Study No.: A3007 Title: A Randomized, Double-Blind, -Controlled, Parallel-Group Trial Evaluating the Safety and Efficacy of the DISKUS Formulations of Salmeterol (SAL) 50mcg BID and Fluticasone Propionate (FP) 250mcg BID Individually and in Combination as Salmeterol 50mcg/Fluticasone Propionate 250mcg BID ( ) Compared to in COPD Subjects Rationale: To compare the efficacy and safety of SAL,FP and placebo individually and in combination when administered as a micronized powder via a multidose powder inhaler (DISKUS) to subjects with COPD over 24 weeks Phase: III Study Period: 10 November 1998 28 August 2000 Study Design: A Randomized, Double-Blind, -Controlled, Parallel-Group, 24-Week Clinical Trial Centres: 75 centers in the U.S.A., one in Puerto Rico Indication: COPD Treatment: # Denotes treatment approved in the US and at least one country in the European Union. During the 2-week, single-blind, Run-In Period, subjects received placebo via the DISKUS BID and prn albuterol Metered Dose Inhaler (MDI) or nebules, to establish a Baseline. Subjects who completed the Run-In Period were assigned to one of four double-blind treatments via the DISKUS for 24 weeks: mcg BID#, mcg BID, mcg BID#, or BID. Objectives: To compare the efficacy and safety of,,, and placebo when administered via the DISKUS over a 24-week treatment period in the treatment of COPD subjects. To compare quality of life in COPD subjects receiving the aforementioned treatments. Primary Outcome/Efficacy Variable: The primary analysis was the Endpoint (last post-baseline assessment excluding Discontinuation) analysis comparing the mean change from Baseline in AM pre-dose and 2-hr post-dose Forced Expiratory Volume in one second (FEV1) among treatment groups. Secondary Outcome/Efficacy Variable(s): Chronic Bronchitis Symptoms Questionnaire (CBSQ); Baseline/Transition Dyspnea Index (BDI/TDI); Exacerbations of COPD; Chronic Respiratory Disease Questionnaire (CRDQ); Evaluation of subject diary cards: morning (AM) peak expiratory flow rate (PEFR), supplemental albuterol (MDI or nebules) use; Night-time awakenings requiring the use of albuterol. Statistical Methods: Enrollment was planned for 720 subjects (180 per treatment group). Using a two sample t-test and a significance level of 0.05, a sample size of 180 subjects per treatment would provide >90% power to detect a difference of 0.1 liter for any pairwise treatment comparisons. The primary analysis was that performed on data from Endpoint (last post-baseline assessment excluding Discontinuation) comparing the mean change from Baseline in AM pre-dose and 2-hour post dose FEV1 among treatment groups. Analyses based on the intent-to-treat (ITT) population consisted of all randomized subjects who had taken at least one dose of double-blind study drug. Study Population: Males and females 40 years of age with a diagnosis of COPD. Subjects must have had a current or prior history of 20-pack years of cigarette smoking and a history of cough productive of sputum on most days for at least 3 months of the year, for at least 2 years, that was not attributable to another disease process. Subjects were also required to have a FEV1/FVC ratio of 70% at Screening and a baseline FEV1 of <65% of predicted normal but >0.70L or FEV1 1
0.70L and >40% but still <65% of predicted normal. Number of Subjects: Planned, N 180 180 180 180 Randomised, N 185 177 183 178 Completed, 126 (68) 121 (68) 133 (73) 125 (70) Withdrawn, 59 (32) 56 (32) 50 (27) 53 (30) Demographics N (ITT) 185 177 183 178 Females: Males 59:126 75:102 62:121 70:108 Mean Age, years (SD) 64.8 (8.7) 64.2 (9.8) 63.3 (9.4) 63.4 (10.6) White, 173 (94) 165 (93) 167 (91) 170 (96) Primary Efficacy Results: Pre-Dose FEV1 (ITT) Mean Pre-Dose FEV1 at Baseline (ml) 1232 1205 1236 1207 Mean Change in Pre-Dose FEV1 at Endpoint (ml) 1 91a 109a 165a,b p-values: a differs from placebo p 0.005; b differs from SAL p=0.012; c differs from FP p=0.009 2-hr Post-Dose FEV1 (ITT) Mean 2-hr Post-Dose FEV1 at Baseline(mL) 1232 1205 1236 1207 Mean Change in 2-hr Post-Dose FEV1 at Endpoint (ml) 58 200a 147a 281a,b,c p-values: a differs from placebo p 0.007; b differs from SAL p=0.010; c differs from FP p 0.003 Secondary Outcome Variable(s): Summary of Mean Change from Baseline in CBSQ Global Assessment Scores (GAS) (ITT) Mean CBSQ GAS at Baseline 7.5 7.0 7.4 7.3 Mean Change in CBSQ GAS at Endpoint 1.4 1.5 2.2 2.1 Summary of Baseline/Transition Dyspnea Index- Total Score (BDI/TDI) (ITT) Mean BDI Score at Baseline 5.7 6.1 6.2 6.1 Mean TDI Score at Endpoint 1.0 1.6 1.7 1.7 Incidence of COPD Exacerbations (ITT) COPD Exacerbation of Any Severity, None 112 (61) 112 (63) 104 (57) 107 (60) 1 73 (39) 65 (37) 79 (43) 71 (40) 1 49 (26) 42 (24) 50 (27) 45 (25) 2 10 (5) 14 (8) 17 (9) 12 (7) 3 3 (2) 2 (1) 3 (2) 6 (3) 4 11 (6) 7 (4) 9 (5) 8 (4) 2
Moderate/Severe COPD Exacerbation, None 122 (66) 122 (69) 114 (62) 117 (66) 1 63 (34) 55 (31) 69 (38) 61 (34) 1 49 (26) 45 (25) 54 (30) 50 (28) 2 11 (6) 9 (5) 15 (8) 10 (6) 3 2 (1) 1 (<1) 0 1 (<1) 4 1 (<1) 0 0 0 Summary of Mean Change from Baseline in Chronic Respiratory Disease Questionnaire Scores (CRDQ) (ITT) Mean CRDQ Score at Baseline 84.8 86.3 85.5 84.1 Mean Change in CRDQ Score at Endpoint 5.0 6.4 10.4 10 AM PEFR (L/min) (ITT) Mean AM PEFR at Baseline 220.3 210.3 220.0 206.1 Mean Overall Change from Baseline in AM PEFR 0.8 14.7 11.3 30.6 Supplemental Albuterol Use (ITT) - Number of Puffs of Albuterol Used per Day FP250 Mean at Baseline, no. of puffs 4.8 4.6 4.6 5.1 Mean Overall Change from Baseline, no. of puffs 0.1-0.7-0.2-1.0 Supplemental Albuterol Use (ITT) - Percent of Days Without Albuterol Use Mean at Baseline, % of Days 24.8 25.2 24.7 24.4 Mean Overall Change from Baseline, % of Days 4.0 5.8 5.0 10.0 Night-time Awakenings Requiring Albuterol (ITT) Number of Awakenings/Night Requiring Albuterol Mean at Baseline, no. of awakenings 0.23 0.20 0.24 0.24 Mean Overall Change from Baseline, no. of 0.02-0.06-0.03-0.12 awakenings Night-time Awakenings Requiring Albuterol (ITT) % of Nights with No Awakenings Requiring Albuterol Mean at Baseline, % of Nights 83.2 84.7 84.9 82.7 Mean Overall Change from Baseline, % of Nights 0.3 5.1 4.8 8.3 Safety Results: On-therapy adverse events and serious adverse events included all events with onset dates on or after treatment start date and on or before treatment stop date + 1 day. Most Frequent Adverse Events On- Therapy Subjects with any AE(s), 118 (64) 114 (64) 129 (70) 124 (70) 3
Headaches 22 (12) 17 (10) 21 (11) 28 (16) URTI 26 (14) 16 (9) 18 (10) 22 (12) Candidiasis mouth/throat 2 (1) 5 (3) 11 (6) 17 (10) Musculoskeletal pain 16 (9) 21 (12) 14 (8) 16 (9) Throat irritation 13 (7) 7 (4) 10 (5) 15 (8) Sinusitis 5 (3) 8 (5) 14 (8) 6 (3) Serious Adverse Events On-Therapy N (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, 11 (6) 5 (3) 10 (5) 8 (4) COPD 1 (<1) [0] 2 (1) [0] 3 (2) [0] 0 Pneumonia 0 1 (<1) [0] 1 (<1) [0] 0 Pleura disorders 0 0 0 1 (<1) [0] Arrhythmias 0 0 0 1 (<1) [1] Cerebrovascular accidents 0 1 (<1) [0] 0 0 Coronary artery disorders 1 (<1) [0] 0 0 0 Disturbances of intracranial blood flow 0 1 (<1) [0] 0 0 Myocardial infarction 0 0 1 (<1) [0] 0 Cholelithiasis 1 (<1) [0] 0 2 (1) [0] 0 Cholecystitis 0 0 1 (<1) [0] 1 (<1) [0] Cholangitits 0 0 1 (<1) [0] 0 Pancreatitis 0 0 1 (<1) [0] 0 Chest symptoms 2 (1) [0] 0 0 1 (<1) [0] Bacterial infections 0 0 0 1 (<1) [0] Primary malignant blood & lymphatic 0 0 0 1 (<1) [0] neoplasia Spleen disorders 0 0 1 (<1) [0] 0 Fractures 1 (<1) [0] 0 0 1 (<1) [0] Contusions & hematomas 1 (<1) [0] 0 0 0 Epistaxis 1 (<1) [0] 0 0 0 Pharyngitis/ throat infection 0 0 0 1 (<1) [0] Primary malignant breast neoplasia 1 (<1) [0] 0 0 0 Hypoglycemia 0 0 1 (<1) [0] 0 Appendicitis 1 (<1) [0] 0 0 0 Muscle atrophy weakness & tiredness 0 1 (<1) [0] 0 0 Depressive disorders 1 (<1) [0] 0 0 0 Primary malignant skin neoplasia 0 0 0 1 (<1) [0] Subjects with fatal SAEs, 0 0 0 0 Conclusions: See publications below. Date Updated: 21-Sep-2004 4
Publications Hanania N, Darken P, Horstman D, et al.the efficacy and safety of fluticasone propionate (250mcg)/salmeterol (50mcg) combined in the Diskus inhaler for the treatment of COPD. Chest 2003; 124:834-841. Hanania NA, Ramsdell J, Payne K, et al. Improvements in airflow and dyspnea in COPD patients following 24-weeks treatment with salmeterol 50mcg and fluticasone propionate 250mcg alone or in combination via the Diskus. Am J Respir Crit Care Med 2001;163(Suppl 5):A279 The bronchodilator response to salmeterol is maintained with regular, long-term use in patients with copd. Hanania, N. A., Kalberg, C., Yates, J., Emmett, A., Horstman, D., and Knobil, K. Pulm Pharmacol Ther 2005; 18(1):19-22 Abstract: Improvements in airflow and dyspnea in copd patients following 24 weeks treatment with salmeterol 50 mug fluticasone propionate 250mug alone or in combination via the diskus. Hanania, N A, Ramsdell, J, Ramsdell, J, Payne, K, Davis, S, Horstman, D, Lee, B, and Darken, P American Lung Association/American Thoracic Society 97th International Conference 5/18/2001 San Francisco, California Abstract: Rapid onset of improvement in airflow with combination salmeterol and fluticasone propionate therapy administered by a single diskus in patients with copd. Hanania, N A, Knobil, K, Watkins, M, Wire, P, Yates, J, and Darken, P. 68th Annual International Scientific Assembly and the Clinical World Congress on Diseases of the Chest 11/2/2002 68th Annual International Scientific Assembly and the Clinical World Congress on Diseases of the Chest San Diego, CA 5