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(Chest. 2003;124:834-843.)
© 2003 American College of Chest Physicians

The Efficacy and Safety of Fluticasone Propionate (250 µg)/Salmeterol (50 µg) Combined in the Diskus Inhaler for the Treatment of COPD*

Nicola A. Hanania, MD, FCCP; Patrick Darken, PhD; Donald Horstman, PhD; Colin Reisner, MD; Benjamin Lee, PharmD; Suzanne Davis, BA and Tushar Shah, MD{dagger}

* From the Baylor College of Medicine (Dr. Hanania), Houston, TX; and GlaxoSmithKline, Inc (Drs. Darken, Horstman, Reisner, Lee, and Shah, and Ms. Davis), Research Triangle Park, NC. {dagger} A list of investigators who contributed to this study is located in the Appendix.

Correspondence to: Nicola A. Hanania, MD, FCCP, Ben Taub General Hospital, Pulmonary/Critical Care, 1504 Taub Loop, Houston, TX 77030; e-mail: hanania{at}bcm.tmc.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Study objectives: To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting ß2-agonist salmeterol (SM), when administered together in a single device (Diskus; GlaxoSmithKline, Inc; Research Triangle Park, NC), with that of placebo and the individual agents alone in patients with COPD.

Design: Randomized, double-blind, multicenter, placebo-controlled study.

Setting: Seventy-six investigative sites in the United States.

Patients: Seven hundred twenty-three patients >= 40 years of age with COPD and a mean baseline FEV1 of 42% predicted.

Interventions: FP (250 µg), SM (50 µg), FP plus SM combined in a single inhaler (FSC), or placebo administered twice daily through the Diskus device for 24 weeks.

Measurements: Primary efficacy measures were morning predose (ie, trough FEV1) for FSC compared with SM and 2-h postdose FEV1 for FSC compared with FP. Other efficacy measures were as follows: morning peak expiratory flow rate (PEF); transition dyspnea index; chronic respiratory disease questionnaire; chronic bronchitis symptom questionnaire; exacerbations; and other symptomatic measures.

Results: At Endpoint (ie, the last on-treatment, post-baseline assessment), treatment with FSC significantly (p <= 0.012) increased the morning predose FEV1 (165 mL) compared with SM (91 mL) and placebo (1 mL), and significantly (p <= 0.001) increased the 2-h postdose FEV1 (281 mL) compared with FP (147 mL) and placebo (58 mL). Improvements in lung function with FSC compared with FP and SM, and with FP and SM compared with placebo, as measured by the average daily morning PEF, was observed within approximately 24 h after the initiation of treatment, indicating an early onset of effect (p <= 0.034). Compared with placebo, FSC significantly improved dyspnea, quality of life, and symptoms of chronic bronchitis. The incidence of adverse effects (except for an increase in oral candidiasis with FSC and FP) were similar among the treatment groups.

Conclusions: Treatment with FSC (FP, 250 µg, and SM, 50 µg) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD, with no additional safety concerns for the combination treatment vs that with the individual components.

Key Words: adrenergic ß-agonists • COPD • fluticasone propionate • glucocorticoids • inhaled corticosteroid • long-acting ß2-agonist • salmeterol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
COPD, a disease state characterized by airflow limitation that is not fully reversible, is the fourth leading cause of death in the United States, accounting for > 119,000 deaths in 2000.1 2 COPD (including chronic bronchitis and emphysema) affects approximately 15 to 17 million Americans,3 4 although recent data indicate that > 24 million Americans have evidence of impaired lung function.2 The economic burden of COPD in the United States is high with an annual cost of $30.4 billion (in 1993).5

The current approach to treatment of COPD advocated by evidence-based international guidelines (ie, Global Initiative for Chronic Obstructive Lung Disease)6 consists of the use of bronchodilators as first-line therapy and, depending on disease severity, inhaled corticosteroids (ICSs). In short-term studies,7 8 9 ICSs appeared to have no significant effect on sputum neutrophil counts. However, these studies were limited in duration, patient numbers, and the range of mediators and cells that were studied. Contradicting these findings are results from other studies that indicate a positive outcome on a range of inflammatory indices with ICS therapy.10 11 12 13 14 15 16 17 18 Although studies have shown that disease progression (as measured by decline in FEV1 over time) is not affected by therapy with ICSs, several short-term and long-term studies have shown clinical benefits with various ICS medications, including fluticasone propionate (FP).19 20 21 22 23 24 25 26 An epidemiologic study27 has suggested that therapy with ICSs reduces COPD-related morbidity and mortality in elderly patients. Salmeterol (SM), a long-acting ß2-agonist, has been shown in clinical trials28 29 30 to be effective in improving lung function, symptoms, and quality of life in patients with COPD. SM also has nonbronchodilator effects including inhibition of inflammatory mediators, from mast cells (such as histamine, leukotrienes, and prostaglandin D2)31 decrease in airway edema by reducing plasma leakage,32 attenuation of neutrophil recruitment and activation,33 34 and reduction of allergen-induced bronchial hyperresponsiveness,35 but it is not clear whether these effects contribute to the clinical benefits of SM in the treatment of asthma or COPD.

Recent in vitro and in vivo evidence suggesting a mechanistic interaction at the molecular level between ICSs and ß2-agonists may explain the improved efficacy of therapy with a combination of FP and SM compared with therapy using either medication alone. Corticosteroids have been shown36 37 to up-regulate the ß2-receptor in the human airways, which may provide more receptors for ß2-agonists to activate. Long-acting ß2-agonists have been shown to facilitate the entry of the glucocorticoid receptor/ligand complex into the nucleus and to improve the anti-inflammatory effect of corticosteroids.38 The complementary benefits of these two classes of medications have been observed in patients with asthma.39 40 This evidence further supports the rationale for combining a long-acting ß2-agonist with an ICS in the treatment of patients with COPD.

The current study was designed to compare the efficacy and safety of 24 weeks’ treatment with SM, 50 µg, and FP, 250 µg, administered together twice daily in a single inhaler device (Diskus) with that of placebo and the individual agents alone in patients with COPD.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
Patients
Patients were >= 40 years of age, were current or former smokers with a >= 20 pack-year history, and had received a diagnosis of COPD, as defined by the American Thoracic Society.1 Inclusion criteria required a baseline FEV1/FVC ratio of <= 70% and a baseline FEV1 of < 65% of predicted normal, but > 0.70 L (or if <= 0.70 L, then > 40% of predicted normal). Patients were required to have symptoms of chronic bronchitis and moderate dyspnea. The specific exclusion criteria were as follows: current diagnosis of asthma; use of oral corticosteroids within the past 6 weeks; abnormal clinically significant ECG; long-term oxygen therapy; moderate or severe exacerbation during the run-in period; and any significant medical disorder that would place the patient at risk, interfere with evaluations, or influence study participation.

Study Design
This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial (protocol No. SFCA3007) that was conducted in 76 investigative sites in the United States. Patients began a 2-week, single-blind run-in period during which they received placebo, via Diskus (GlaxoSmithKline, Inc; Research Triangle Park, NC), and albuterol, via metered-dose inhaler and/or nebules (VENTOLIN Inhalation Aerosol or VENTOLIN Nebules; GlaxoSmithKline, Inc) on an as-needed basis and discontinued the use of corticosteroids and bronchodilators with the exception of stable regimens of theophylline (no change in dose for 1 month prior to screening). Following the run-in period, eligible patients were randomized as follows: FP, 250 µg (FLOVENT DISKUS; GlaxoSmithKline, Inc); SM, 50 µg (SEREVENT DISKUS; GlaxoSmithKline, Inc); FP, 250 µg, plus SM, 50 µg, in combination (FSC) [ADVAIR DISKUS; GlaxoSmithKline, Inc]; or placebo via the Diskus device twice daily for 24 weeks. Randomization was stratified by reversibility (defined as a >= 12% and 200 mL increase in FEV1 from baseline following the administration of 400 µg albuterol) and investigative site. Patients also were given as-needed albuterol and were evaluated weekly for the first 4 weeks of treatment, every 2 weeks until week 8, and then every 4 weeks until study completion.

Since SM and FP exert their benefits by different mechanisms of action, the following two different FEV1 time points were measured to determine treatment efficacy: predose FEV1; and 2-h postdose FEV1. Decreases in airway obstruction due to reduced inflammation (ie, the contribution of FP in the combination) were assessed by comparing changes in predose FEV1 between FSC and SM. Bronchodilation (ie, the contribution of SM) was assessed by comparing the changes in the 2-h postdose FEV1 between FSC and FP. Other efficacy parameters included morning peak expiratory flow (PEF), dyspnea (assessed by the transition dyspnea index [TDI]41 ), supplemental albuterol use, health status (as assessed by the chronic respiratory disease questionnaire [CRDQ]42 ) symptoms of chronic bronchitis (assessed by the chronic bronchitis symptom questionnaire [CBSQ]43 44 ), and exacerbations (defined by treatment, with moderate exacerbations requiring treatment with antibiotics and/or corticosteroids, and severe exacerbations requiring hospitalization). For the TDI, a clinically meaningful difference between treatments has been defined as 1.0.45 Clinically meaningful changes from baseline for the CRDQ has been determined to be 10.0.46 CBSQ total scores range from 0 to 16, and a minimum clinically important change has been determined to be 1.4 (unpublished data). The validation of this instrument, including face validity, reliability, internal consistency, and the determination of the minimum clinically important change, will be the subject of a future article. A patient was discontinued from the study after the first exacerbation requiring corticosteroids (oral or inhaled) or hospitalization, or after the third exacerbation requiring antibiotics.

Safety was assessed using adverse event reporting, ECGs, vital signs, clinical laboratory evaluations, oropharyngeal examination, and short cosyntropin stimulation testing at selected sites according to the cosyntropin (CORTROSYN; Organon; West Orange, NJ) prescribing information.47 The protocol was approved by the institutional review board for each site, and all patients provided written informed consent.

Statistical Methods
Study enrollment was planned for 720 patients (175 per treatment group) at 75 centers. This sample size provided approximately 80% power to detect differences between treatment groups of 75 mL in predose FEV1 and 80 mL in 2-h postdose FEV1 at Endpoint. In order to account for patient withdrawals, Endpoint was used as the primary time point and was defined as the last on-treatment postbaseline assessment excluding any data from the discontinuation visit.

Differences between treatments at Endpoint and at all other time points in the change from baseline in predose FEV1, postdose FEV1, CBSQ, and CRDQ were estimated and analyzed using contrasts from analysis of covariance adjusting for baseline values and investigator. Thus, estimated differences between treatments may vary from differences between actual means due to model adjustment. The estimation of treatment effects and the analysis of differences between treatments for the baseline dyspnea index and TDI were performed using contrasts with analysis of variance, adjusting for investigator. Time to exacerbation was analyzed using Wald {chi}2 tests based on a Cox proportional hazards model, with age and baseline FEV1 as covariates. Overall average and monthly average morning PEF values, number of nighttime awakenings, and albuterol use were analyzed using the van Elteren modification of the Wilcoxon test to adjust for investigator.48


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
Study Population
Of the 1,489 patients screened in this study, 723 were randomized and treated. A total of 218 patients (placebo group, 32%; SM group, 32%; FP group, 27%; and FSC group, 30%) were discontinued from the study. The reasons for discontinuation were an exacerbation of COPD (59 patients), adverse events (31 patients), consent withdrawn (35 patients), lack of efficacy (31 patients), lost to follow-up (13 patients), protocol violations (33 patients), consisting primarily of the use of excluded medications, and other miscellaneous reasons (16 patients). Demographic and disease characteristics at screening were similar across the treatment groups (Table 1 ). Patients had a significant smoking history with a median of 53 to 60 pack-years. Screening spirometry results indicated moderate-to-severe airflow obstruction, with a mean FEV1 of 42% of predicted (55 to 56% of patients exhibited a >= 12% and at least a 200-mL increase in FEV1 following the administration of 400 µg albuterol). Median compliance over the 24-week study period was 96% for each treatment group.


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  		Table 1. Key Demographics and Characteristics at Screening*

 
Lung Function
Morning Predose FEV1:
A significantly greater increase in morning predose FEV1 (ie, FEV1 trough) at Endpoint (ie, the last treatment value) was observed following treatment with FSC (165 mL) compared with treatment with SM alone (91 mL; p = 0.012) and placebo (1 mL; p < 0.001) [Fig 1 ]. The increase in predose FEV1 at Endpoint following treatment with FSC was 16.6% over baseline. At week 1, significantly greater increases in predose FEV1 were observed after treatment with FSC (165 mL) compared with that for SM alone (122 mL; p = 0.026) and placebo (- 1 mL; p < 0.001). These differences were sustained throughout the 24-week study. A significantly greater increase in predose FEV1 also was observed for treatment with FP (109 mL) vs placebo (1 mL; p < 0.001) at Endpoint. Estimated differences between treatment groups at Endpoint are summarized in Table 2 .



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  		Figure 1. Improvement in predose FEV1 with FSC compared with the individual components (FP and SM) and placebo. SEM ranged from 20 to 35 mL.

 

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  		Table 2. Estimated Differences in Efficacy Parameters at Endpoint*

 
2-h Postdose FEV1:
A significantly greater increase in 2-h postdose FEV1 at Endpoint was observed following treatment with FSC (281 mL) compared with treatment with FP alone (147 mL; p < 0.001) and placebo (58 mL; p < 0.001) [Fig 2 ]. The increase in 2-h postdose FEV1 at Endpoint following treatment with FSC was 27.0% over baseline. At day 1 and week 1, significantly greater increases in 2-h postdose FEV1 values were observed for treatment with FSC (day 1, 206 mL; week 1, 266 mL) compared with that for FP (day 1, 70 mL; week 1, 143 mL; p < 0.001) and placebo (day 1, 54 mL; week 1, 67 mL; p < 0.001). These differences were maintained throughout the 24-week study. Significantly greater increases in 2-h postdose FEV1 also were observed for the SM treatment group (200 mL; p < 0.001) vs placebo at Endpoint. Estimated differences between treatment groups at Endpoint are summarized in Table 2 .



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  		Figure 2. Improvement in 2-h postdose FEV1 with FSC compared with the individual components (FP and salmeterol) and placebo. SEM ranged from 18 to 37 mL.

 
Response by Reversibility:
The magnitude of response in lung function and TDI for patients who demonstrated the reversibility of airflow obstruction with albuterol was higher compared with nonreversible patients. Importantly, the effects were clinically meaningful in both subgroups (Table 3 ).


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  		Table 3. Response by Reversibility*

 
Morning PEF:
Improvements in lung function with FSC treatment compared those with FP treatment alone and SM treatment alone, and with FP and SM treatment alone compared with placebo, as measured by average daily morning PEF, was observed on day 2, approximately 24 h after the initiation of treatment, indicating an early onset of effect (p <= 0.034). Greater increases in morning PEF from baseline were observed overall and throughout each month of the 24-week treatment period with FSC compared with FP, SM, and placebo (p <= 0.002 for all comparisons) [Fig 3 ]. Mean overall changes from baseline were also significantly greater for both FP and SM treatment alone vs placebo (p < 0.001).



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  		Figure 3. Morning PEF rate. Baseline morning PEF values were 220.3 L/min in the placebo group, 220.0 L/min in the FP group, 210.3 L/min in the SM group, and 206.1 L/min in the FSC group. SEM ranged from 1.7 to 6.8 L/min.

 
Dyspnea
The mean baseline dyspnea index (BDI) scores for the placebo, FSC, FP, and SM groups were 5.7, 6.1, 6.2, and 6.1, respectively, indicating a moderate level of dyspnea at the beginning of the treatment period. At Endpoint, the mean TDI score for treatment with FSC (+ 1.7) was significantly greater than that following treatment with placebo (+ 1.0; p = 0.023).

At Endpoint, TDI scores were numerically greater for SM treatment alone (1.6; p = 0.043) and FP treatment alone (1.7; p = 0.057) compared with placebo. Estimated differences at Endpoint in TDI scores between treatment groups are summarized in Table 2 .

Supplemental Albuterol Use
A significant reduction in overall albuterol use (ie, the number of inhalations per day) was observed during treatment with FSC (overall, - 1.0) compared with FP treatment alone (overall, - 0.2; p = 0.036) and placebo (overall, 0.1; p = 0.002). In addition, treatment with FSC provided a numerically greater change compared with SM treatment alone (overall, - 0.7). Treatment with FSC significantly increased the percentage of nights with no awakening requiring albuterol compared with treatment with SM alone and placebo. A significant increase in the overall percentage of days without albuterol use also was noted during treatment with FSC compared with SM treatment alone and placebo. The frequency of nighttime awakenings requiring albuterol use (ie, the number of awakenings per week) was significantly reduced by half during treatment with FSC (overall, - 0.12) compared with placebo (overall, 0.02; p < 0.001).

Health Status
The baseline mean overall CRDQ scores were 84.8 in the placebo group, 84.1 in the FSC group, 85.5 in the FP group, and 86.3 in the SM group. At Endpoint, treatment with FSC resulted in a clinically important increase from baseline in the mean overall CRDQ score (10.0), which was significantly greater compared with placebo (5.0; p = 0.006). The mean increases from baseline in the FP and SM groups were 10.4 and 6.4, respectively (p = 0.002 [FP vs placebo]). When evaluating the individual domains of the CRDQ, mean increases from baseline in dyspnea score (3.9; p = 0.031 [FSC vs placebo]), fatigue score (2.2; p <= 0.015 [FSC vs SM and placebo]), and the resulting physical summary score (6.1; p <= 0.032 [FSC vs SM and placebo]) were clinically important with FSC, and were greater than scores attained with FP, SM, or placebo. In addition, treatment with FSC demonstrated significantly greater increases at Endpoint in emotional summary score (3.9) compared with placebo (p = 0.019). Estimated differences at Endpoint in CRDQ scores among treatment groups are summarized in Table 2 .

Other Efficacy Measures
Baseline mean global assessment scores on the CBSQ were 7.5, 7.4, 7.0, and 7.3, respectively, in placebo, FP, SM, and FSC groups, indicating moderate symptoms of bronchitis. At Endpoint, improvements in CBSQ with FP (2.2) and FSC (2.1) were significantly greater compared with placebo (1.4; p <= 0.017). The mean change from baseline was also numerically greater with FSC compared with SM throughout the study. Similar mean changes were observed on the CBSQ for FSC and FP throughout the study. Estimated differences at Endpoint in CBSQ scores between treatment groups are summarized in Table 2 . No significant differences were observed among treatment groups in terms of the numbers of exacerbations or the time to first exacerbation.

Safety
The average time that patients remained in the study was similar among treatment groups (FSC group, 141 days; placebo group, 132 days; FP group, 139 days; and SM group, 136 days). A total of 485 patients (67%) experienced at least one adverse event during the study (Table 4 ). A greater percentage of patients in the FP and the FSC groups experienced candidiasis (of the mouth and throat) compared with the placebo and SM groups, as would be expected with the use of an ICS.


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  		Table 4. Incidence of Adverse Events >= 10%*

 
Adverse events that were judged by investigators to be potentially related to use of the study drug occurred in 9%, 11%, 15%, and 20%, respectively, of patients in the placebo, SM, FP, and FSC groups. Drug-related adverse events that occurred at a frequency of >= 4% in any one treatment group were throat irritation, hoarseness/dysphonia, headaches, and candidiasis of the mouth and throat (incidence of candidiasis: placebo group, < 1%; SM group, 3%; FP group, 6%; and FSC group, 9%). The number of patients who experienced adverse events resulting in withdrawal from the study was similar across treatment groups (range, 4 to 5%).

No deaths occurred, and the incidence of serious adverse events was low and was similar across treatment groups (placebo group, 6%; SM group, 3%; FP group, 5%; FSC group, 4%). At the selected sites where cosyntropin stimulation testing occurred, the incidence of abnormal cosyntropin stimulation values at Endpoint was similar for the patients taking an ICSs (ie, FP and FSC, nine patients) compared with those not taking an ICS (ie, placebo and SM, six patients). The incidence of clinically significant ECG abnormalities was comparable among treatment groups (placebo group, three patients; SM group, no patients; FP group, one patient; and FSC group, no patients). No treatment-related effects on vital signs, QTc, or cardiac rate were observed.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
The results from this clinical trial demonstrated that treatment with FSC (FP, 250 µg/SM, 50 µg) provided significantly greater improvements in predose FEV1, compared with treatment with SM and placebo, and significantly greater improvements in 2-h postdose FEV1, compared with treatment with FP, 250 µg, and placebo. Furthermore, the increases in FEV1 with treatment with FSC were clinically relevant for the treatment of COPD (predose FEV1, 165 mL; postdose FEV1, 281 mL). The improvements in FEV1 were apparent with FP, SM, and FSC after the first week of treatment, and continued during the subsequent 24 weeks of the study with no evidence of tolerance (Fig 1 , 2) . Moreover, PEF was improved within 24 h, and the increase was greater with FSC treatment than with SM treatment alone, indicating that there are early benefits to using an ICS along with a long-acting ß2-agonist.

Relief of dyspnea after treatment with FSC was demonstrated in this study by TDI scores (1.7) that were both substantial and clinically important (defined as >= 1.045 compared with baseline). Numerically greater TDI scores with the individual components (FP, 1.7; SM, 1.6) compared with placebo (1.0) also indicated clinically important relief of dyspnea, but to a lesser extent than with FSC. In addition to relief of dyspnea, treatment with FSC resulted in significantly greater relief of symptoms of chronic bronchitis (using the CBSQ) when compared with placebo at Endpoint. The CBSQ is a reliable and internally consistent measure of symptoms of chronic bronchitis.

Because patients often modify their lifestyles to compensate for their dyspnea, activity limitation associated with reduced expiratory airflow, and other symptoms, it is important that treatment also result in improvements in the patient’s quality of life. It is therefore noteworthy that the mean change from baseline in overall CRDQ scores after treatment with FSC (FP, 250 µg/SM, 50 µg) were clinically important, which was defined as a change of >= 10.0,46 in addition to being significantly greater than placebo.

The responses to the individual components, FP and SM, in improving lung function (the primary efficacy measure) were significantly greater than that seen with placebo and were generally comparable to each other in other efficacy measures throughout the study. However, only treatment with FSC resulted in consistently significant differences from placebo in secondary efficacy measures. These improvements indicate that both components of FSC may be needed to achieve clinically important differences. The inability of the components to achieve clinically meaningful differences from placebo may have been due to the improvements observed in the placebo group. Unfortunately, lung volume measurement using plethysmography was not performed in this study. Since there is very little information about the effect of ICSs on lung volumes, it would be interesting to investigate the effect of treatment with FSC and the relative contributions of FP and SM in future studies.

Previous studies24 25 have demonstrated a reduction in COPD exacerbation rates after treatment with an ICS. This study was designed and powered to evaluate the treatment effect on FEV1, which was the primary measure of efficacy, rather than to evaluate the rates of exacerbations. In this trial, no significant differences were observed between active and placebo treatment groups in the number of patients who experienced exacerbations. Elements of the study design that prevented a definitive evaluation of exacerbations include the following: the relatively short duration of the trial; the lack of an inclusion criterion requiring a history of exacerbations prior to entering the study; and the requirement of patient withdrawal after one exacerbation requiring oral or ICS therapy, or three exacerbations requiring antibiotic therapy. Future appropriately designed studies will be needed to determine the merits of this therapy in reducing exacerbation rates.

There are limited published data describing the efficacy of the concurrent use of a long-acting ß2-agonist and an ICS in COPD patients. A recently published study by Mahler et al49 evaluated the use of an ICS and a long-acting ß-agonist in combination for the treatment of COPD. Six hundred ninety-one patients with COPD were treated with FSC (FP, 500 µg/SM, 50 µg) twice daily, with the individual components alone at the same doses, or placebo for 24 weeks. The magnitude of improvements in predose and postdose FEV1 values for these parameters were comparable to those in this study, thus corroborating the findings of Mahler et al.49

The safety profile of FSC in this study was consistent with what would be expected with the administration of both an inhaled long-acting ß2-agonist plus an ICS and was not different from that for the administration of the individual components alone. While a slightly higher incidence of topical adverse events were noted with the treatment groups receiving an ICS, these events were regarded as mild to moderate in severity and rarely led to patient withdrawal. No unexpected cardiovascular effects were observed with combination therapy. There was no evidence that treatment with FSC was associated with any increased risk for hypothalamic-pituitary-adrenal axis suppression, as measured by short cosyntropin stimulation testing compared with treatment with FP, SM, or placebo.

In conclusion, treatment with FSC (FP, 250 µg/SM, 50 µg) twice daily over a period of 24 weeks provided clinically important and statistically significant benefits in patients with COPD, and was superior to those provided by treatment with FP or SM alone. These benefits were not associated with any additional clinically significant topical or systemic adverse effects. These results indicate that, for many patients, the treatment of both the inflammation and bronchoconstriction associated with COPD may be needed to achieve clinically important effects. Because many patients require multiple medications to adequately manage the symptoms of COPD, patient adherence with COPD therapy is poor, with reported adherence rates as low as 40%.50 51 The need to simplify medical regimens in COPD patients is especially critical in this situation since many patients have significant comorbid illnesses that also require other pharmacologic therapies. A combination product containing two common classes of medications used in the treatment of COPD in a single inhaler may simplify therapy for many patients, may improve adherence, and may represent a valuable treatment option for many patients.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
Contributing Study Investigators
R.J. Albin, MD, Atlanta, GA; K.C. Anderson, MD, Louisville, KY; L.V. Anderson, MD, Bay Pines, FL; W.M. Anderson, MD, Tampa, FL; W.J. Belliveau, MD, Johnston, RI; R. Benkert, MD, Arvada, CO; S.A. Brazinsky, MD, San Diego, CA; P. Chervinsky, MD, North Dartmouth, MA; M.C. Clark, MD, Austin, TX; D.P. Clifford, MD, Wheat Ridge, CO; L. Cosmo, MD, Tampa, FL; R.O. Crapo, MD, Salt Lake City, UT; C.F. Diener, MD, Tucson, AZ; D. Elias, MD, La Jolla, CA; N.A. Ettinger, MD, Chesterfield, MO; R.Y. Feibelman, MD, Longwood, FL; E. Fein, MD, Bridgewater, NJ; C. Fogarty, MD, Spartanburg, SC; A. Gelb, MD, Lakewood, CA; D.C. George, MD, Lebanon, KY; G.M. Giessel, MD, Richmond, VA; R. Gilman, MD, East Providence, RI; J.R. Grady, MD, Boulder, CO; G.I. Greenwald, MD, Rancho Mirage, CA; H. Guy, MD, San Diego, CA; D.K. Handshoe, MD, Charleston, SC; J. Harris, MD, South Bend, IN; D.W. Hudgel, MD, Detroit, MI; S.D. Hurley, MD, Spokane, WA; T.M. Hyers, MD, St. Louis, MO; K.W. Jacobson, MD, Eugene, OR; A.K. Jain, MD, Slidell, LA; M.G. Kaye, MD, Minneapolis, MN; E.M. Kerwin, MD, Medford, OR; K.T. Kim, MD, Long Beach, CA; B.Q. Lanier, MD, Fort Worth, TX; M. Lawrence, MD, Taunton, MA; T.M. Lee, MD, Atlanta, GA; D. Levin, MD, Oklahoma City, OK; R.S. Lipetz, DO, Spring Valley, CA; W. Lumry, MD, Dallas, TX; P.V. Maiorano, MD, Gilford, NH; E.O. Meltzer, MD, San Diego, CA; F. Montealegre, DVM, PhD, Ponce, PR; T.G. Moriarty, MD, Panama City, FL; W.S. Mullican, MD, Evansville, IN; D. Olson, MD, Toledo, OH; D.E. Ost, MD, Manhasset, NY; D.K. Payne, MD, Shreveport, LA; E.P. Pequegnat, MD, Tucson, AZ; J.D. Plitman, MD, High Point, NC; S.J. Pollard, MD, Louisville, KY; K.J. Popovich, MD, Butte, MT; A.D. Pratt, MD, La Crosse, WI; J.W. Ramsdell, MD, San Diego, CA; A. Razzetti, MD, DeLand, FL; D.R. Rollins, MD, Loveland, CO; L. Findley, MD, Loveland, CO; A.R. Rooklin, MD, Upland, PA; G.C. Scott, MD, Charleston, SC; E.R. Sher, MD, Ocean, NJ; S.J. Simon, MD, Austell, GA; H.R. Smith, MD, Boulder, CO; W.N. Sokol, MD, Newport Beach, CA; R. Sussman, MD, Springfield, NJ; J.R. Taylor, MD, Tacoma, WA; H.A. Tilker, PhD, Paducah, KY; J.P. Tillinghast, MD, St. Louis, MO; D.E. Weiner, MD, Tamarac, FL; L.A. Weiss, MD, Hallandale, FL.


   Acknowledgements
 
We would also like to thank Kim Poinsett-Holmes, PharmD, for editorial assistance in the preparation of this manuscript.


   Footnotes
 
Abbreviations: CBSQ = chronic bronchitis symptom questionnaire; CRDQ = chronic respiratory disease questionnaire; FP = fluticasone propionate; FSC = fluticasone propionate/salmeterol combination; ICS = inhaled corticosteroid; PEF = peak expiratory flow; SM = salmeterol; TDI = transition dyspnea index

This study was presented in part at the 2001 International Conference of the American Thoracic Society, San Francisco, CA, May 18 to 23, 2002.

Patrick Darken, Donald Horstman, Colin Reisner, Benjamin Lee, Suzanne Davis, and Tushar Shah are all employees of GlaxoSmithKline. Nicola Hanania received research support from GlaxoSmithKline, Inc, to participate in this study.

Received for publication May 15, 2002. Accepted for publication March 19, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

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