Secondary Outcome/Efficacy Variable(s):

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1 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. GSK Medicine: Nebulized fluticasone propionate Study Number: LOC Title: A multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study to determine the efficacy and safety of nebulized fluticasone propionate (FLIXOTIDE Nebules, )1mg twice daily compared with oral prednisone administered for 7 days to Chinese pediatric and adolescent subjects (aged 4 to 16 years) with an acute exacerbation of asthma Rationale: is an inhaled glucoticosteroid with a high affinity for the human lung glucocorticoid receptor, which is 3 times higher than BUD. It has almost twice anti-inflammatory potency than BDP. imposes low suppression of HPA due to its low absorption in gut and extensive complete first-pass metabolism in the liver, which may help children with an acute exacerbation of asthma with reduction or cessation in use of oral glucocorticosteroids. aerosol suspension solution (NebulesTM) is administrated via nebulized inhalation. Nebulized inhalation can deliver drug directly to the lung in a manner that is not dependent on aspiratory flow or the patients co-ordination. A study of nebulized high-dose in children with an acute exacerbation of asthma for 7 days demonstrated, that nebulized got patients lung function (morning and evening PEF, PEF, FVC, et al) improved similar to oral prednisone, and indicates that nebulized at least as effective as oral prednisone for treatment of children with an acute exacerbation of asthma. The aim of this study is to evaluate the efficacy and safety of nebulized 1mg BID for 7 days in Chinese children and teenagers with an acute exacerbation of asthma, compared with oral prednisone (2mg/kg.day, up to 40mg/day for 4 days, then 1mg/kg.day or half of the original dose, up to 20mg/day for 3 days). This study will be used for registration of aerosol suspension for treatment of children with an acute exacerbation of asthma. Phase: IIIB Study Period: 12-Nov-2012 to 21-Jun-2013 Study Design: A randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-center study comprising a 7-day treatment period and a 14-day follow-up period. Centres: 12 centres Indication: asthma exacerbation Treatment: subjects were randomly assigned(1:1) to receive: Fluticasone propionate nebules 2 0.5mg/2mL twice daily and Placebo soluble tablets once daily tablets once daily (2mg/kg.day, up to 40mg/day for 4 days, then 1mg/kg.day or half of the original dose, up to 20mg/day for 3 days) and Placebo nebules 2 2mL 0.9% saline twice daily Objectives: To determine the efficacy and safety of nebulized fluticasone propionate 1mg BID compared with oral prednisone administered for 7 days to Chinese pediatric and adolescent subjects (aged 4 to 16 years) with an acute exacerbation of asthma. Primary Outcome/Efficacy Variable: Mean morning PEF on diary card over the treatment assessment period Secondary Outcome/Efficacy Variable(s): Mean evening PEF on diary card over the treatment assessment period Median Day-time and night-time symptom scores over the treatment assessment period Median number of use of rescue medications during day and night over the treatment assessment period Clinic lung function results performed in the clinic (FEV1 and FVC) Clinical scoring index Patient/parent and investigator global evaluation Statistical Methods: A total of 250 patients were required to be randomized to achieve totally 200 evaluable subjects (100 per treatment group) in the PP population. With this sample size, it had 80% power to reject the null hypothesis that nebulized (1 mg BID) was inferior to oral prednisone (2 mg/kg/day for 4 days then 1mg/kg/day for 3 days) with regard to the primary efficacy endpoint (mean AM PEF) using one-side t test at significance level of 2.5%, and assuming the true treatment difference (-) was 3.6 L/min, the non-inferiority margin was 12L/min, and the common standard deviation was 39 L/min. The efficacy analyses were based on both ITT and PP populations. The ITT population comprised all subjects randomized to treatment and who received at least one dose of study drug. The PP population included all subjects in the ITT population who did not have any full protocol violations which could impact treatment effect. The PP population 1

2 was of equal importance to the ITT population in assessing non-inferiority of nebulized to oral prednisone on mean AM PEF on diary card over the treatment assessment period. The safety analyses based on safety population which consisted of all subjects randomized to treatment and who received at least one dose of study drug. The analysis of the mean AM PEF on diary card over the treatment assessment period was performed using an ANCOVA model with effects due to sex, age, and center and treatment group. Should the lower bound of 95% confidence interval (CI) for the LS mean treatment difference ( minus ) fall above -12L/min then non-inferiority would be claimed. PM PEF, FEV1 and FVC were analysed using the similar ANCOVA model. Median day-time and night-time symptom scores, median rescue medications taken during day and night, clinical scoring index, and patient/parent and investigator global evaluation were analysed using the Wilcoxon-rank sum test. Descriptive statistics were applied to all safety endpoints. Study Population: Male and female subjects aged 4 to 16 years, inclusive, with an established diagnosis of asthma, who presented to an acute care setting with an acute exacerbation of asthma, with a PEF of 50%-75% of the predicted normal value, and had a clinical scoring index of 2 (clinical score index was based on the sum of scores for respiratory rate, wheezing, inspiration/expiration ratio and accessory muscle use). Subjects were excluded if they: had treatment with oral or parenteral corticosteroids for more than 7 days during the previous 4 weeks; had treatment with systemic corticosteroids or parenteral methylxanthines within the previous 72 hours; had severe respiratory dysfunction; had a history of medical ventilation due to respiratory failure; had been admitted to hospital with respiratory disease within the previous 2 weeks; had clinical or laboratory evidence of a serious systemic disease; presented to an acute care setting with any respiratory infection or disease other than acute asthma exacerbation; presented to the clinic with wheezing due to a respiratory infection. Number of Subjects: Randomised, Completed, n (%) 116 (94%) 123 (96%) Total Number Subjects Withdrawn, N (%) 7 (6%) 5 (4%) Withdrawn due to Adverse Events n (%) 0 0 Withdrawn due to Lack of Efficacy n (%) 1 (<1%) 1 (<1%) Withdrawn for other reasons n (%) 6 (5%) 3 (2%) Demographics N (ITT) Females: Males 51:72 51:77 Mean Age, years (SD) 6.6 (2.41) 6.5 (2.32) Asia, n (%) 130(100%) 131(100%) Primary Efficacy Results: Mean AM PEF(L/min) (ITT population): Mean (SD) (68.89) (69.67) LS Mean (SE) (3.774) (3.790) LS Mean Difference % Confidence Interval (-9.85, 10.76) p-value Mean AM PEF(L/min) (PP population): n Mean (SD) (67.53) (70.62) LS Mean (SE) (3.724) (3.712) LS Mean Difference % CI of LS Mean Difference (-9.64, 10.65) p-value Secondary Outcome Results Mean PM PEF(L/min) (ITT population) Mean (SD) (68.62) (69.70) LS Mean (SE) (3.723) (3.751) 2

3 LS Mean Difference % Confidence Interval (-9.02, 11.34) Mean PM PEF(L/min) (PP population) Mean (SD) (67.40) (70.61) LS Mean (SE) (3.708) (3.709) LS Mean Difference % CI of LS Mean Difference (-9.32, 10.92) Median Daytime Symptom Score(ITT population) n Mean (SD) 0.8 (0.89) 0.9 (0.90) Median Median Daytime Symptom Score(PP population) Mean (SD) 0.8 (0.85) 0.9 (0.92) Median Median Night-time Symptom Score(ITT population) Mean (SD) 0.5 (0.75) 0.6 (0.78) Median Median Night-time Symptom Score(PP population) n Mean (SD) 0.5 (0.72) 0.6 (0.78) Median Analysis of Median Numbers of Times Rescue Medication (ITT Population) n Mean (SD) 2.1 (0.52) 2.1 (0.52) Median Analysis of Median Numbers of Times Rescue Medication (PP Population) Mean (SD) 2.1 (0.52) 2.1 (0.53) Median FEV1 (L) (ITT Population) on Visit 3 (Day 8) n Mean (SD) (0.5126) (0.5228) LS Mean (SE) (0.0294) (0.0280) LS Mean Difference % CI of LS Mean Difference (-0.074, 0.083) FEV1 (L) (PP Population) on Visit 3 (Day 8) 3

4 n Mean (SD) (0.4844) (0.5289) LS Mean (SE) (0.0276) (0.0265) LS Mean Difference % CI of LS Mean Difference (-0.109, 0.040) FVC (L) (ITT Population) on Visit 3 (Day 8) n Mean (SD) (0.6009) (0.6347) LS Mean (SE) (0.0326) (0.0316) LS Mean Difference % CI of LS Mean Difference (-0.126, 0.049) FVC (L) (PP Population) on Visit 3 (Day 8) n Mean (SD) (0.5868) (0.6412) LS Mean (SE) (0.0313) (0.0306) LS Mean Difference % CI of LS Mean Difference (-0.165, 0.004) Analysis of Change from Baseline in Clinical Scoring Index (ITT Population) Visit 3 (Day 8) n Mean (SD) -3.4 (1.26) -3.4 (1.26) Median Analysis of Change from Baseline in Clinical Scoring Index (PP Population) Visit 3 (Day 8) n Mean (SD) -3.4 (1.22) -3.3 (1.26) Median Analysis of Patient/Parent and Investigator Global Evaluation for Efficacy (ITT Population) Patient/Parent Global Evaluation n Mean (SD) 1.5 (0.59) 1.5 (0.52) Median Investigator Global Evaluation n Mean (SD) 1.5 (0.56) 1.5 (0.52) Median Analysis of Patient/Parent and Investigator Global Evaluation for Efficacy (PP Population) Patient/Parent Global Evaluation n Mean (SD) 1.4 (0.53) 1.5 (0.52) Median Investigator Global Evaluation Mean (SD) 1.4 (0.52) 1.5 (0.52) Median Safety Results: Most Frequent Adverse Events On-Therapy n (%) n (%) 4

5 Subjects with any AE(s), n(%) 22 (18%) 38 (30%) White blood cell count increased 1 (<1%) 10 (8%) Upper respiratory tract infection 3 (2%) 5 (4%) Vomiting 1 (<1%) 5 (4%) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 2 (<2%) 3 (3%) n (%) [related] n (%) [related] 0 0 Subjects with fatal SAEs, n (%) 0 0 Conclusion: Nebulized fluticasone propionate was shown to be non-inferior to oral prednisone for the treatment of acute exacerbation of asthma in Chinese pediatric and adolescent patients for the predefined entry criteria, and also the results of AM PEF, PM PEF and median daytime symptom score were numerically slightly in favor of Nebulized fluticasone propionate. Safety data indicated that the AE, SAE and drug-related AE were all less in the group compared with the oral prednisone group in the treatment period, which demonstrated that Nebulized fluticasone propionate was safe and well tolerated. The results of this study can support aerosol suspension as an effective and safe treatment for children with an acute exacerbation of asthma. 5