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.: SALMP/AH91/D89 Title: A phase III, multi-centre, double-blind, placebo controlled, parallel group study assessing the efficacy and safety of inhaled salmeterol xinafoate (Serevent ) 50 micrograms BD via the Diskhaler when added to the existing treatment of moderate to severe asthmatic children. Rationale: The study was designed to assess the efficacy and safety of inhaled salmeterol xinafoate (SAL) 50µg twice daily (BD) when added to the existing therapy for moderate to severe asthmatic children. Phase: III Study Period: 14 March 1992 to 14 March 1993 Study Design: Multi-centre, double-blind, placebo-controlled, parallel-group study Centres: 78 centres in the United Kingdom Indication: Asthma Treatment: Subjects remained on their usual prophylactic therapy of at least the maximum licensed dose of beclomethasone dipropionate (BDP) or equivalent during the 2-week baseline period, and their usual beta2-adrenoceptor agonist therapy was replaced by commercially available salbutamol 200µg Diskhaler (Ventodisks) to be used as required for symptomatic relief. Subjects were then randomised to receive either via the Diskhaler or matching placebo () BD in addition to their usual prophylactic therapy for 12 weeks. Objectives: To assess the efficacy and safety of inhaled via the Diskhaler when added to the existing therapy for moderate to severe asthmatic children. Primary Outcome/Efficacy Variable: Change from baseline in mean morning percent predicted peak expiratory flow (PEF). Secondary Outcome/Efficacy Variable(s): Mean evening percent PEF Diurnal variation Proportion of symptom-free days and symptom-free nights Day-time and night-time relief medication Global assessment of control of asthma Lung function measurements (PEF and forced expiratory volume at 1second (FEV1)) recorded at clinic visits Statistical Methods: The total sample (TOT; all subjects who received at least 1 puff of medication and recorded at least 1 day of valid diary or clinic data during the treatment period) was used for efficacy and safety analyses. Daily record booklet (DRB) data for analysis were grouped into the study periods: baseline (Weeks 1-2), treatment period 1 (Weeks 3-6), treatment period 2 (Weeks 7-10), treatment period 3 (Weeks 11-14), and follow-up (Weeks 15-16). All DRB variables and the subject assessment of asthma control were analysed using the van Elteren test adjusting for the values of the variables in the baseline period. For continuous data, the baseline data were categorised into 4 categories such that each category contained 1 quarter of the data. Confidence intervals (CIs) for the median treatment differences were not calculable. PEF and FEV1 were converted into percentage of predicted values and summarised statistically at each visit. The changes from baseline to Visit 5 were compared between treatment groups using analysis of covariance incorporating baseline values as a covariate. 95% CIs of the adjusted treatment mean differences were determined. Study Population: Male and female asthmatic children aged 4 to 16 years, inclusive, who had been taking at least 200mcg daily of BDP or equivalent for at least 6 months and who were symptomatic and demonstrated a mean PEF of 90% or less of predicted normal on at least 4 days of baseline. Subjects excluded were those receiving oral 2- adrenoceptor agonist therapy or maintenance oral corticosteroid therapy or those who had a short course of oral corticosteroids in the two weeks prior to the start of the baseline period. Also excluded were those who had received newly prescribed asthma therapy, or had changed asthma therapy in the two weeks prior to the start of the baseline period. Number of Subjects: Planned, N 210 210 Randomised, N a 100 110 Completed, n (%) 77 (77) 89 (81) Total Number Subjects Withdrawn*, N (%) 22 (22) 18 (16) Withdrawn due to Adverse Events, n (%) 4 (4) 2 (2) 1
Withdrawn due to Lack of Efficacy, n (%) 1 (1) 2 (2) Withdrawn for other reasons, n (%) 18 (18) 15 (14) a One subject in the SAL group and 3 subjects in the group and were considered to have unevaluable data and were excluded from all analyses. *subjects could withdraw due to more than one reason N (TOT) 99 107 Females: Males 40:59 42:65 Mean Age, years (SD) 10.2 (2.7) 10.3 (2.7) Race, n (%) Not available (NA) NA Primary Efficacy Results: Total sample Change from baseline in mean morning percent predicted PEF Median 6.5 2.1 Lower quartile, upper quartile 2.6, 14.5-2.4, 8.6 Interquartile range 11.9 11.0 Minimum, maximum -34.8, 42.2-28.5, 28.0 p-value <0.001 Median 8.0 4.8 Lower quartile, upper quartile 3.0, 18.2-0.7, 13.2 Interquartile range 15.3 13.8 Minimum, maximum -5.3, 41.5-37.2, 30.4 p-value 0.003 Median 8.2 4.9 Lower quartile, upper quartile 2.6, 15.0-0.9, 11.2 Interquartile range 12.4 12.1 Minimum, maximum -13.8, 50.3-48.1, 52.6 p-value 0.017 Median 5.2 4.8 Lower quartile, upper quartile -1.7, 15.4-0.8, 10.5 Interquartile range 17.1 11.3 Minimum, maximum -21.0, 48.5-42.0, 54.4 p-value Secondary Outcome Variable(s): Total sample Change from baseline in mean evening percent predicted PEF NA Median 3.4 0.9 Lower quartile, upper quartile -0.9, 8.7-3.2, 6.4 Interquartile range 9.6 9.6 Minimum, maximum -29.3, 42.2-48.4, 24.3 Median 5.1 3.8 Lower quartile, upper quartile 1.7, 9.5-0.7, 9.1 Interquartile range 7.8 9.9 Minimum, maximum -10.7, 41.7-28.4, 28.0 2
Median 4.5 3.2 Lower quartile, upper quartile -1.8, 9.6-1.8, 8.1 Interquartile range 11.4 10.0 Minimum, maximum -18.3, 49.2-51.0, 47.7 Median 2.9 2.7 Lower quartile, upper quartile -4.5, 9.0-0.9, 9.1 Interquartile range 13.5 10.0 Minimum, maximum -19.8, 51.7-36.7, 47.7 Change from baseline in diurnal variation (%) Median -1.8-1.9 Lower quartile, upper quartile -5.9, 0.9-4.1, 0.5 Interquartile range 6.8 4.6 Minimum, maximum -29.3, 11.9-12.4, 15.9 Median -2.7-2.5 Lower quartile, upper quartile -8.1, 0.3-5.8, -0.1 Interquartile range 8.4 5.7 Minimum, maximum -25.0, 8.1-18.1, 11.0 N subjects (N missing) [N present] 82 (15) [97] 95 (11) [106] Median -3.3-3.0 Lower quartile, upper quartile -9.0, -0.2-6.4, -0.2 Interquartile range 8.9 6.3 Minimum, maximum -23.5, 9.7-17.9, 17.2 N subjects (N missing) [N present] 78 (4 ) [82] 89 (6) [95] Median -1.9-2.7 Lower quartile, upper quartile -8.0, 1.6-7.2, 0.6 Interquartile range 9.6 7.8 Minimum, maximum -23.8, 11.6-15.0, 19.0 Change from baseline in proportion of symptom-free days Median 0.15 0.00 Lower quartile, upper quartile 0.00, 0.44 0.00, 0.21 Interquartile range 0.44 0.21 Minimum, maximum -0.85, 0.93-0.46, 0.89 Median 0.24 0.10 Lower quartile, upper quartile 0.00, 0.51 0.00, 0.36 Interquartile range 0.51 0.36 Minimum, maximum -1.00, 0.97-0.60, 0.89 Median 0.21 0.05 3
Lower quartile, upper quartile 0.00, 0.55 0.00, 0.41 Interquartile range 0.55 0.41 Minimum, maximum -0.55, 1.00-0.56, 0.97 Median 0.29 0.14 Lower quartile, upper quartile 0.00, 0.55 0.00, 0.57 Interquartile range 0.55 0.57 Minimum, maximum -0.55, 1.00-0.56, 1.00 Change from baseline in proportion of symptom-free nights Median 0.12 0.03 Lower quartile, upper quartile -0.04, 0.28-0.09, 0.25 Interquartile range 0.33 0.34 Minimum, maximum -0.79, 0.75-0.40, 0.73 Median 0.20 0.07 Lower quartile, upper quartile -0.01, 0.38-0.10, 0.33 Interquartile range 0.39 0.43 Minimum, maximum -0.96, 0.81-1.00, 0.83 Median 0.15 0.02 Lower quartile, upper quartile -0.01, 0.31-0.07, 0.35 Interquartile range 0.32 0.42 Minimum, maximum -0.47, 0.88-0.75, 0.75 Median 0.05 0.04 Lower quartile, upper quartile -0.10, 0.31-0.11, 0.33 Interquartile range 0.41 0.44 Minimum, maximum -0.62, 0.86-0.92, 0.86 Change from baseline in use of day-time relief medication (blisters) Median -0.5-0.3 Lower quartile, upper quartile -0.8, 0.1-0.9, 0.1 Interquartile range 0.9 1.0 Minimum, maximum -5.0, 2.4-4.1, 4.0 N subjects (N missing) [N present] 97 (2) [99] 107 (0) [107] Median -0.7-0.3 Lower quartile, upper quartile -1.4, -0.0-1.0, 0.0 Interquartile range 1.4 1.1 Minimum, maximum -6.0, 2.1-7.6, 4.2 Median -0.8-0.3 Lower quartile, upper quartile -1.4, 0.1-1.3, 0.3 Interquartile range 1.5 1.5 Minimum, maximum -6.0, 2.2-7.6, 4.5 4
N subjects (N missing) [N present] 77 (5) ]82] 89 (6) [95] Change from baseline in use of night-time relief medication (blisters) Median -0.1-0.0 Lower quartile, upper quartile -0.4, 0.0-0.4, 0.2 Interquartile range 0.4 0.6 Minimum, maximum -1.7, 3.2-2.5, 1.9 N subjects (N missing) [N present] 98 (1) [99] 105 (2) [107] Median -0.1-0.0 Lower quartile, upper quartile -0.4, 0.0-0.3, 0.2 Interquartile range 0.4 0.5 Minimum, maximum -1.4, 3.1-2.9, 2.1 N subjects (N missing) [N present] 80 (17) [97] 94 (12) 106 Median -0.1-0.1 Lower quartile, upper quartile -0.3, 0.0-0.3, 0.3 Interquartile range 0.3 0.6 Minimum, maximum -1.9, 1.9-2.9, 2.9 N subjects (N missing) [N present] 75 (7) [82] 86 (9) [95] Subject s global assessment of control of asthma at Visit 5 Very good, n (%) 19 (26) 12 (13) Good, n (%) 18 (24) 27 (30) Not bad, n (%) 31 (42) 43 (48) Bad, n (%) 6 (8) 8 (9) Parent s global assessment of control of asthma at Visit 5 Very good, n (%) 20 (25) 18 (20) Good, n (%) 29 (37) 26 (29) Not bad, n (%) 25 (32) 35 (39) Bad, n (%) 5 (6) 10 (11) Physician s global assessment of control of asthma at Visit 5 Very effective, n (%) 18 (23) 15 (17) Effective, n (%) 23 (29) 23 (26) Satisfactory, n (%) 28 (35) 31 (34) Ineffective, n (%) 10 (13) 21 (23) Global assessment of control of asthma at Visit 5 (level of activity restriction) Never, n (%) 28 (35) 33 (37) Sometimes, n (%) 39 (49) 38 (43) Frequently, n (%) 10 (13) 16 (18) Always, n (%) 2 (3) 2 (2) Change from baseline to Visit 5 in percent predicted PEF recorded at the clinic visits Mean (SD) 6.8 (20.9) 1.2 (16.7) Minimum, maximum -59.1, 66.1-54.7, 40.6 Change from baseline to Visit 5 in percent predicted FEV1 recorded at the clinic visits 5
Mean (SD) 5.2 (20.0) 1.8 (15.7) Minimum, maximum -60.1, 62.7-35.9, 41.5 Safety Results: Most Frequent Adverse Events (AEs) On Therapy n (%) n (%) Subjects with any AE(s), n (%) 74 (75) 81 (76) Exacerbation of asthma 23 (23) 19 (18) Headache 20 (20) 9 (8) Sore throat 14 (14) 6 (6) Cough 12 (12) 14 (13) Wheezing 12 (12) 12 (11) Upper respiratory infection 11 (11) 11 (10) Acute nasopharyngitis 8 (8) 12 (11) Tonsillitis 5 (5) 2 (2) Fever 5 (5) 1 (1) Stomach ache 4 (4) 2 (2) Seasonal allergic rhinitis 4 (4) 4 (4) Chest infection 2 (2) 9 (8) Asthma attack 2 (2) 5 (5) Eczema 1 (1) 4 (4) Chest pain 2 (2) 4 (4) Serious Adverse Events (SAEs) - On Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 10 (10) [NA] 13 (12) [NA] SAEs n (%) [related] n (%) [related] Exacerbation of asthma 10 (10) [1] 8 (7) [3] Severe acute asthma 2 (2) [0] 0 Chest infection 1 (1) [0] 0 Virosis 1 (1) [0] 0 Eczema 0 2 (2) [0] Asthma attack 0 1 (<1) [0] Reduced PEF rate 0 1 (<1) [0] Shortness of breath 0 1 (<1) [0] Tonsillitis 0 1 (<1) [0] Fracture of carpal bone(s) 0 1 (<1) [0] Subjects with fatal SAEs, n (%) 0 0 Conclusion: See publication below Publications: Russell G, Williams DA, Weller P, Price JF. Salmeterol xinafoate in children on high dose inhaled steroids. Ann Allergy Asthma Immunol. 1995: 75(5); 423-428 Date Updated: 08-Mar-2006 6