The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SAM40049 (150905) Title: A Danish, multi-centre, comparative, parallel-group study to determine whether initiation of combination treatment with Seretide (salmeterol + fluticasone propionate) 50/100 µg bd offers better asthma control than monotherapy with Flixotide (fluticasone propionate) 100 µg bd to adult asthmatic subjects uncontrolled on shortacting bronchodilator alone. Rationale: This clinical trial was designed to determine whether initiation of combination treatment with salmeterol (SAL) + fluticasone propionate (FP) improves asthma control greater than initiation of treatment with the inhaled corticosteroid, in asthmatic subjects uncontrolled on short-acting bronchodilator alone. Phase: IV Study Period: 8 May 2001 to 4 September 2002. Study Design: A multi-centre, randomised, controlled, double-blind, parallel-group, comparative study. Centres: 45 active centres in Denmark. Indication: Asthma. Treatment: Following a 2 week baseline period, subjects were randomised (1:1) to 1 of 2 treatment groups. Subjects either received 50/100 µg twice daily (bd) for 24 weeks or FP 100 µg bd for 24 weeks. Subjects were instructed to take 1 inhalation each morning and each evening. Objectives: The primary objective was to determine whether initiation of combination treatment with (50/100 µg bd) offers better asthma control, determined as fewer day+night s with symptoms, than initiation of monotherapy with FP (100 µg bd) to asthmatic subjects uncontrolled on short-acting bronchodilator alone. Primary Outcome/Efficacy Variable: The primary efficacy variable was symptom-free day+night s. Secondary Outcome/Efficacy Variable(s): The secondary efficacy variables were: morning peak expiratory flow (PEFam); evening peak expiratory flow (PEFpm); diurnal PEF variation; albuterol use, as needed (prn [pro re nata]); days and nights without albuterol prn use; day symptom score; night symptom score; symptom-free days; symptom-free nights; asthma exacerbations; episode-free day+night s (day symptom score = 0, night symptom score = 0, no albuterol prn use, no adverse events [AEs], no exacerbations); weeks with treatment success (+1 more symptom-free day+night /week vs. baseline mean); time to improved asthma control; subject treatment preference, and AEs. Statistical Methods: The percentage of symptom-free day+night s (psfree) was analysed using the analysis of variance (ANOVA) F-tests, allowing for effects due to treatment, subject, period and sequence. P-values and 95% confidence intervals (CI) for treatment differences were calculated. If normal distribution assumptions were not met, psfree was analysed using non-parametric alternatives testing for treatment difference. The Total Population comprised all subjects who entered the study; this population was used for tabulating reasons for withdrawal before randomisation. All subjects who entered the study and were randomised, with the exception of those for whom documented evidence existed that they did not take any treatment, were included in the Intent-to-Treat (ITT) Population; this population was used for all tables and analyses and was the primary population for the analysis of the primary endpoint, secondary endpoints and safety. Study Population: Male and non-pregnant female subjects using adequate contraception were eligible if they: were at least 18 years old; had been diagnosed with asthma, as defined by the American Thoracic Society with a clinical history of symptoms of episodic cough, wheezing, and dyspnea; had an asthma medical history of at least 3 months; and had only been treating their asthma with a short-acting bronchodilator, which had been used for relief of symptoms for at least 1 episode per week according to prescription, for at least 2 months prior to Visit 1. Subjects were eligible for randomisation, following the baseline period, if the following applied: a diary completed for at least 11 days and 11 nights; either diurnal PEF variation 20% on at least 2 days or one of the following must have been determined within 3 years prior to baseline: forced expiratory volume in 1 second (FEV1) reversibility 15% in response to bronchodilator, provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) 4 mg/ml, diurnal PEF variation 20%; mean relief medication (albuterol) use 1 episode/week; and day or night symptom score 1 at least once/week. Subjects were excluded if they had: upper or lower respiratory tract infection or middle ear infection within 1 month prior to Visit 1; problems with wrong or inadequate inhaler or peak flow meter technique; other lung diseases than asthma; known or suspected other diseases or situations likely to affect the outcome of the study results; and known serious cardiovascular disease, diabetes mellitus, untreated hypokalaemia, or thyrotoxicosis. Other exclusion criteria included: use of long-acting bronchodilators, inhaled corticosteroids, or other long-acting asthma medication within 2 1
months prior to Visit 1; use of daily oral corticosteroid treatment within 2 months of Visit 1 or oral corticosteroid therapy within 1 month prior to Visit 1; use of other medication that could affect the course of asthma or interfere with study results; known or suspected hypersensitivity reaction to drug recipients. Subjects with involvement in another clinical study with a study drug within 4 weeks prior to Visit 1 or during this study, or who had previously been randomised to this study were not eligible. Number of Subjects: Planned, N 72 72 Randomised, N 78 72 Completed, n (%) 67 (86) 59 (82) Total Number Subjects Withdrawn, n (%) 11 (14) 13 (18) Withdrawn due to Adverse Events, n (%) 1 (1) 2 (3) Withdrawn due to Lack of Efficacy, n (%) Not reported Not reported Withdrawn for Other Reasons, n (%) 10 (13) 11 (15) Demographics N (ITT) 78 72 Females: Males 40: 38 45: 27 Mean Age, years (SD) 39.3 (15.4) 38.4 (15.1) Race, n (%) Not reported Not reported Primary Efficacy Results: (ITT Population) Percentage of symptom-free day+night s: Baseline period, N evaluable 72 71 Mean percentage of psfree at baseline (SD) 19.5 (28.5) 23.7 (29.1) Run-in period, N evaluable 66 67 Mean percentage of psfree at run-in (SD) 53.7 (36.6) 42.5 (37.9) Mean percentage of psfree at assessment (SD) 63.8 (34.6) 50.6 (36.9) 95% CI 55.2, 72.3 41.9, 59.3 Difference between treatments, vs FP 13.15 95% CI 0.94, 25.37 p-value 0.0350 Secondary Outcome Variable(s): (ITT Population) PEFam: Mean PEFam at baseline (SD) 380.0 (117.0) 396.8 (108.7) Mean PEFam at run-in (SD) 424.9 (126.9) 407.0 (116.7) Mean PEFam at assessment (SD) 436.1 (130.2) 420.1 (126.0) 95% CI 405.8, 466.4 389.2, 451.1 Difference between treatments, vs FP 15.97 95% CI -27.36, 59.29 PEFpm: Mean PEFpm at baseline (SD) 407.7 (123.5) 417.5 (113.3) Mean PEFpm at run-in (SD) 440.1 (127.9) 423.3 (118.0) Mean PEFpm at assessment (SD) 448.4 (127.5) 432.4 (125.8) 95% CI 418.4, 478.3 401.7, 463.0 Difference between treatments, vs FP 16.00 2
95% CI -26.81, 58.83 Diurnal PEF variation: Mean diurnal PEF at baseline (SD) 6.1 (10.1) 4.6 (5.7) Mean diurnal PEF at run-in (SD) 2.7 (6.3) 3.2 (5.4) Mean diurnal PEF at assessment (SD) 2.6 (6.4) 2.6 (4.8) 95% CI 1.2, 3.9 1.2, 4.0 Difference between treatments, vs FP -0.03 95% CI -1.95, 1.89 Albuterol prn use: Mean albuterol use at baseline (SD), episodes per day+night 2.3 (1.7) 2.1 (1.3) Run-in period, N evaluable 57 58 Mean albuterol use at run-in (SD) 1.1 (1.2) 1.7 (1.7) Assessment period, N evaluable 57 61 Mean albuterol use at assessment (SD) 1.1 (1.2) 1.3 (1.2) 95% CI 0.8, 1.4 1.0, 1.6 Difference between treatments, vs FP -0.18 95% CI -0.61, 0.24 Day+night s without albuterol prn use: Mean percentage of days/nights without use at baseline (SD) 21.5 (29.4) 24.8 (29.3) Run-in period, N evaluable 66 68 Mean percentage of days/nights without use at run-in (SD) 63.2 (35.9) 47.5 (37.7) Mean percentage of days/nights without use at assessment (SD) 70.8 (33.4) 62.5 (34.6) 95% CI 62.6, 78.9 54.2, 70.8 Difference between treatments, vs FP 8.25 95% CI -3.38, 19.88 Day symptom score: Baseline period, N evaluable 74 71 Mean day symptom score at baseline (SD) 1.4 (0.8) 1.3 (0.9) Run-in period, N evaluable 69 67 Mean day symptom score at run-in (SD) 0.7 (0.7) 0.9 (1.0) Mean day symptom score at assessment (SD) 0.5 (0.6) 0.7 (0.9) 95% CI 0.3, 0.7 0.6, 0.9 Difference between treatments, vs FP -0.22 95% CI -0.48, 0.03 Night symptom score: Mean night symptom score at baseline (SD) 0.6 (0.6) 0.5 (0.5) Run-in period, N evaluable 68 68 Mean night symptom score at run-in (SD) 0.3 (0.4) 0.4 (0.5) Assessment period, N evaluable 68 67 Mean night symptom score at assessment (SD) 0.2 (0.4) 0.2 (0.3) 95% CI 0.1, 0.3 0.1, 0.3 Difference between treatments, vs FP -0.005 95% CI -0.120, 0.111 Percentage of symptom-free days: Baseline period, N evaluable 74 71 Mean percentage of symptom-free days at baseline (SD) 24.6 (31.6) 30.7 (31.9) Run-in period, N evaluable 69 67 3
Mean percentage of symptom-free days at run-in (SD) 55.8 (37.5) 49.6 (37.8) Mean percentage of symptom-free days at assessment (SD) 65.8 (33.8) 56.6 (36.1) 95% CI 57.4, 74.2 48.0, 65.1 Difference between treatments, vs FP 9.22 95% CI -2.74, 21.17 Percentage of symptom-free nights: Mean percentage of symptom-free nights at baseline (SD) 55.8 (36.7) 61.1 (34.8) Run-in period, N evaluable 68 68 Mean percentage of symptom-free nights at run-in (SD) 78.6 (29.2) 73.5 (31.1) Assessment period, N evaluable 68 67 Mean percentage of symptom-free nights at assessment (SD) 82.8 (27.7) 80.4 (26.7) 95% CI 76.3, 89.3 73.8, 87.0 Difference between treatments, vs FP 2.41 95% CI -6.86, 11.67 Asthma exacerbations: N evaluable 75 70 Subjects with asthma exacerbation, n (%) 1 (1) 1 (1) Subjects without asthma exacerbation, n (%) 74 (99) 69 (99) Episode-free day+night s: Baseline period, N evaluable 72 71 Mean percentage of episode-free days at baseline (SD) 14.8 (26.0) 17.0 (25.4) Run-in period, N evaluable 66 67 Mean percentage of episode-free days at run-in (SD) 49.0 (36.8) 36.8 (36.4) Mean percentage of episode-free days at assessment (SD) 60.0 (36.1) 46.7 (37.2) 95% CI 51.2, 68.8 37.8, 55.6 Difference between treatments, vs FP 13.30 95% CI 0.79, 25.82 Weeks with treatment success: Assessment period, N evaluable 64 65 Mean percentage of psfree at assessment (SD) 14.1 (8.9) 12.1 (9.2) Time to improved asthma control (days): A definition of improved asthma control was not defined pre-study or pre-analysis. Therefore not determined. If defined and analysed later the analysis will clearly be marked post-hoc. N evaluable Mean time to improved asthma control (SD) Subject treatment preference: N evaluable 58 50 Prefer the same drug in the future n (%) Yes 46 (79) 30 (60) No 8 (14) 12 (24) Don t know 3 (5) 8 (16) Safety Results: ITT Population - All AEs and serious adverse events (SAEs) occurring during the treatment period of the study, from Visit 1 to Follow-up, were reported. Most Frequent Adverse Events On-Therapy n (%) n (%) Subjects with any AE(s), n (%) 48 (62) 42 (58) Headache 17 (22) 23 (32) Common cold 6 (8) 6 (8) Cough 4 (5) 6 (8) Back pain 4 (5) 3 (4) 4
Myalgia(s) 3 (4) 1 (1) Odontalgia 2 (3) 2 (3) Hay fever 2 (3) 1 (1) Influenza 2 (3) 1 (1) Oral candidiasis 2 (3) 1 (1) Sore throat 2 (3) 1 (1) Allergic conjunctivitis 2 (3) 0 Arthralgia 2 (3) 0 Bronchitis 2 (3) 0 Hoarseness 2 (3) 0 Nasal congestion 2 (3) 0 Tachycardia 2 (3) 0 Tonsillitis 2 (3) 0 Eczema 1 (1) 3 (4) Psychiatric depression 1 (1) 3 (4) Sinusitis 1 (1) 3 (4) Gastric pain 1 (1) 2 (3) Shoulder pain 1 (1) 2 (3) Cystitis 0 2 (3) Diarrhea 0 2 (3) Dysmenorrhea 0 2 (3) Fever 0 2 (3) Gastric disorder 0 2 (3) Neck pain 0 2 (3) Pneumonia 0 2 (3) Pruritus 0 2 (3) Recurrent sore throat 0 2 (3) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 1 (1) 2 (3) Suspected asthma exacerbation 1 (1) [0] 0 Fracture of the tibia 0 1 (1) [0] Ascites 0 1 (1) [0] Subjects with fatal SAEs, n (%) 0 1 (1) Death 0 1 (1) [0] Conclusion: See publications below Publications: Strand AM & Luckow A: Initiation of maintenance treatment of persistent asthma: salmeterol/fluticasone propionate. Respiratory Medicine 2004, 98: 1008-1015 Strand AM & Luckow A: Initiation of treatment with salmeterol/fluticasone propionate combination product is more effective than inhaled steroid alone in asthmatic patients symptomatic on short-acting bronchodilator alone, ERS 2003 Date Updated: 07-Dec-2005 5