- Email: [email protected]
50 mcg Diskus administered once daily
ARTICLE IN PRESS Respiratory Medicine (2008) 102, 495–504
Efficacy and safety of fluticasone propionate/ salmeterol 250/50 mcg Diskus administered once daily$ Edward M. Kerwina,, Robert A. Nathanb, Eli O. Meltzerc, Hector G. Ortegad, Steven W. Yanceyd, Lynne Schoafd, Paul M. Dorinskyd a
Clinical Research Institute of Southern Oregon, 3860 Crater Lake Avenue, Suite B, Medford, OR 97504, USA Asthma and Allergy Associates, Colorado Springs, CO, USA c Allergy and Asthma Research Group and Medical Center, San Diego, CA, USA d GlaxoSmithKline, Research Triangle Park, NC, USA b
Received 7 September 2007; accepted 3 December 2007 Available online 21 February 2008
KEYWORDS Asthma; Long-acting beta2-agonist; Inhaled corticosteroid; Fluticasone propionate; Salmeterol; Once daily
Summary Background: The twice daily administration of an inhaled corticosteroid (ICS) and longacting beta2-agonist (LABA) has been shown to be effective in achieving asthma control. The once daily administration of an ICS/LABA may be a treatment option for some patients. Objective: To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler (FSC) administered once daily compared with FP once daily, FSC twice daily, or placebo. Methods: A 12-week, randomized, double-blind multicenter study conducted in 844 patients X12 years of age who were symptomatic while using a short-acting beta2-agonist alone. Blinded treatments included: FSC 250/50 mcg once daily in the evening (FSC 250/50 QD), FP 250 mcg once daily in the evening (FP 250 QD), FSC 100/50 mcg twice daily (FSC 100/50 mcg BID), or placebo. All treatments were delivered via the Diskuss device. Results: All treatments demonstrated greater improvements in efficacy measures compared with placebo. Overall, the greatest improvements were observed in the patients receiving FSC, either once or twice daily, compared with the FP 250 QD group. The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24 h compared with twice daily dosing. All treatments were well
$ This study was supported by a grant from GlaxoSmithKline, Research Triangle Park, NC. Results of this study were presented in part at the Annual Meetings of the American Academy of Allergy, Asthma and Immunology, San Francisco, CA, March 19–23, 2004, The American Thoracic Society, Orlando, FL, May 21–26, 2004, and the 14th Annual Congress of the European Respiratory Society, Glasgow, GBR, September 4–8, 2004. Corresponding author. Tel.: +1 541 858 1018; fax: +1 541 858 1091. E-mail addresses: [email protected] (E.M. Kerwin), [email protected] (H.G. Ortega).
0954-6111/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2007.12.002
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E.M. Kerwin et al. tolerated. No suppression of HPA axis, as assessed by 24-h urinary cortisol excretion, was observed in any of the active treatment groups. Conclusion: In patients symptomatic on a short-acting beta2-agonist alone, FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength (FSC 250/50 mcg) administered once daily. However, a once daily regimen was effective and may be a valuable treatment option for some patients. Registered at http://ctr.gsk.co.uk/welcome.asp (SAS30022) & 2007 Elsevier Ltd. All rights reserved.
Introduction Current guidelines recommend the use of anti-inflammatory medications, including inhaled corticosteroids (ICS), and long-acting beta2-agonists (LABA) for the treatment of persistent asthma. It is also recommended that the least amount of medication be used to maintain asthma control.1,2 Fluticasone propionate (FP), an ICS, is available in multiple strengths to aid the individualization of treatment and is approved for twice daily administration. However, data suggest that FP may be suitable for once daily administration in some patients. For example, clinical studies have shown FP to be effective when compared with placebo when given once-a-day.3–6 Nonetheless, when the total daily dose of FP is given twice daily, it is generally more effective than once daily dosing.7 Salmeterol is also approved for use as a twice daily regimen. Clinical studies have shown that the effect of salmeterol on bronchodilation, protection against bronchial hyperresponsiveness, and other clinical measures exceed 12 h, suggesting that in some patients, salmeterol may exert therapeutic efficacy when given once daily.8–12 Given the results obtained in some studies with once daily dosing with FP and other ICS,13–17 together with studies demonstrating a duration of action of salmeterol exceeding 12 h, this study was conducted to determine the efficacy and safety of FP/salmeterol 250/50 mcg administered once daily in the evening (FSC 250/50 QD) compared with FP 250 mcg administered once daily in the evening (FP 250 QD), FSC 100/50 mcg administered twice daily (FSC 100/50 BID), or placebo (PLA) in symptomatic adolescent and adult patients with asthma using short-acting beta2-agonists alone. All treatments in this study were delivered via the Diskuss.
Methods Patients Male and female patients were eligible for the study if they were at least 12 years of age, had a medical history of asthma (as defined by the American Thoracic Society)18 requiring physician prescribed asthma therapy for at least 3 months duration, and were using short-acting beta2agonists alone for at least 1 month prior to screening. At screening, patients were required to have a forced expiratory volume in 1 s (FEV1) between 50% and 85% predicted value before administration of a bronchodilator and demonstrate a X12% increase in FEV1 within 30 min following two puffs (180 mcg) of inhaled albuterol.
Exclusion criteria included: history of life-threatening asthma, smoking within the previous year or a history of 410 pack years, respiratory tract infection within 2 weeks of screening, history of significant concurrent disease, or the use of prophylactic short-acting beta2-agonists of more than two puffs/day or use on more than 5 days/week. All patients (or parent/guardian if o18 years of age) provided written informed consent prior to entry into the study. The protocol was approved by the appropriate Institutional Review Board or Ethics Committee for each participating site.
Study design and interventions This 12-week, randomized, double-blind, placebo-controlled, parallel-group study (SAS30022) was conducted at 103 sites in the United States and 18 sites in Canada. Eligible patients entered a 2-week placebo run-in period to assess compliance with therapy, obtain baseline data, confirm asthma stability, and evaluate eligibility for randomization to blinded treatment. All patients were supplied with albuterol inhalation aerosol for the relief of asthma symptoms as needed. Patients who met the entry criteria for the run-in period were provided two Diskus inhalers, each containing placebo to administer twice daily (one Diskus to be administered in the morning and the other in the evening, approximately 12 h apart). The morning and evening Diskus devices were differentiated by a different color label. Compliance with blinded study treatment was measured by the dose counter on the Diskus. Patients were instructed on the use of a peak flow meter (MiniWrights, Clement Clark, Inc., London, United Kingdom) and completing a daily diary record of morning and evening peak flow measurements, albuterol use, and asthma symptoms. A nighttime asthma symptom score was recorded in the morning (scale 0–4 [0 ¼ no symptoms; 4 ¼ symptoms so severe patient did not sleep at all]) and every evening, a daytime asthma symptom score was recorded (scale 0–5 [0 ¼ no symptoms; 5 ¼ symptoms so severe that patient could not go to work/school or perform normal daily activities]). To be eligible for randomization patients had to have during the 7 days prior to the randomization visit: an asthma symptom score (combined daytime and nighttime) of X2 or used albuterol on X4 days, an evening PEF between 50% and 90% of predicted, and demonstrate an FEV1 within 715% of the pre-bronchodilation screening FEV1 at the randomization visit. Patients entering the double-blind phase were randomly assigned to receive one of the following four treatments for 12 weeks: FSC 250/50 mcg QD, FP 250 mcg QD, FSC 100/50 mcg BID, or placebo BID. Patients assigned to once daily treatment had
ARTICLE IN PRESS Use of fluticasone propionate/salmeterol once daily the active treatment administered in the evening and placebo in the morning.
Efficacy measures The primary efficacy measure was change from baseline over Weeks 1–12 in percent predicted evening PEF. Secondary and other efficacy measures included change from baseline over Weeks 1–12 in evening and morning PEF, change from baseline in the evening PEF 2 h following the first dose of study medication, and change from baseline at endpoint in clinic FEV1, rescue albuterol use, and asthma symptom scores. The morning and evening PEF measurements (highest value of three attempts) were recorded by the patient each day prior to taking the morning and evening dose of study medication. Baseline for the efficacy measures obtained from diary data was defined as the average of the 7 days prior to randomization. The 24-h asthma symptom score was calculated from the addition of the daytime score and nighttime score where an increase in score correlated to an increase in symptoms. Endpoint for evening and morning PEF was the average over Weeks 1–12. Endpoint for FEV1 was the last, on-treatment FEV1, and for 24-h albuterol use and 24-h asthma symptom scores endpoint was average of the last 7 consecutive days of treatment values. In order to assess the relative onset of effect following the first dose of blinded study medication lung function was measured 2 h after the first dose. Baseline for the 2-h post-dose evening PEF measurement was the evening PEF measured prior to taking the first dose of blinded medication and post-dose was the measurement taken 2 h later. Since this was patient-recorded data and not observed in the clinic, data from patients who did not perform both measurements or conduct the 2-h measure within 715 min of the scheduled time point were excluded from this analysis.
Safety assessments Safety was evaluated through adverse event (AE) monitoring, 24-h urinary cortisol excretion, and percentage of patients withdrawn due to worsening of asthma. AEs were assessed at all clinic visits and a 24-h urine collection for urinary cortisol excretion was collected at baseline and after 12 weeks of treatment. A patient was required to be withdrawn from the study for worsening of asthma if the following occurred in the 7 days prior to a clinic visit: (1) 42 days in which X12 puffs of albuterol were used or; (2) 43 days in which the morning or evening PEF fell below the stability limit (20% drop from mean baseline morning or evening PEF). A patient was withdrawn at anytime during the study if an asthma exacerbation occurred (defined as need for treatment with medication other than rescue albuterol or double-blind study medication).
Statistical analysis The Intent-to-Treat (ITT) population, defined as all patients who were randomized and received at least one dose of double-blind study medication, was the population used for the analyses of all data (e.g., demographic, efficacy and safety) with the exception of urinary cortisol excretion. The
497 urinary cortisol population was defined as the ITT population excluding patients providing inadequate urine volumes or collection times, or samples from patients who used prohibited corticosteroid medication or were missing the baseline and/or end of treatment assessment. This was the primary population for analysis of 24-h urinary cortisol excretion. The treatment comparison of primary interest was FSC 250/50 QD vs. FP 250 QD. Other treatment comparisons of interest included FP 250 QD vs. placebo and FSC 250/50 QD vs. FSC 100/50 BID. Using a two-sample, two-sided t-test, with a 0.05 significance level the standard deviation across all treatment groups of 8.9%, 208 patients per treatment group provided 95% power to detect a difference of 3.2% in mean change from baseline over Weeks 1–12 in percent of predicted evening PEF between any two treatment groups. The 3.2% difference was estimated to be 15 L/min in PEF. The efficacy measures, with the exception of 24-h albuterol use, were analyzed using analysis of covariance (ANCOVA) adjusting for region (geographical grouping of investigational sites), baseline value, age, and gender. Twenty-four hour albuterol use was analyzed using nonparametric ANCOVA (an extension of the aligned ranks test).19 All statistical tests performed tested two-sided hypotheses of no difference between treatment groups. The endpoint analyses for measures over Weeks 1–12 included all randomized subjects and was the average on-treatment non-missing values during those weeks. Endpoint for FEV1 was the last on-treatment FEV1 measurement and for albuterol use and asthma symptom scores was the average of the last 7 days on-treatment values. Multiple comparisons were controlled using the primary treatment comparison of the primary efficacy endpoint as a gatekeeper, and performing tests of the secondary efficacy endpoints sequentially. To control for multiplicity across other efficacy endpoints, step-down rules whereby for a given measure statistical testing may only be interpreted if the test of the previous measure was considered inferentially significant were used for interpretation of results.
Results A total of 1946 patients were screened for the study, of whom 844 were randomly assigned to one of four treatments (Figure 1). Randomization resulted in comparable treatment groups at baseline with respect to demographics and pulmonary function (Table 1). Approximately 3/4 of patients were Caucasian and mean morning FEV1 per treatment group was approximately 74% of predicted normal with a mean FEV1 reversibility of 24–25%. For patients with a baseline FEV1% predicted of o60% (12% of patients) the mean reversibility was 35%; for those 60% to o80% of predicted (58% of patients) the mean reversibility was 25%; and for those X80% of predicted (30% of patients) the mean reversibility was 21%. More patients randomized to placebo withdrew from the study compared with the active treatment groups (Figure 1). Compliance with double-blind study medication was 94–97% across treatment groups.
Efficacy Efficacy results for this study are presented in Tables 2 and 3. At baseline, the percent of predicted evening PEF
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E.M. Kerwin et al.
Patients assessed for eligibility (n=1,946)
Patients excluded at screening or during run-in (n=1,102) Reasons for exclusion*: Not meeting entry criteria (n=1379) Withdrawal of consent (n=41) Prohibited medication use (n=7) Adverse event (n=14) Lost to follow-up (n=28) Other (n=21)
Randomized (n=844)
FSC 250/50 QD (n=210)
Discontinued (n=36) Worsening asthma 4 Adverse event 5 Protocol violation 14 Other 13
FSC 100/50 BID (n=210)
FP 250 QD (n=212)
Discontinued (n=31) Worsening asthma 4 Adverse event 6 Protocol violation 14 Other 7
Discontinued (n=30) Worsening asthma 6 Adverse event 1 Protocol violation 10 Other 13
Completed (n=179)
Completed (n=182)
Completed (n=174)
Placebo (n=212)
Discontinued (n=49) Worsening asthma 17 Adverse event 3 Protocol violation 11 Other 18
Completed (n=163)
*A patient could have had more than one reason for withdrawal prior to randomization. A tot al of 1,490 reasons were recorded for the 1,102 patients who were excluded prior to randomization.
Figure 1 Enrollment, randomization, and follow-up of patients. Table 1
Baseline demographics and pulmonary function. FSC 250/50 mcg QD N ¼ 210
FP 250 mcg QD N ¼ 212
FSC 100/50 mcg BID N ¼ 210
PLA N ¼ 212
Male/female (%) Mean age, yr (range)
40/60 33.4 (12–73)
47/53 31.7 (12–85)
50/50 33.5 (12–71)
48/52 33.0 (12–73)
Race/ethnicity, n (%) Caucasian African-American Asian Hispanic Other
160 (76) 23 (11) 6 (3) 16 (8) 5 (2)
167 (79) 26 (12) 2 (o1) 16 (8) 1 (o1)
165 (79) 22 (10) 4 (2) 17 (8) 2 (o1)
160 (75) 29 (14) 4 (2) 16 (8) 3 (1)
FEV1% (L), mean, (SD) FEV1% predicted (SD) FEV1% reversibility, mean (SD)
2.50 (0.63) 74.4 (10.8) 25.9 (14.6)
2.59 (0.68) 74.5 (10.5) 24.6 (11.8)
2.51 (0.66) 72.8 (10.3) 25.9 (13.3)
2.48 (0.58) 73.2 (10.8) 24.1 (11.4)
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo.
ranged from 75.8% to 78.0% across treatment groups. Over 12 weeks of treatment FSC 250/50 QD demonstrated statistically significant (p ¼ 0.001) improvement compared with FP 250 QD in percent predicted evening PEF corres-
ponding to a 10.9 L/min difference between the two treatments. Improvements in evening PEF for FSC 250/50 QD were seen at Week 1 and sustained throughout all weekly time points without loss of effect (Figure 2). Significant
ARTICLE IN PRESS Use of fluticasone propionate/salmeterol once daily
Table 2
499
Efficacy measures: change from baseline. FSC 250/50 mcg QD N ¼ 210
FP 250 mcg QD N ¼ 212
FSC 100/50 mcg BID N ¼ 210
PLA N ¼ 212
% Predicted PM PEF, Weeks 1–12 Baseline mean (SE) Adjusted mean change (SE)
78.0 (0.72) 8.3 (0.61)
76.3 (0.75) 5.5 (0.60)
76.2 (0.79) 10.1 (0.60)
75.8 (0.76) 3.2 (0.60)
PM PEF over Weeks 1–12 (L/min) Baseline mean (SE) Adjusted mean change (SE)
363 (5.5) 38.8 (2.9)
367 (6.0) 27.9 (2.8)
367 (5.6) 48.7 (2.8)
358 (5.2) 15.7 (2.8)
AM PEF over Weeks 1–12 (L/min) Baseline mean (SE) Adjusted mean change (SE)
348 (5.5) 51.7 (3.0)
348 (5.7) 33.6 (3.0)
349 (5.6) 57.1 (3.0)
344 (5.0) 12.6 (3.0)
AM FEV1 at endpoint (L) Baseline mean (SE) Adjusted mean change (SE)
2.50 (0.04) 0.49 (0.03)
2.59 (0.05) 0.36 (0.03)
2.51 (0.05) 0.48 (0.03)
2.48 (0.04) 0.18 (0.03)
24-h asthma symptom score at endpoint Baseline mean (SE) Adjusted mean change (SE)
2.7 (0.09) 1.3 (0.10)
2.9 (0.10) 1.1 (0.10)
2.6 (0.09) 1.4 (0.10)
2.7 (0.10) 0.7 (0.10)
24-h albuterol use at endpoint Baseline (SE) Adjusted mean change (SE)
3.3 (0.19) 1.9 (0.18)
3.4 (0.20) 1.5 (0.19)
2.9 (0.18) 1.8 (0.17)
3.2 (0.17) 0.4 (0.15)
2-h post-dose PM PEF (L/min) Baseline (SE) Adjusted mean change (SE)
366 (7.54) 40.2 (3.88)
373 (9.44) 13.1 (4.11)
371 (8.07) 38.4 (3.53)
368 (7.42) 13.2 (3.91)
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo.
(pp0.001) improvement was seen for FSC 250/50 QD compared with FP 250 QD in the 2-h evening PEF measurement after the first dose of study medication (Figure 3). In addition, patients receiving FSC 250/50 QD demonstrated greater improvements in the 24-h asthma symptom scores than those treated with FP 250 QD. These improvements started at Week 1 and were sustained throughout the study and were statistically significant (pp0.050) at 6 of the 12 weekly time points. At baseline 24-h albuterol use ranged from 2.9 to 3.4 puffs/day across groups. At endpoint a statistically significant (p ¼ 0.041) decrease in albuterol use was seen for FSC 250/50 QD compared with FP 250 QD (decrease of 1.85 vs. 1.45 puffs, respectively). The reduction in the need for rescue albuterol was seen across all weekly time points over the 12 weeks of treatment. The results observed in morning PEF were consistent with those seen in evening PEF for the FSC 250/50 QD and FP 250 QD groups. The improvements in morning clinic FEV1 were also statistically significantly (p ¼ 0.003) greater in the FSC 250/50 QD compared with FP 250 QD group. The three active treatments demonstrated greater improvements in all measures of efficacy compared with placebo, with the exception of FP 250 QD vs. placebo for the 2-h post-dose evening PEF. However, the greatest improvements were observed in patients treated with FSC, administered as FSC 250/50 QD or FSC 100/50 BID compared with those who received an equivalent daily dose of an ICS
alone administered once daily (FP 250 QD). The administration of FSC 100/50 BID resulted in greater improvements than FSC 250/50 QD in evening PEF and morning PEF. At endpoint no difference was demonstrated in FEV1 between FSC 250/50 QD and FSC 100/50 BID, and the improvements seen in 24-h albuterol use and 24-h asthma symptom scores were comparable for these two groups. To assess the effect of acute dosing, PEF measures were taken 2 h after the first dose of blinded treatment. A total of 95–117 patients in each treatment group were included in the measure. Treatment with both FSC 100/50 BID and FSC 250/50 QD resulted in similar improvements from baseline (increase of 38.4 and 40.2 L/min, respectively) whereas FP 250 QD produced smaller changes (increase of 13.1 L/min, Figure 3).
Safety Overall, each of the treatments was well tolerated in this 12-week study. AEs were generally similar across groups with 52–61% of subjects reporting any AE (Table 4). The incidence of events considered potentially drug related by the investigator ranged from 8% to 9% in each of the active treatment groups and 4% in the placebo group (Table 4). The most commonly reported drug-related AEs (41 patient in any treatment group) were pharyngolaryngeal pain and headache. A total of 11 serious adverse events
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Table 3
E.M. Kerwin et al.
Efficacy measures: treatment differences. Treatment differences FSC 250/50 mcg QD vs. FP 250 mcg QD
% Predicted PM PEF (weeks 1–12) Treatment difference (SE) 95% Confidence interval
FP 250 mcg QD vs. PLA
FSC 250/50 mcg QD vs. FSC 100/50 mcg BID
2.8 (0.83)a 1.2, 4.4
2.3 (0.82)b 0.7, 3.9
1.8 (0.83)b 3.4, 0.1
PM PEF (weeks 1–12) Treatment difference (SE) 95% Confidence interval
10.9 (3.88)b 3.3, 18.5
12.2 (3.87)b 4.6, 19.8
9.9 (3.89)b 17.6, 2.3
AM PEF (weeks 1–12) Treatment difference (SE) 95% Confidence interval
18.1 (4.08)a 10.1, 26.1
21.0 (4.06)a 13.0, 29.0
5.4 (4.08) 13.4, 2.6
AM FEV1 (endpoint) Treatment difference (SE) 95% Confidence interval
0.1 (0.04)b 0.0, 0.2
0.2 (0.04)a 0.1, 0.3
0.0 (0.04) 0.1, 0.1
24-h symptom score (endpoint) Treatment difference (SE) 95% Confidence interval
0.2 (0.13) 0.5, 0.0
2-h post-dose PM PEF Treatment difference (SE) 95% Confidence interval
27.0 (5.38)a 16.5, 37.6
24-h albuterol use (endpoint) p value
0.4 (0.13) 0.7, 0.2
0.1 (0.13) 0.2, 0.3
0.1 (5.47) 10.8, 10.7
1.8 (5.04) 8.1, 11.7
o0.001
0.041
0.061
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo. Comparison of treatment groups based on adjusted mean changes using ANCOVA. Comparison based on non-parametric ANCOVA. a pp0.001. b pp0.033.
Mean change from base line in weekly % predicted PM PEF
FSC 250/50 QD PM
FSC 100/50 BID
FP 250 QD PM
Placebo
14 12 10 *
8 6
†
4 2 0 0
1
2
3
4
5
6
7
8
9
10
11
* FSC 250/50 QD vs FP 250 QD, p<0.001; FSC 250/50 QD vs FSC 100/50 BID, p=0.033 † FP 250 QD vs PLA, p=0.006
12
Weeks 1-12
Week
Figure 2
Mean change from baseline in % predicted PM PEF.
(SAEs), in eight patients, were reported. In the placebo group, three patients had SAEs: appendicitis (two patients) and asthma exacerbation. In the FSC 250/50 QD group, four patients had SAEs: 4th degree glioblastoma (one patient),
right flank pain and renal calculi (one patient), acute cholecystitis and cholelithiasis (one patient), atrial fibrillation and supraventricular tachycardia (one patient). In the FSC 100/50 BID group, one SAE of urinary tract infection was
ARTICLE IN PRESS Use of fluticasone propionate/salmeterol once daily
501
Adjusted mean change in PM PEF (L/min)
50 45
*
40 35 30 25 20 15 10 5 0 Placebo
FP 250 QD
FSC 250/50 QD
FSC 100/50 BID
* FSC 250/50 QD vsFP 250 QD, p<0.001
Figure 3 Change from baseline in 2-h post-dose PEF (L/min).
Table 4
Adverse events incidence X3% during treatment.
Any AE Headache Nasopharyngitis Upper respiratory tract infection, NOS Pharyngolaryngeal pain Sinusitis NOS Back pain Myalgia Nasal congestion Dyspepsia Diarrhea Nausea Influenza
FSC 250/50 mcg QD n (%)
FP 250 mcg QD n (%)
FSC 100/50 mcg BID n (%)
PLA n (%)
126 26 20 12 14 7 6 4 3 3 2 6 6
112 28 27 6 11 8 8 7 6 4 1 3 4
128 28 23 11 21 11 8 5 5 8 4 4 1
(61) (13) (11) (5) (10) (5) (4) (2) (2) (4) (2) (2) (o1)
110 24 19 8 12 11 5 3 2 2 7 2 1
17 5 2 3 1 2 2 2 0 2 2
(8) (2) (o1) (1) (o1) (o1) (o1) (o1)
(60) (12) (10) (6) (7) (3) (3) (2) (1) (1) (o1) (3) (3)
(53) (13) (13) (3) (5) (4) (4) (3) (3) (2) (o1) (1) (2)
Treatment related adverse events occurring in 41 patient in any treatment group Any treatment related AE 19 (9) 16 (8) Pharyngolaryngeal pain 4 (2) 3 (1) Headache 4 (2) 5 (2) Throat irritation 0 1 (o1) Oral candidiasis 2 (o1) 1 (o1) Nausea 0 2 (o1) Hoarseness 1 (o1) 0 Tremor 1 (o1) 0 Dyspepsia 1 (o1) 3 (1) Diarrhea 0 0 Dry mouth 0 0
(o1) (o1)
(52) (11) (9) (4) (6) (5) (2) (1) (o1) (o1) (3) (o1) (o1)
8 (4) 3 (1) 1 (o1) 0 0 0 0 0 0 0 0
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo. NOS, not otherwise specified.
reported. None of the SAEs reported were considered by the investigator to be related to the study drug. The one asthmarelated SAE (asthma exacerbation) reported was in a patient receiving placebo.
Thirty-one patients were withdrawn due to worsening of asthma, which was defined as either a patient not meeting one or more pre-defined stability criteria or the occurrence of an asthma exacerbation. Four patients in each FSC group
ARTICLE IN PRESS E.M. Kerwin et al.
FREQUENCIES
502 5 4 3 2 1 0 4 3 2 1 0 4 3 2 1 0 4 3 2 1 0 -90
-60
-30 0 30 60 90 120 150 180 210 Change from Baseline in Urinary Cortisol Excretion
Treatment:
Placebo
FSC 250/50 QD
FP 250 QD
FSC 100/50 BID
240
270
Figure 4 Change from baseline in urinary cortisol excretion, mcg/24 h.
(2% each group), six patients in the FP 250 group (3%), and 17 patients in the placebo group (8%) were withdrawn of whom 18 were classified as an asthma exacerbation (two patients in each of the active treatment groups and 12 patients in the placebo group). A total of 570 patients (X132 patients in each treatment group) were included in the analysis of urinary cortisol excretion. After 12 weeks of treatment the incidence of a urinary cortisol excretion below the lower limit of normal ranged from 0 to o1% in any group. Two subjects, one in the FSC 250/50 QD group and one in the FP 250 QD group, had a urine cortisol excretion result below the lower limit of normal. A histogram illustrating the distribution of the change from baseline urinary cortisol excretion data is presented in Figure 4.
Discussion The twice daily administration of an ICS has been shown to effectively control asthma in patients with persistent asthma. However, adherence to twice daily regimens of asthma medications is low and complex dosing regimens may be a contributing factor.20–22 The combination of an ICS and LABA in one inhaler provides greater asthma control compared with an ICS alone. A pooled analysis showed that asthma outcomes are improved to a greater extent when FP and salmeterol are administered in a single inhaler compared with separate inhalers.23 In addition, two retrospective, observational studies found that the refill rate for patients taking FP plus salmeterol in one inhaler had a greater refill rate than those taking each in separate inhalers or FP alone.24,25 Since a once daily dosing regimen may lead to improved adherence and outcomes we investigated the role of FSC once daily in a single inhaler. Previous studies have evaluated the once daily administration of FP in combination with salmeterol. In a cross-over
study in adolescent/adult patients, Masoli et al.26 demonstrated that a single dose of FSC 100/50 mcg in the evening resulted in a duration of bronchodilation of at least 24 h with a linear decline in lung function contrasted with the biphasic pattern of placebo or salmeterol alone. In another singledose, cross-over study in children Aldington et al.27 showed that FSC 100/50 mcg resulted in bronchodilation of at least 20 h when administered in the evening. In two studies evaluating the combination of budesonide/formoterol once daily in the evening compared with twice daily administration at the same total daily dose, the once daily regimen was shown to be similar to the twice daily regimen in improving asthma control.28,29 The patients in the current study, using only short-acting beta2-agonists, demonstrated uncontrolled asthma upon study entry with an FEV1 73–75% of predicted normal and corresponding baseline asthma symptoms and rescue albuterol use. All treatments were effective compared with placebo and the two FSC treatments demonstrated the greatest improvements in all efficacy measures compared with ICS alone (FP 250 QD). The FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24 h compared with twice daily dosing. Improvements in lung function and the patient reported outcomes of asthma symptoms and rescue albuterol use were observed during the first week of treatment and sustained throughout the study for the FSC 250/50 QD and FSC 100/50 BID patients. These findings suggest that a subgroup of patients may benefit with the once-a-day approach, but future work is warranted for identifying the specific phenotypic characteristics on this type of patients. Clinical differences in asthma presentation have been recognized and led to its description as a heterogeneous disorder. A better understanding of patient’s phenotypic profile will aid in tailoring the most appropriate therapeutic approach. Recently, Peters et al.30 reported that patients with mild persistent asthma who were well controlled on a low dose ICS (FP 100 mcg BID) could be stepped down to a once daily
ARTICLE IN PRESS Use of fluticasone propionate/salmeterol once daily treatment. Patients were randomized to receive FP 100 mcg BID, or montelukast (5 or 10 mg) QD at night, or FSC 100/50 mcg QD at night. The number of subjects who had treatment failure was similar for FP 100 mcg BID and FSC 100/50 mcg QD groups (failure rate 20.2% and 20.4%, respectively) compared with 30.3% for montelukast suggesting that patients in this study who were well controlled on a twice daily ICS could be stepped down to a once daily treatment in the evening of FSC 100/50 mcg. The current study showed that, regardless of asthma severity, some patients could be controlled on a once daily treatment in the evening (FSC 250/50 QD). For these patients these results could help by improving compliance and simplifying asthma management. However, FSC 100/50 mcg BID produced greater benefits compared with a higher dose once daily when lung function at the end of the therapeutic dosing interval was compared. Whereas in Peters et al.,30 patients were stepped down after achieving control on an ICS, in the current study patients needed to achieve control from an unstable baseline. Current guidelines recommend a stepwise approach to pharmacologic therapy to gain and maintain control of asthma in both the impairment and risk domains. However, the type, amount, and scheduling of medication is dictated by asthma severity for initiating therapy and the level of asthma control for adjusting therapy. A step-down therapy approach is essential to identify the minimum medication necessary to maintain control.1 All study treatments were well tolerated. Drug-related AE rates were low and consistent with known pharmacological effects. Importantly, this study included 570 patients in the 24-h urine cortisol excretion analysis. This large sample showed that urine cortisol excretion for all active treatment groups was generally similar to placebo demonstrating the safety of these products with respect to HPA axis activity. In conclusion, this study confirmed that FSC administered either once daily in the evening (FSC 250/50 QD) or twice daily (FSC 100/50 BID) achieves asthma control quickly and more effectively than a once daily in the evening regimen of FP 250 QD. For outcomes that measured the effect of treatment on lung function after 24 h (evening [PM] PEF) twice daily FSC compared with once daily FSC was more effective, likely the result of the inherent bronchodilatory properties of salmeterol. Nonetheless, the study suggests that once daily FSC 250/50 may be an effective treatment option for some patients. Current asthma guidelines suggest an effective asthma management plan should achieve asthma control resulting in a productive normal life style not altered by asthma symptoms. In addition, asthma treatment should be targeted to protect or alter the airway from remodeling and subsequent fixed obstructive lung disease. ICS are the only therapy available today that effectively treat airway inflammation.1,2 Thus, strategies to reduce inflammation and bronchoconstriction and subsequently improve asthma control and enhance drug adherence to inhaled therapy such as once-a-day dosing are of critical value. However, the goal of convenient once-a-day dosing should not supersede the goal of asthma control for patients who require twice-a-day dosing to achieve optimal asthma control.
503 The need remains for the development of combination ICS plus LABA asthma therapies that have a pharmacological 24-h duration for all patients.
Conflict of interest statement Dr. Kerwin has the following potential conflicts of interest: Dr. Kerwin has served on speakers panels or advisory boards for AstraZeneca, Dey Laboratories, GlaxoSmithKline, Merck, Pfizer, Sanofi Aventis, Schering Plough, Teva Labs, and UCB Pharma. He has conducted clinical research trials for Abbott, Adams, Alk-Abello, Allergy Therapeutics, Almirall, Astra Zeneca, Boehringer-Ingleheim, Centocor, Chiesi, Dey Labs, Elixir, Exelixis, Eli Lilly, Forest, Genentech, GlaxoSmithKline, Inflazyme, Johnson & Johnson, MAP, Medicinova, Med Pointe, Merck, Novartis, Novo Nordisk, Nycomed-Altana, Otsuka, Pfizer, Phenomix, Replidyne, Roche, Sanofi-Aventis, Schering Plough, Sepracor, Skye Pharma, TAP, Takeda, Wellstat, and Wyeth Pharmaceuticals. Dr. Nathan has the following potential conflicts of interest: Grant/Research Support: Altana, AstraZeneca, Dey, Genentech, GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, Schering, Skye Pharma. Consultant/Scientific Advisor: Altana, Genentech, GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, Schering, Teva/IVAX. Speaker’s Bureau: Altana, Genentech, GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, Schering. Dr. Meltzer has the following potential conflicts of interest: Grant/Research Support: Alcon, Allux, Altana, AstraZeneca, Capnia, Clay-Park, Critical Therapeutics, Genentech, GlaxoSmithKline, Hoffmann-LaRoche, KOS, Medicinova, MedPointe, Merck, Novartis, Pharmaxis, Rigel, SanofiAventis, Schering-Plough, Teva, Wyeth. Consultant: Abbott, Adelphi, Alcon, Allux, Altana, Amgen, AstraZeneca, Capnia, Critical Therapeutics, Dey, Evolutec, Genentech, GlaxoSmithKline, Greer, Inspire, KOS, MedPointe, Merck, Novartis, Pfizer, Rigel, Sanofi-Aventis, ScheringPlough, Shionogi, Verus, Wyeth. Speaker: AstraZeneca, Alcon, Altana, Genentech, Genesis, GlaxoSmithKline, MedPointe, Merck, Pfizer, SanofiAventis, Schering-Plough, Verus. Dr. Ortega, Mr. Yancey, Ms. Schoaf, and Dr. Dorinsky are employees of GlaxoSmithKline.
Acknowledgments The authors would like to thank Karen W. House, M.S. (GlaxoSmithKline) for assistance with conducting the study and assistance in preparing the manuscript and Anna V. Ellsworth, B.S. (GlaxoSmithKline) for statistical support and analyses of the data and assistance in preparation of the manuscript.
References 1. Expert Panel Report III Full Report Update 2007. National asthma education and prevention program expert panel report:
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E.M. Kerwin et al. guidelines for the diagnosis and management of asthma availiable at /http://www.nhlbi.nih.gov/guidelines/asthma/ index.htmS. Global Initiative for Asthma (GINA): Global strategy for asthma management and prevention. Revised 2006. Available from: /www.ginasthma.orgS. Accessed July 12, 2007. Nathan R, Li J, Finn A, et al. A dose-ranging study of fluticasone propionate administered once daily via multidose powder inhaler to patients with moderate asthma. Chest 2000;118: 296–302. Wolfe J, Rooklin A, Grady J, et al. Comparison of once- and twice-daily dosing of fluticasone propionate 200 mcg per day administered by DISKUS device in patients with asthma treated with or without inhaled corticosteroids. J Allergy Clin Immunol 2000;105:1153–61. ZuWallack R, Adelglass J, Clifford D, et al. Long-term efficacy and safety of fluticasone propionate powder administered once or twice daily via inhaler to patients with moderate asthma. Chest 2000;118:303–12. Berger WE, Ford LB, Mahr T, et al. Efficacy and safety of fluticasone propionate 250 mcg administered once daily in patients with persistent asthma treated with or without inhaled corticosteroids. Ann Allergy Asthma Immunol 2002;89:393–9. Purucker M, Rosebraugh C, Zhou F, et al. Inhaled fluticasone propionate by Diskus in the treatment of asthma a comparison of the efficacy of the same nominal dose given either once or twice daily. Chest 2003;124:1584–93. Bootsma GP, Dekhuijen PNR, Festen J, et al. Sustained protection against distilled water provocation by a single dose of salmeterol in patients with asthma. Eur Respir J 1997;10: 2230–6. Faurschou P, Engel A-M, Haannaes OC. Salmeterol in two different doses in the treatment of nocturnal bronchial asthma poorly controlled by other therapies. Allergy 1994;49:827–32. Cartier A, Ghezzo H, L’Archeveque J, Trudeau C, Malo JL. Duration and magnitude of action of 50 and 100 micrograms of inhaled salmeterol in protecting against bronchoconstriction induced by hyperventilation of dry cold air in subjects with asthma. J Allergy Clin Immunol 1993;92:488–92. Kemp JP, Bierman CW, Cocchetto DM. Dose-response study of inhaled salmeterol in asthmatic patients with 24-h spirometry and Holter monitoring. Ann Allergy 1993;70:316–22. Rabe KF, Jorres R, Nowak D, et al. Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 h in bronchial asthma. Am Rev Respir Dis 1993;147: 1436–41. Pincus DJ, Humeston TR, Martin RJ. Further studies on the chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol 1997; 100:771–4. Chisholm SL, Dekker FW, Neven AK, Petri H. Once-daily budesonide in mild asthma. Respir Med 1998;92:421–5.
15. Weiner P, Weiner M, Azgad Y. Long term clinical comparison of single versus twice daily administration of inhaled budesonide in moderate asthma. Thorax 1995;50:1270–3. 16. Jones AH, Langdon CGF, Lee PS, et al. Pulmicort Turbuhaler once daily as initial prophylactic therapy for asthma. Respir Med 1994;88:293–9. 17. Herjavecz I, Blomqvist P, Serrano A. Efficacy of once- and twicedaily administration of budesonide via Turbuhaler as initial therapy in patients with persistent asthma. Respir Med 1999; 93:230–5. 18. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225–44. 19. Stokes M, Davis C, Koch G. Categorical data analysis using the SASs system, 2nd ed. Cary, NC: SAS Institute Inc.; 2000. p. 170–1. 20. Chambers CV, Markson L, Diamond JJ, et al. Health beliefs and compliance with inhaled corticosteroids by asthmatic patients in primary care practices. Respir Med 1999;93:88–93. 21. Cochrane GM, Horne R, Chanez P. Compliance in asthma. Respir Med 1999;93:763–9. 22. Rand CS, Nidies M, Cowles MK, et al. Long-term metered-dose inhaler adherence in a clinical trial. Am J Respir Crit Care Med 1995;152:580–8. 23. Nelson HS, Beasley R, Yancey SW, et al. No increase in asthmarelated hospitalizations following the addition of salmeterol to an inhaled corticosteroid in patients with asthma: a metaanalysis. Am J Respir Crit Care Med 2007;175:A59. 24. Stoloff SW, Stempel MA, Meyer J, et al. Improved refill persistence with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies. J Allergy Clin Immunol 2004;113:245–51. 25. Stempel DA, Stoloff SW, Rosenzweig JRC, et al. Adherence to asthma controller medication regimens. Respir Med 2005;99: 1263–7. 26. Masoli M, Weatherall M, Ayling J, et al. The 24 h duration of bronchodilator action of the salmeterol/fluticasone combination inhaler. Respir Med 2005;99:545–52. 27. Aldington S, Williams M, Weatherall M, Beasley R. Duration of action of the salmeterol/fluticasone combination inhaled administered in the evening. A randomized controlled trial in childhood asthma. Respirology 2006;11:638–42. 28. Buhl R, Creemers J, Vondra V, et al. Once-daily budesonide/ formoterol in a single inhaler in adults with moderate persistent asthma. Respir Med 2003;97:323–30. 29. Kuna P, Creemers J, Vondra V, et al. Once-daily budesonide/ formoterol compared with twice-daily budesonide/formoterol and once daily budesonide in adults with mild to moderate asthma. Respir Med 2006;100:2151–9. 30. Peters S, Anthonisen N, Castro M, et al. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007;356:2027–39.
Efficacy and safety of fluticasone propionate/ salmeterol 250/50 mcg Diskus administered once daily$ Edward M. Kerwina,, Robert A. Nathanb, Eli O. Meltzerc, Hector G. Ortegad, Steven W. Yanceyd, Lynne Schoafd, Paul M. Dorinskyd a
Clinical Research Institute of Southern Oregon, 3860 Crater Lake Avenue, Suite B, Medford, OR 97504, USA Asthma and Allergy Associates, Colorado Springs, CO, USA c Allergy and Asthma Research Group and Medical Center, San Diego, CA, USA d GlaxoSmithKline, Research Triangle Park, NC, USA b
Received 7 September 2007; accepted 3 December 2007 Available online 21 February 2008
KEYWORDS Asthma; Long-acting beta2-agonist; Inhaled corticosteroid; Fluticasone propionate; Salmeterol; Once daily
Summary Background: The twice daily administration of an inhaled corticosteroid (ICS) and longacting beta2-agonist (LABA) has been shown to be effective in achieving asthma control. The once daily administration of an ICS/LABA may be a treatment option for some patients. Objective: To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler (FSC) administered once daily compared with FP once daily, FSC twice daily, or placebo. Methods: A 12-week, randomized, double-blind multicenter study conducted in 844 patients X12 years of age who were symptomatic while using a short-acting beta2-agonist alone. Blinded treatments included: FSC 250/50 mcg once daily in the evening (FSC 250/50 QD), FP 250 mcg once daily in the evening (FP 250 QD), FSC 100/50 mcg twice daily (FSC 100/50 mcg BID), or placebo. All treatments were delivered via the Diskuss device. Results: All treatments demonstrated greater improvements in efficacy measures compared with placebo. Overall, the greatest improvements were observed in the patients receiving FSC, either once or twice daily, compared with the FP 250 QD group. The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24 h compared with twice daily dosing. All treatments were well
$ This study was supported by a grant from GlaxoSmithKline, Research Triangle Park, NC. Results of this study were presented in part at the Annual Meetings of the American Academy of Allergy, Asthma and Immunology, San Francisco, CA, March 19–23, 2004, The American Thoracic Society, Orlando, FL, May 21–26, 2004, and the 14th Annual Congress of the European Respiratory Society, Glasgow, GBR, September 4–8, 2004. Corresponding author. Tel.: +1 541 858 1018; fax: +1 541 858 1091. E-mail addresses: [email protected] (E.M. Kerwin), [email protected] (H.G. Ortega).
0954-6111/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2007.12.002
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E.M. Kerwin et al. tolerated. No suppression of HPA axis, as assessed by 24-h urinary cortisol excretion, was observed in any of the active treatment groups. Conclusion: In patients symptomatic on a short-acting beta2-agonist alone, FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength (FSC 250/50 mcg) administered once daily. However, a once daily regimen was effective and may be a valuable treatment option for some patients. Registered at http://ctr.gsk.co.uk/welcome.asp (SAS30022) & 2007 Elsevier Ltd. All rights reserved.
Introduction Current guidelines recommend the use of anti-inflammatory medications, including inhaled corticosteroids (ICS), and long-acting beta2-agonists (LABA) for the treatment of persistent asthma. It is also recommended that the least amount of medication be used to maintain asthma control.1,2 Fluticasone propionate (FP), an ICS, is available in multiple strengths to aid the individualization of treatment and is approved for twice daily administration. However, data suggest that FP may be suitable for once daily administration in some patients. For example, clinical studies have shown FP to be effective when compared with placebo when given once-a-day.3–6 Nonetheless, when the total daily dose of FP is given twice daily, it is generally more effective than once daily dosing.7 Salmeterol is also approved for use as a twice daily regimen. Clinical studies have shown that the effect of salmeterol on bronchodilation, protection against bronchial hyperresponsiveness, and other clinical measures exceed 12 h, suggesting that in some patients, salmeterol may exert therapeutic efficacy when given once daily.8–12 Given the results obtained in some studies with once daily dosing with FP and other ICS,13–17 together with studies demonstrating a duration of action of salmeterol exceeding 12 h, this study was conducted to determine the efficacy and safety of FP/salmeterol 250/50 mcg administered once daily in the evening (FSC 250/50 QD) compared with FP 250 mcg administered once daily in the evening (FP 250 QD), FSC 100/50 mcg administered twice daily (FSC 100/50 BID), or placebo (PLA) in symptomatic adolescent and adult patients with asthma using short-acting beta2-agonists alone. All treatments in this study were delivered via the Diskuss.
Methods Patients Male and female patients were eligible for the study if they were at least 12 years of age, had a medical history of asthma (as defined by the American Thoracic Society)18 requiring physician prescribed asthma therapy for at least 3 months duration, and were using short-acting beta2agonists alone for at least 1 month prior to screening. At screening, patients were required to have a forced expiratory volume in 1 s (FEV1) between 50% and 85% predicted value before administration of a bronchodilator and demonstrate a X12% increase in FEV1 within 30 min following two puffs (180 mcg) of inhaled albuterol.
Exclusion criteria included: history of life-threatening asthma, smoking within the previous year or a history of 410 pack years, respiratory tract infection within 2 weeks of screening, history of significant concurrent disease, or the use of prophylactic short-acting beta2-agonists of more than two puffs/day or use on more than 5 days/week. All patients (or parent/guardian if o18 years of age) provided written informed consent prior to entry into the study. The protocol was approved by the appropriate Institutional Review Board or Ethics Committee for each participating site.
Study design and interventions This 12-week, randomized, double-blind, placebo-controlled, parallel-group study (SAS30022) was conducted at 103 sites in the United States and 18 sites in Canada. Eligible patients entered a 2-week placebo run-in period to assess compliance with therapy, obtain baseline data, confirm asthma stability, and evaluate eligibility for randomization to blinded treatment. All patients were supplied with albuterol inhalation aerosol for the relief of asthma symptoms as needed. Patients who met the entry criteria for the run-in period were provided two Diskus inhalers, each containing placebo to administer twice daily (one Diskus to be administered in the morning and the other in the evening, approximately 12 h apart). The morning and evening Diskus devices were differentiated by a different color label. Compliance with blinded study treatment was measured by the dose counter on the Diskus. Patients were instructed on the use of a peak flow meter (MiniWrights, Clement Clark, Inc., London, United Kingdom) and completing a daily diary record of morning and evening peak flow measurements, albuterol use, and asthma symptoms. A nighttime asthma symptom score was recorded in the morning (scale 0–4 [0 ¼ no symptoms; 4 ¼ symptoms so severe patient did not sleep at all]) and every evening, a daytime asthma symptom score was recorded (scale 0–5 [0 ¼ no symptoms; 5 ¼ symptoms so severe that patient could not go to work/school or perform normal daily activities]). To be eligible for randomization patients had to have during the 7 days prior to the randomization visit: an asthma symptom score (combined daytime and nighttime) of X2 or used albuterol on X4 days, an evening PEF between 50% and 90% of predicted, and demonstrate an FEV1 within 715% of the pre-bronchodilation screening FEV1 at the randomization visit. Patients entering the double-blind phase were randomly assigned to receive one of the following four treatments for 12 weeks: FSC 250/50 mcg QD, FP 250 mcg QD, FSC 100/50 mcg BID, or placebo BID. Patients assigned to once daily treatment had
ARTICLE IN PRESS Use of fluticasone propionate/salmeterol once daily the active treatment administered in the evening and placebo in the morning.
Efficacy measures The primary efficacy measure was change from baseline over Weeks 1–12 in percent predicted evening PEF. Secondary and other efficacy measures included change from baseline over Weeks 1–12 in evening and morning PEF, change from baseline in the evening PEF 2 h following the first dose of study medication, and change from baseline at endpoint in clinic FEV1, rescue albuterol use, and asthma symptom scores. The morning and evening PEF measurements (highest value of three attempts) were recorded by the patient each day prior to taking the morning and evening dose of study medication. Baseline for the efficacy measures obtained from diary data was defined as the average of the 7 days prior to randomization. The 24-h asthma symptom score was calculated from the addition of the daytime score and nighttime score where an increase in score correlated to an increase in symptoms. Endpoint for evening and morning PEF was the average over Weeks 1–12. Endpoint for FEV1 was the last, on-treatment FEV1, and for 24-h albuterol use and 24-h asthma symptom scores endpoint was average of the last 7 consecutive days of treatment values. In order to assess the relative onset of effect following the first dose of blinded study medication lung function was measured 2 h after the first dose. Baseline for the 2-h post-dose evening PEF measurement was the evening PEF measured prior to taking the first dose of blinded medication and post-dose was the measurement taken 2 h later. Since this was patient-recorded data and not observed in the clinic, data from patients who did not perform both measurements or conduct the 2-h measure within 715 min of the scheduled time point were excluded from this analysis.
Safety assessments Safety was evaluated through adverse event (AE) monitoring, 24-h urinary cortisol excretion, and percentage of patients withdrawn due to worsening of asthma. AEs were assessed at all clinic visits and a 24-h urine collection for urinary cortisol excretion was collected at baseline and after 12 weeks of treatment. A patient was required to be withdrawn from the study for worsening of asthma if the following occurred in the 7 days prior to a clinic visit: (1) 42 days in which X12 puffs of albuterol were used or; (2) 43 days in which the morning or evening PEF fell below the stability limit (20% drop from mean baseline morning or evening PEF). A patient was withdrawn at anytime during the study if an asthma exacerbation occurred (defined as need for treatment with medication other than rescue albuterol or double-blind study medication).
Statistical analysis The Intent-to-Treat (ITT) population, defined as all patients who were randomized and received at least one dose of double-blind study medication, was the population used for the analyses of all data (e.g., demographic, efficacy and safety) with the exception of urinary cortisol excretion. The
497 urinary cortisol population was defined as the ITT population excluding patients providing inadequate urine volumes or collection times, or samples from patients who used prohibited corticosteroid medication or were missing the baseline and/or end of treatment assessment. This was the primary population for analysis of 24-h urinary cortisol excretion. The treatment comparison of primary interest was FSC 250/50 QD vs. FP 250 QD. Other treatment comparisons of interest included FP 250 QD vs. placebo and FSC 250/50 QD vs. FSC 100/50 BID. Using a two-sample, two-sided t-test, with a 0.05 significance level the standard deviation across all treatment groups of 8.9%, 208 patients per treatment group provided 95% power to detect a difference of 3.2% in mean change from baseline over Weeks 1–12 in percent of predicted evening PEF between any two treatment groups. The 3.2% difference was estimated to be 15 L/min in PEF. The efficacy measures, with the exception of 24-h albuterol use, were analyzed using analysis of covariance (ANCOVA) adjusting for region (geographical grouping of investigational sites), baseline value, age, and gender. Twenty-four hour albuterol use was analyzed using nonparametric ANCOVA (an extension of the aligned ranks test).19 All statistical tests performed tested two-sided hypotheses of no difference between treatment groups. The endpoint analyses for measures over Weeks 1–12 included all randomized subjects and was the average on-treatment non-missing values during those weeks. Endpoint for FEV1 was the last on-treatment FEV1 measurement and for albuterol use and asthma symptom scores was the average of the last 7 days on-treatment values. Multiple comparisons were controlled using the primary treatment comparison of the primary efficacy endpoint as a gatekeeper, and performing tests of the secondary efficacy endpoints sequentially. To control for multiplicity across other efficacy endpoints, step-down rules whereby for a given measure statistical testing may only be interpreted if the test of the previous measure was considered inferentially significant were used for interpretation of results.
Results A total of 1946 patients were screened for the study, of whom 844 were randomly assigned to one of four treatments (Figure 1). Randomization resulted in comparable treatment groups at baseline with respect to demographics and pulmonary function (Table 1). Approximately 3/4 of patients were Caucasian and mean morning FEV1 per treatment group was approximately 74% of predicted normal with a mean FEV1 reversibility of 24–25%. For patients with a baseline FEV1% predicted of o60% (12% of patients) the mean reversibility was 35%; for those 60% to o80% of predicted (58% of patients) the mean reversibility was 25%; and for those X80% of predicted (30% of patients) the mean reversibility was 21%. More patients randomized to placebo withdrew from the study compared with the active treatment groups (Figure 1). Compliance with double-blind study medication was 94–97% across treatment groups.
Efficacy Efficacy results for this study are presented in Tables 2 and 3. At baseline, the percent of predicted evening PEF
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E.M. Kerwin et al.
Patients assessed for eligibility (n=1,946)
Patients excluded at screening or during run-in (n=1,102) Reasons for exclusion*: Not meeting entry criteria (n=1379) Withdrawal of consent (n=41) Prohibited medication use (n=7) Adverse event (n=14) Lost to follow-up (n=28) Other (n=21)
Randomized (n=844)
FSC 250/50 QD (n=210)
Discontinued (n=36) Worsening asthma 4 Adverse event 5 Protocol violation 14 Other 13
FSC 100/50 BID (n=210)
FP 250 QD (n=212)
Discontinued (n=31) Worsening asthma 4 Adverse event 6 Protocol violation 14 Other 7
Discontinued (n=30) Worsening asthma 6 Adverse event 1 Protocol violation 10 Other 13
Completed (n=179)
Completed (n=182)
Completed (n=174)
Placebo (n=212)
Discontinued (n=49) Worsening asthma 17 Adverse event 3 Protocol violation 11 Other 18
Completed (n=163)
*A patient could have had more than one reason for withdrawal prior to randomization. A tot al of 1,490 reasons were recorded for the 1,102 patients who were excluded prior to randomization.
Figure 1 Enrollment, randomization, and follow-up of patients. Table 1
Baseline demographics and pulmonary function. FSC 250/50 mcg QD N ¼ 210
FP 250 mcg QD N ¼ 212
FSC 100/50 mcg BID N ¼ 210
PLA N ¼ 212
Male/female (%) Mean age, yr (range)
40/60 33.4 (12–73)
47/53 31.7 (12–85)
50/50 33.5 (12–71)
48/52 33.0 (12–73)
Race/ethnicity, n (%) Caucasian African-American Asian Hispanic Other
160 (76) 23 (11) 6 (3) 16 (8) 5 (2)
167 (79) 26 (12) 2 (o1) 16 (8) 1 (o1)
165 (79) 22 (10) 4 (2) 17 (8) 2 (o1)
160 (75) 29 (14) 4 (2) 16 (8) 3 (1)
FEV1% (L), mean, (SD) FEV1% predicted (SD) FEV1% reversibility, mean (SD)
2.50 (0.63) 74.4 (10.8) 25.9 (14.6)
2.59 (0.68) 74.5 (10.5) 24.6 (11.8)
2.51 (0.66) 72.8 (10.3) 25.9 (13.3)
2.48 (0.58) 73.2 (10.8) 24.1 (11.4)
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo.
ranged from 75.8% to 78.0% across treatment groups. Over 12 weeks of treatment FSC 250/50 QD demonstrated statistically significant (p ¼ 0.001) improvement compared with FP 250 QD in percent predicted evening PEF corres-
ponding to a 10.9 L/min difference between the two treatments. Improvements in evening PEF for FSC 250/50 QD were seen at Week 1 and sustained throughout all weekly time points without loss of effect (Figure 2). Significant
ARTICLE IN PRESS Use of fluticasone propionate/salmeterol once daily
Table 2
499
Efficacy measures: change from baseline. FSC 250/50 mcg QD N ¼ 210
FP 250 mcg QD N ¼ 212
FSC 100/50 mcg BID N ¼ 210
PLA N ¼ 212
% Predicted PM PEF, Weeks 1–12 Baseline mean (SE) Adjusted mean change (SE)
78.0 (0.72) 8.3 (0.61)
76.3 (0.75) 5.5 (0.60)
76.2 (0.79) 10.1 (0.60)
75.8 (0.76) 3.2 (0.60)
PM PEF over Weeks 1–12 (L/min) Baseline mean (SE) Adjusted mean change (SE)
363 (5.5) 38.8 (2.9)
367 (6.0) 27.9 (2.8)
367 (5.6) 48.7 (2.8)
358 (5.2) 15.7 (2.8)
AM PEF over Weeks 1–12 (L/min) Baseline mean (SE) Adjusted mean change (SE)
348 (5.5) 51.7 (3.0)
348 (5.7) 33.6 (3.0)
349 (5.6) 57.1 (3.0)
344 (5.0) 12.6 (3.0)
AM FEV1 at endpoint (L) Baseline mean (SE) Adjusted mean change (SE)
2.50 (0.04) 0.49 (0.03)
2.59 (0.05) 0.36 (0.03)
2.51 (0.05) 0.48 (0.03)
2.48 (0.04) 0.18 (0.03)
24-h asthma symptom score at endpoint Baseline mean (SE) Adjusted mean change (SE)
2.7 (0.09) 1.3 (0.10)
2.9 (0.10) 1.1 (0.10)
2.6 (0.09) 1.4 (0.10)
2.7 (0.10) 0.7 (0.10)
24-h albuterol use at endpoint Baseline (SE) Adjusted mean change (SE)
3.3 (0.19) 1.9 (0.18)
3.4 (0.20) 1.5 (0.19)
2.9 (0.18) 1.8 (0.17)
3.2 (0.17) 0.4 (0.15)
2-h post-dose PM PEF (L/min) Baseline (SE) Adjusted mean change (SE)
366 (7.54) 40.2 (3.88)
373 (9.44) 13.1 (4.11)
371 (8.07) 38.4 (3.53)
368 (7.42) 13.2 (3.91)
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo.
(pp0.001) improvement was seen for FSC 250/50 QD compared with FP 250 QD in the 2-h evening PEF measurement after the first dose of study medication (Figure 3). In addition, patients receiving FSC 250/50 QD demonstrated greater improvements in the 24-h asthma symptom scores than those treated with FP 250 QD. These improvements started at Week 1 and were sustained throughout the study and were statistically significant (pp0.050) at 6 of the 12 weekly time points. At baseline 24-h albuterol use ranged from 2.9 to 3.4 puffs/day across groups. At endpoint a statistically significant (p ¼ 0.041) decrease in albuterol use was seen for FSC 250/50 QD compared with FP 250 QD (decrease of 1.85 vs. 1.45 puffs, respectively). The reduction in the need for rescue albuterol was seen across all weekly time points over the 12 weeks of treatment. The results observed in morning PEF were consistent with those seen in evening PEF for the FSC 250/50 QD and FP 250 QD groups. The improvements in morning clinic FEV1 were also statistically significantly (p ¼ 0.003) greater in the FSC 250/50 QD compared with FP 250 QD group. The three active treatments demonstrated greater improvements in all measures of efficacy compared with placebo, with the exception of FP 250 QD vs. placebo for the 2-h post-dose evening PEF. However, the greatest improvements were observed in patients treated with FSC, administered as FSC 250/50 QD or FSC 100/50 BID compared with those who received an equivalent daily dose of an ICS
alone administered once daily (FP 250 QD). The administration of FSC 100/50 BID resulted in greater improvements than FSC 250/50 QD in evening PEF and morning PEF. At endpoint no difference was demonstrated in FEV1 between FSC 250/50 QD and FSC 100/50 BID, and the improvements seen in 24-h albuterol use and 24-h asthma symptom scores were comparable for these two groups. To assess the effect of acute dosing, PEF measures were taken 2 h after the first dose of blinded treatment. A total of 95–117 patients in each treatment group were included in the measure. Treatment with both FSC 100/50 BID and FSC 250/50 QD resulted in similar improvements from baseline (increase of 38.4 and 40.2 L/min, respectively) whereas FP 250 QD produced smaller changes (increase of 13.1 L/min, Figure 3).
Safety Overall, each of the treatments was well tolerated in this 12-week study. AEs were generally similar across groups with 52–61% of subjects reporting any AE (Table 4). The incidence of events considered potentially drug related by the investigator ranged from 8% to 9% in each of the active treatment groups and 4% in the placebo group (Table 4). The most commonly reported drug-related AEs (41 patient in any treatment group) were pharyngolaryngeal pain and headache. A total of 11 serious adverse events
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Table 3
E.M. Kerwin et al.
Efficacy measures: treatment differences. Treatment differences FSC 250/50 mcg QD vs. FP 250 mcg QD
% Predicted PM PEF (weeks 1–12) Treatment difference (SE) 95% Confidence interval
FP 250 mcg QD vs. PLA
FSC 250/50 mcg QD vs. FSC 100/50 mcg BID
2.8 (0.83)a 1.2, 4.4
2.3 (0.82)b 0.7, 3.9
1.8 (0.83)b 3.4, 0.1
PM PEF (weeks 1–12) Treatment difference (SE) 95% Confidence interval
10.9 (3.88)b 3.3, 18.5
12.2 (3.87)b 4.6, 19.8
9.9 (3.89)b 17.6, 2.3
AM PEF (weeks 1–12) Treatment difference (SE) 95% Confidence interval
18.1 (4.08)a 10.1, 26.1
21.0 (4.06)a 13.0, 29.0
5.4 (4.08) 13.4, 2.6
AM FEV1 (endpoint) Treatment difference (SE) 95% Confidence interval
0.1 (0.04)b 0.0, 0.2
0.2 (0.04)a 0.1, 0.3
0.0 (0.04) 0.1, 0.1
24-h symptom score (endpoint) Treatment difference (SE) 95% Confidence interval
0.2 (0.13) 0.5, 0.0
2-h post-dose PM PEF Treatment difference (SE) 95% Confidence interval
27.0 (5.38)a 16.5, 37.6
24-h albuterol use (endpoint) p value
0.4 (0.13) 0.7, 0.2
0.1 (0.13) 0.2, 0.3
0.1 (5.47) 10.8, 10.7
1.8 (5.04) 8.1, 11.7
o0.001
0.041
0.061
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo. Comparison of treatment groups based on adjusted mean changes using ANCOVA. Comparison based on non-parametric ANCOVA. a pp0.001. b pp0.033.
Mean change from base line in weekly % predicted PM PEF
FSC 250/50 QD PM
FSC 100/50 BID
FP 250 QD PM
Placebo
14 12 10 *
8 6
†
4 2 0 0
1
2
3
4
5
6
7
8
9
10
11
* FSC 250/50 QD vs FP 250 QD, p<0.001; FSC 250/50 QD vs FSC 100/50 BID, p=0.033 † FP 250 QD vs PLA, p=0.006
12
Weeks 1-12
Week
Figure 2
Mean change from baseline in % predicted PM PEF.
(SAEs), in eight patients, were reported. In the placebo group, three patients had SAEs: appendicitis (two patients) and asthma exacerbation. In the FSC 250/50 QD group, four patients had SAEs: 4th degree glioblastoma (one patient),
right flank pain and renal calculi (one patient), acute cholecystitis and cholelithiasis (one patient), atrial fibrillation and supraventricular tachycardia (one patient). In the FSC 100/50 BID group, one SAE of urinary tract infection was
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501
Adjusted mean change in PM PEF (L/min)
50 45
*
40 35 30 25 20 15 10 5 0 Placebo
FP 250 QD
FSC 250/50 QD
FSC 100/50 BID
* FSC 250/50 QD vsFP 250 QD, p<0.001
Figure 3 Change from baseline in 2-h post-dose PEF (L/min).
Table 4
Adverse events incidence X3% during treatment.
Any AE Headache Nasopharyngitis Upper respiratory tract infection, NOS Pharyngolaryngeal pain Sinusitis NOS Back pain Myalgia Nasal congestion Dyspepsia Diarrhea Nausea Influenza
FSC 250/50 mcg QD n (%)
FP 250 mcg QD n (%)
FSC 100/50 mcg BID n (%)
PLA n (%)
126 26 20 12 14 7 6 4 3 3 2 6 6
112 28 27 6 11 8 8 7 6 4 1 3 4
128 28 23 11 21 11 8 5 5 8 4 4 1
(61) (13) (11) (5) (10) (5) (4) (2) (2) (4) (2) (2) (o1)
110 24 19 8 12 11 5 3 2 2 7 2 1
17 5 2 3 1 2 2 2 0 2 2
(8) (2) (o1) (1) (o1) (o1) (o1) (o1)
(60) (12) (10) (6) (7) (3) (3) (2) (1) (1) (o1) (3) (3)
(53) (13) (13) (3) (5) (4) (4) (3) (3) (2) (o1) (1) (2)
Treatment related adverse events occurring in 41 patient in any treatment group Any treatment related AE 19 (9) 16 (8) Pharyngolaryngeal pain 4 (2) 3 (1) Headache 4 (2) 5 (2) Throat irritation 0 1 (o1) Oral candidiasis 2 (o1) 1 (o1) Nausea 0 2 (o1) Hoarseness 1 (o1) 0 Tremor 1 (o1) 0 Dyspepsia 1 (o1) 3 (1) Diarrhea 0 0 Dry mouth 0 0
(o1) (o1)
(52) (11) (9) (4) (6) (5) (2) (1) (o1) (o1) (3) (o1) (o1)
8 (4) 3 (1) 1 (o1) 0 0 0 0 0 0 0 0
FSC, fluticasone propionate/salmeterol; FP, fluticasone propionate; PLA, placebo. NOS, not otherwise specified.
reported. None of the SAEs reported were considered by the investigator to be related to the study drug. The one asthmarelated SAE (asthma exacerbation) reported was in a patient receiving placebo.
Thirty-one patients were withdrawn due to worsening of asthma, which was defined as either a patient not meeting one or more pre-defined stability criteria or the occurrence of an asthma exacerbation. Four patients in each FSC group
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FREQUENCIES
502 5 4 3 2 1 0 4 3 2 1 0 4 3 2 1 0 4 3 2 1 0 -90
-60
-30 0 30 60 90 120 150 180 210 Change from Baseline in Urinary Cortisol Excretion
Treatment:
Placebo
FSC 250/50 QD
FP 250 QD
FSC 100/50 BID
240
270
Figure 4 Change from baseline in urinary cortisol excretion, mcg/24 h.
(2% each group), six patients in the FP 250 group (3%), and 17 patients in the placebo group (8%) were withdrawn of whom 18 were classified as an asthma exacerbation (two patients in each of the active treatment groups and 12 patients in the placebo group). A total of 570 patients (X132 patients in each treatment group) were included in the analysis of urinary cortisol excretion. After 12 weeks of treatment the incidence of a urinary cortisol excretion below the lower limit of normal ranged from 0 to o1% in any group. Two subjects, one in the FSC 250/50 QD group and one in the FP 250 QD group, had a urine cortisol excretion result below the lower limit of normal. A histogram illustrating the distribution of the change from baseline urinary cortisol excretion data is presented in Figure 4.
Discussion The twice daily administration of an ICS has been shown to effectively control asthma in patients with persistent asthma. However, adherence to twice daily regimens of asthma medications is low and complex dosing regimens may be a contributing factor.20–22 The combination of an ICS and LABA in one inhaler provides greater asthma control compared with an ICS alone. A pooled analysis showed that asthma outcomes are improved to a greater extent when FP and salmeterol are administered in a single inhaler compared with separate inhalers.23 In addition, two retrospective, observational studies found that the refill rate for patients taking FP plus salmeterol in one inhaler had a greater refill rate than those taking each in separate inhalers or FP alone.24,25 Since a once daily dosing regimen may lead to improved adherence and outcomes we investigated the role of FSC once daily in a single inhaler. Previous studies have evaluated the once daily administration of FP in combination with salmeterol. In a cross-over
study in adolescent/adult patients, Masoli et al.26 demonstrated that a single dose of FSC 100/50 mcg in the evening resulted in a duration of bronchodilation of at least 24 h with a linear decline in lung function contrasted with the biphasic pattern of placebo or salmeterol alone. In another singledose, cross-over study in children Aldington et al.27 showed that FSC 100/50 mcg resulted in bronchodilation of at least 20 h when administered in the evening. In two studies evaluating the combination of budesonide/formoterol once daily in the evening compared with twice daily administration at the same total daily dose, the once daily regimen was shown to be similar to the twice daily regimen in improving asthma control.28,29 The patients in the current study, using only short-acting beta2-agonists, demonstrated uncontrolled asthma upon study entry with an FEV1 73–75% of predicted normal and corresponding baseline asthma symptoms and rescue albuterol use. All treatments were effective compared with placebo and the two FSC treatments demonstrated the greatest improvements in all efficacy measures compared with ICS alone (FP 250 QD). The FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24 h compared with twice daily dosing. Improvements in lung function and the patient reported outcomes of asthma symptoms and rescue albuterol use were observed during the first week of treatment and sustained throughout the study for the FSC 250/50 QD and FSC 100/50 BID patients. These findings suggest that a subgroup of patients may benefit with the once-a-day approach, but future work is warranted for identifying the specific phenotypic characteristics on this type of patients. Clinical differences in asthma presentation have been recognized and led to its description as a heterogeneous disorder. A better understanding of patient’s phenotypic profile will aid in tailoring the most appropriate therapeutic approach. Recently, Peters et al.30 reported that patients with mild persistent asthma who were well controlled on a low dose ICS (FP 100 mcg BID) could be stepped down to a once daily
ARTICLE IN PRESS Use of fluticasone propionate/salmeterol once daily treatment. Patients were randomized to receive FP 100 mcg BID, or montelukast (5 or 10 mg) QD at night, or FSC 100/50 mcg QD at night. The number of subjects who had treatment failure was similar for FP 100 mcg BID and FSC 100/50 mcg QD groups (failure rate 20.2% and 20.4%, respectively) compared with 30.3% for montelukast suggesting that patients in this study who were well controlled on a twice daily ICS could be stepped down to a once daily treatment in the evening of FSC 100/50 mcg. The current study showed that, regardless of asthma severity, some patients could be controlled on a once daily treatment in the evening (FSC 250/50 QD). For these patients these results could help by improving compliance and simplifying asthma management. However, FSC 100/50 mcg BID produced greater benefits compared with a higher dose once daily when lung function at the end of the therapeutic dosing interval was compared. Whereas in Peters et al.,30 patients were stepped down after achieving control on an ICS, in the current study patients needed to achieve control from an unstable baseline. Current guidelines recommend a stepwise approach to pharmacologic therapy to gain and maintain control of asthma in both the impairment and risk domains. However, the type, amount, and scheduling of medication is dictated by asthma severity for initiating therapy and the level of asthma control for adjusting therapy. A step-down therapy approach is essential to identify the minimum medication necessary to maintain control.1 All study treatments were well tolerated. Drug-related AE rates were low and consistent with known pharmacological effects. Importantly, this study included 570 patients in the 24-h urine cortisol excretion analysis. This large sample showed that urine cortisol excretion for all active treatment groups was generally similar to placebo demonstrating the safety of these products with respect to HPA axis activity. In conclusion, this study confirmed that FSC administered either once daily in the evening (FSC 250/50 QD) or twice daily (FSC 100/50 BID) achieves asthma control quickly and more effectively than a once daily in the evening regimen of FP 250 QD. For outcomes that measured the effect of treatment on lung function after 24 h (evening [PM] PEF) twice daily FSC compared with once daily FSC was more effective, likely the result of the inherent bronchodilatory properties of salmeterol. Nonetheless, the study suggests that once daily FSC 250/50 may be an effective treatment option for some patients. Current asthma guidelines suggest an effective asthma management plan should achieve asthma control resulting in a productive normal life style not altered by asthma symptoms. In addition, asthma treatment should be targeted to protect or alter the airway from remodeling and subsequent fixed obstructive lung disease. ICS are the only therapy available today that effectively treat airway inflammation.1,2 Thus, strategies to reduce inflammation and bronchoconstriction and subsequently improve asthma control and enhance drug adherence to inhaled therapy such as once-a-day dosing are of critical value. However, the goal of convenient once-a-day dosing should not supersede the goal of asthma control for patients who require twice-a-day dosing to achieve optimal asthma control.
503 The need remains for the development of combination ICS plus LABA asthma therapies that have a pharmacological 24-h duration for all patients.
Conflict of interest statement Dr. Kerwin has the following potential conflicts of interest: Dr. Kerwin has served on speakers panels or advisory boards for AstraZeneca, Dey Laboratories, GlaxoSmithKline, Merck, Pfizer, Sanofi Aventis, Schering Plough, Teva Labs, and UCB Pharma. He has conducted clinical research trials for Abbott, Adams, Alk-Abello, Allergy Therapeutics, Almirall, Astra Zeneca, Boehringer-Ingleheim, Centocor, Chiesi, Dey Labs, Elixir, Exelixis, Eli Lilly, Forest, Genentech, GlaxoSmithKline, Inflazyme, Johnson & Johnson, MAP, Medicinova, Med Pointe, Merck, Novartis, Novo Nordisk, Nycomed-Altana, Otsuka, Pfizer, Phenomix, Replidyne, Roche, Sanofi-Aventis, Schering Plough, Sepracor, Skye Pharma, TAP, Takeda, Wellstat, and Wyeth Pharmaceuticals. Dr. Nathan has the following potential conflicts of interest: Grant/Research Support: Altana, AstraZeneca, Dey, Genentech, GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, Schering, Skye Pharma. Consultant/Scientific Advisor: Altana, Genentech, GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, Schering, Teva/IVAX. Speaker’s Bureau: Altana, Genentech, GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, Schering. Dr. Meltzer has the following potential conflicts of interest: Grant/Research Support: Alcon, Allux, Altana, AstraZeneca, Capnia, Clay-Park, Critical Therapeutics, Genentech, GlaxoSmithKline, Hoffmann-LaRoche, KOS, Medicinova, MedPointe, Merck, Novartis, Pharmaxis, Rigel, SanofiAventis, Schering-Plough, Teva, Wyeth. Consultant: Abbott, Adelphi, Alcon, Allux, Altana, Amgen, AstraZeneca, Capnia, Critical Therapeutics, Dey, Evolutec, Genentech, GlaxoSmithKline, Greer, Inspire, KOS, MedPointe, Merck, Novartis, Pfizer, Rigel, Sanofi-Aventis, ScheringPlough, Shionogi, Verus, Wyeth. Speaker: AstraZeneca, Alcon, Altana, Genentech, Genesis, GlaxoSmithKline, MedPointe, Merck, Pfizer, SanofiAventis, Schering-Plough, Verus. Dr. Ortega, Mr. Yancey, Ms. Schoaf, and Dr. Dorinsky are employees of GlaxoSmithKline.
Acknowledgments The authors would like to thank Karen W. House, M.S. (GlaxoSmithKline) for assistance with conducting the study and assistance in preparing the manuscript and Anna V. Ellsworth, B.S. (GlaxoSmithKline) for statistical support and analyses of the data and assistance in preparation of the manuscript.
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