bronchodilatory or anti-inflammatory activity needed for effective asthma control in older patients.