Study No.: SFCA3007 Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial Evaluating the Safety and Efficacy of the DISKUS

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1 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 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

2 0.70L and >40% but still <65% of predicted normal. Number of Subjects: Planned, N Randomised, N Completed, 126 (68) 121 (68) 133 (73) 125 (70) Withdrawn, 59 (32) 56 (32) 50 (27) 53 (30) Demographics N (ITT) 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) 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= hr Post-Dose FEV1 (ITT) Mean 2-hr Post-Dose FEV1 at Baseline(mL) Mean Change in 2-hr Post-Dose FEV1 at Endpoint (ml) a 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 Secondary Outcome Variable(s): Summary of Mean Change from Baseline in CBSQ Global Assessment Scores (GAS) (ITT) Mean CBSQ GAS at Baseline Mean Change in CBSQ GAS at Endpoint Summary of Baseline/Transition Dyspnea Index- Total Score (BDI/TDI) (ITT) Mean BDI Score at Baseline Mean TDI Score at Endpoint 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

3 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) Summary of Mean Change from Baseline in Chronic Respiratory Disease Questionnaire Scores (CRDQ) (ITT) Mean CRDQ Score at Baseline Mean Change in CRDQ Score at Endpoint AM PEFR (L/min) (ITT) Mean AM PEFR at Baseline Mean Overall Change from Baseline in AM PEFR Supplemental Albuterol Use (ITT) - Number of Puffs of Albuterol Used per Day FP250 Mean at Baseline, no. of puffs Mean Overall Change from Baseline, no. of puffs Supplemental Albuterol Use (ITT) - Percent of Days Without Albuterol Use Mean at Baseline, % of Days Mean Overall Change from Baseline, % of Days Night-time Awakenings Requiring Albuterol (ITT) Number of Awakenings/Night Requiring Albuterol Mean at Baseline, no. of awakenings Mean Overall Change from Baseline, no. of awakenings Night-time Awakenings Requiring Albuterol (ITT) % of Nights with No Awakenings Requiring Albuterol Mean at Baseline, % of Nights Mean Overall Change from Baseline, % of Nights 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

4 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 (<1) [0] Arrhythmias (<1) [1] Cerebrovascular accidents 0 1 (<1) [0] 0 0 Coronary artery disorders 1 (<1) [0] Disturbances of intracranial blood flow 0 1 (<1) [0] 0 0 Myocardial infarction (<1) [0] 0 Cholelithiasis 1 (<1) [0] 0 2 (1) [0] 0 Cholecystitis (<1) [0] 1 (<1) [0] Cholangitits (<1) [0] 0 Pancreatitis (<1) [0] 0 Chest symptoms 2 (1) [0] (<1) [0] Bacterial infections (<1) [0] Primary malignant blood & lymphatic (<1) [0] neoplasia Spleen disorders (<1) [0] 0 Fractures 1 (<1) [0] (<1) [0] Contusions & hematomas 1 (<1) [0] Epistaxis 1 (<1) [0] Pharyngitis/ throat infection (<1) [0] Primary malignant breast neoplasia 1 (<1) [0] Hypoglycemia (<1) [0] 0 Appendicitis 1 (<1) [0] Muscle atrophy weakness & tiredness 0 1 (<1) [0] 0 0 Depressive disorders 1 (<1) [0] Primary malignant skin neoplasia (<1) [0] Subjects with fatal SAEs, Conclusions: See publications below. Date Updated: 21-Sep

5 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: 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/ th Annual International Scientific Assembly and the Clinical World Congress on Diseases of the Chest San Diego, CA 5