Study No.: SAM40012 Title: A multicentre, randomised, double-blind, double-dummy, parallel group comparison of three treatments : 1)

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1 Study No.: SAM40012 Title: A multicentre, randomised, double-blind, double-dummy, parallel group comparison of three treatments : 1) salmeterol/fluticasone propionate () (mcg strength) bd via DISKUS/ACCUHALER inhaler, 2) fluticasone propionate 200mcg bd via DISKUS/ACCUHALER inhaler, 3) fluticasone propionate 100mcg bd via DISKUS/ACCUHALER inhaler in children aged 4-11 years with asthma Rationale: This study was designed to investigate twice daily (bd) doses of mcg DISKUS, compared with fluticasone propionate 100mcg DISKUS and fluticasone propionate 200mcg DISKUS in children who were symptomatic on their current inhaled corticosteroid therapy, and who might benefit from the addition of a long-acting β2-agonist to their therapy. The aim was to compare therapy with the two doses of fluticasone propionate in this population. Phase: IIIb/IV Study Period: 22 June June 2001 Study Design: Randomised, multicentre, 24-week, double-blind, double-dummy, parallel-group Centres: 6 in Bulgaria, 5 in Hungary, 4 in Israel, 8 in Poland, 8 in Russia, 4 in Spain, 3 in United Kingdom Indication: Asthma (paediatric) Treatment: Following a 2-week run-in period, subjects were randomised to receive mcg DISKUS inhaler BD, fluticasone propionate 100mcg DISKUS inhaler BD ( BID DISKUS), or fluticasone propionate 200mcg DISKUS inhaler BD ( BID DISKUS). To maintain the blind, inhalers containing placebo were also administered. Subjects were asked to take one inhalation from each DISKUS (labelled A and B) every morning and every evening, starting the evening of the visit. The maximum dosing period, from the start of treatment to the end of treatment, was 24 weeks. Objectives: The primary objective was to compare BID DISKUS versus BID DISKUS and BID DISKUS in subjects with asthma aged 4-11 years who were symptomatic on daily doses of 400 to 500mcg budesonide (BUD), beclomethasone dipropionate (BDP) or equivalent, as demonstrated by an increase in combined symptom-free days and nights. Primary Outcome/Efficacy Variable: The primary efficacy endpoint was the percentage of combined symptom-free days and nights during weeks Secondary Outcome/Efficacy Variable(s): Secondary efficacy endpoints included percentage of symptom-free days and symptom-free nights, relief medication use, morning and evening PEF, clinic PEF and the incidence of mild, moderate and severe exacerbations. Statistical Methods: The protocol planned to recruit a total of 157 evaluable subjects per treatment group (471 in total). To be evaluable, subjects had to meet the entry and randomisation criteria, receive at least one dose of study medication and have completed at least one day s postrandomisation diary information. Approximately 504 subjects were to be randomised across all centres. It was anticipated that a sample size of 157 subjects per group would give at least 80% power to detect a 10% difference between treatment groups in the mean percentage of combined symptom-free days and nights (assuming a common standard deviation of 30%) using a Mann Whitney U test with a 5% two-sided significance level. The null hypothesis for the comparison of and either of the fluticasone propionate treatments was that there was no treatment difference. This was tested using a 2-sided 5% significance level and CIs for the difference were symmetric and of size 95%. The primary efficacy endpoint was the percentage of combined symptom-free days and nights during Weeks Each pairwise treatment comparison was undertaken using the Van Elteren extension to the Wilcoxon Rank Sum test, stratified by country grouping. The Hodges-Lehmann 1

2 estimator (with associated 95% CI) was used to estimate each pairwise treatment difference. The secondary endpoints: percentage of symptom-free days, the percentage of symptom-free nights, and the percentage of days with no relief medication were analysed for the Weeks 1-24 assessment period only using the same approach as for the primary efficacy endpoint. The treatment groups were compared with respect to mean morning and mean evening PEF and clinic PEF using ANCOVA. In addition to the summaries stated in the protocol, diurnal variation and morning percentage predicted PEF were summarised. Clinic PEF values recorded were analysed using ANCOVA as described above at each visit. The incidence and severity of exacerbations were analysed separately. The treatment groups were compared with regard to the proportion of subjects recording at least one exacerbation, using Fisher's exact test. The severity of exacerbations was analysed using the Wilcoxon Rank Sum test. Patients recorded symptom scores, PEF, rescue medication use and night-time awakenings using electronic diary card devices. Isolated device failure resulted in erroneous data collection for some subjects. However, these data were included in the ITT analysis. AEs, withdrawals due to AEs and the results of the oropharyngeal examinations were summarised by treatment. Urinary cortisols corrected for creatinine, uncorrected for creatinine and a subset analysis excluding incomplete samples (cortisol population) were analysed using ANCOVA. Study Population: Male or female subjects, aged 4-11 years, inclusive, with documented evidence of asthma who were receiving BDP, BUD or equivalent at a dose of mcg/day or fluticasone propionate at a dose of mcg/day for at least 4 weeks before Visit 1. Subjects who completed the baseline period were eligible for randomisation and entry into the treatment period if they had recorded a symptom score (i.e. total score of daytime and night-time scores) on the electronic daily record card (edrc) of 2 on at least three of the last seven consecutive days of the run-in period and had a mean morning PEF (calculated from the last 7 days of the run-in period) of >50% and <85% of the PEF measured 15 minutes after administration of 400mcg of salbutamol at the randomisation visit. In addition, subjects had to have recorded 70% of data into their edrcs. Number of Subjects: Planned, N Randomised, N Completed, n (%) 173/ /175 (94) 175/180 (97) (98) Withdrawn, n (%) 3/176 (2) 10/175 (6) 5/180 (3) Demographics N (ITT) Females: Males, n 50:126 59:116 51:129 Mean age, years (SD) 7.7 (2.0) 8.0 (2.2) 7.8 (2.2) Range, years White, n (%) 176 (100%) 175 (100%) 180 (100%) Primary Efficacy Results: Percentage of combined symptom-free days and nights (ITT population) Median during run-in Median during Weeks Median difference FP dose

3 95% Confidence Interval/p-value: - [-0.3, 5.2] [-1.7, 3.5]

4 Secondary Efficacy Results: Percentage of symptom-free days (ITT population) Median during run-in Median during Weeks Median difference FP dose [95% CI] 1.5 [-0.4, 4.2] 0.7 [-0.8, 3.3] Difference FP200 FP100 [95% CI] 0.6 [-1.4, 3.2] Percentage of symptom-free nights (ITT population) Median during run-in Median during Weeks Median difference FP dose [95% CI] 0 [-0.5, 0.6] 0 [-0.6, 0.6] Difference FP200 FP100 [95% CI] 0 [-0.5, 0.6] Symptomatic use of relief medication (ITT population) (% of days and nights with no rescue use) Median during run-in Median during Weeks Median difference FP dose [95% CI] 0 [0, 0.6] 0 [0, 0.7] Difference FP200 FP100 0 [-0.4, 0.5] Morning PEF, L/min (ITT population) Adjusted mean change from baseline (SE) 45.1 (3.0) 39.4 (3.0) 39.2 (2.9) Difference in adjusted mean change FP dose (SE) [95% CI] 5.7 (3.6) [-1.5, 12.8] 5.9 (3.6) [-1.2, 13.0] Difference in adjusted mean change FP200 FP100 (SE) [95% CI] -0.2 (3.6) [-7.3, 6.9] Evening PEF, L/min (ITT population) Adjusted mean change from baseline (SE) 43.2 (3.1) 38.2 (3.1) 38.8 (3.0) Difference in adjusted mean change FP dose (SE) [95% CI] 5.0 (3.7) [-2.3, 12.3] 4.4 (3.7) [-2.8, 11.6] Difference in adjusted mean change FP200 FP100 (SE) [95% CI] 0.6 (3.7) [-6.6, 7.9] Clinic PEF, L/min (ITT population) Adjusted mean change from baseline (SE) 52.7 (4.0) 46.2 (4.1) 51.1 (4.1) Difference in adjusted mean change FP dose (SE) [95% CI] 6.5 (4.7) [-2.8, 15.8] 1.6 (4.7) [-7.7, 10.8] Difference in adjusted mean change FP200 FP100 (SE) [95% CI] 4.9 (4.8) [-4.5, 14.4] 4

5 Exacerbations (ITT population): Subjects with exacerbations, n (%) 70 (40) 81 (46) 85 (47) Difference in percentage FP dose (SE) [95% CI] -6.5 (7.4) [-21.0, 7.9] -7.5 (8.9) [-25.0, 10.1] Difference in percentage FP200-FP100 (SE) [95% CI] 0.9 (10.3) [-19.3, 21.2] Subjects with mild exacerbations, n (%) 60 (34) 60 (34) 64 (36) Subjects with moderate exacerbations, n (%) 10 (6) 21 (12) 20 (11) Subjects with severe exacerbations, n (%) (<1) Safety Results: Most Frequent Adverse Events On Therapy N Subjects with any AE(s), n (%) 99 (55%) 111 (61%) 112 (60%) Influenza 29 (16%) 27 (15%) 36 (19%) Headache 14 (8%) 10 (6%) 10 (5%) Fever 13 (7%) 10 (6%) 13 (7%) Cough 11 (6%) 16 (9%) 14 (8%) Common cold 11 (6%) 11 (6%) 9 (5%) Viral infection 8 (4%) 5 (3%) 14 (8%) Rhinitis 7 (4%) 4 (2%) 12 (6%) Acute nasopharyngitis 6 (3%) 9 (5%) 6 (3%) Acute rhinitis 6 (3%) 5 (3%) 6 (3%) Sore throat 3 (2%) 8 (4%) 2 (1%) Pharyngitis 2 (1%) 10 (6%) 8 (4%) Acute pharyngitis 2 (1%) 8 (4%) 2 (1%) Rhinorrhoea 2 (1%) 6 (3%) 6 (3%) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with any SAEs, n (%) 2 (1%) 1 (<1%) 4 (2%) n (%) [related] n (%) [related] n (%) [related] Injury to abdomen; laceration; lung injury 1 (<1%) [0] 0 0 Possible coeliac disease 1 (<1%) [0] 0 0 Pneumonia 0 1 (<1%) [0] 0 Acute laryngitis; viral infection (<1%) [0] Fracture (<1%) [0] Head contusion (<1%) [0] Salmonella (<1%) [0] Subjects with fatal SAEs, n (%) Conclusions: 5

6 All subjects experienced a considerable improvement in their combined symptom-free days and nights, with no statistically significant differences between the three treatment groups. The study was designed to enrol symptomatic subjects with compromised lung function, but most subjects in this study had exceptionally mild disease at study entry. The PEF was approximately 88% of percent predicted at baseline and the use of salbutamol, as assessed by salbutamol-free days at baseline was very low (81-85% salbutamol-free days). The mild nature of the asthma disease in the subjects enrolled on this study meant that it was not possible to discern differences between the three treatments. The significant change in symptom-free days that was seen in response to mcg BD (a dose that most closely matched the subjects pre-existing medications) suggests that subjects may also have become more compliant during the study, implying a possible clinical trial effect. In addition, the ITT analysis may have been affected by erroneous diary card data. Date Updated: 28-Sep-2004 Publications No Publications 6