ADVAIR DISKUS ADVAIR - GlaxoSmithKline

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vs 19 out of 6,138; 95% CI: 0.66, 2.23) was observed for those who did report ICS use. For asthma-related death alone the relative risks were: 18.98* (9 vs 0; with 95% CI: 1.10, 326.15) for those without baseline ICS use; and 1.35 (4 vs 3; 95% CI: 0.30, 6.04) for those reporting ICS use. For asthma-related death or life threatening experience, the relative risks were: 2.39 (21 vs 9; 95% CI: 1.10, 5.22) for those without baseline ICS use, and 1.24 (16 vs 13; 95% CI: 0.60, 2.58) for those reporting ICS use; and, for respiratoryrelated death: 2.28 (14 vs 6; 95% CI: 0.88, 5.94) for those without baseline ICS use, and 2.00 (10 vs 5; 95% CI: 0.69, 5.86) for those reporting ICS use. Hence, the apparent protective effect was most notable for asthma-related outcomes. When ICS effect was further analysed by ethnicity, risks of asthma-related outcomes were diminished for the African-American subgroup with ICS use (as reported at study entry), but contrary to the Caucasian subgroup, these risks were not extinguished; although the data for this analysis were sparse. It is to be noted that the SMART study data do not include information regarding the continued use of ICS after study entry, nor information regarding the dose(s) of ICS used throughout the treatment period of 28 weeks. A number of limitations are noted in the clinical trial's design and conduct, such as the ascertainment and enumeration of events, collection of covariate information (i.e., continued concurrent ICS use) and confounding factors, which may make the interpretation of the results problematic. In addition, post-hoc subgroup analyses may be unstable and/or easily influenced by small changes in covariates or additional events. The findings from SMART are similar to the Salmeterol Nationwide Surveillance study conducted in the UK, where increased asthma-related deaths were observed for patients treated with salmeterol as compared to salbutamol over a 16-week period. Given the similar basic mechanisms of action of beta 2 -agonists, it is possible that the findings seen in this study may be consistent with a class effect. *Estimated by adding .5 to each cell of the treatment by event occurrence table. Additional Clinical Study in Asthma Use in adolescents and adults The objective of study SAM40027, also known as the GOAL study (The Gaining Optimal Asthma ControL study), was to determine whether patients could achieve asthma control based upon definitions derived from internationally accepted guidelines (Global Initiative for Asthma/National Institute of Health - GINA/NIH), by comparing the efficacy of an escalated dose of fluticasone propionate alone or in combination with the long acting beta 2 -agonist salmeterol. July 29, 2014 Page 40 of 67
Study Demographics and Trial Design Table 6 Summary of patient demographics for clinical trials in asthma Study # Trial design (Duration) Dosage (mcg), route of administration Study subjects (n=number) Mean age (Range) Gender SAM40027 GOAL (Bateman et. al., 2004) 1 fluticasone propionate Stratified, randomized, double blind, parallel group, step-up, multicentre study Phase 1: 12-36 weeks Phase 2: 16-40 weeks Phase 1 & 2: 52- weeks ADVAIR ® DISKUS ® 50/100, 50/250, 50/500 BID FP 1 DISKUS ® 100, 250, 500 BID Oral inhalation 3416 40 (9-83) 1428M/1988F In SAM40027, the two treatment groups were well matched for all demographic characteristics. The study was divided into two phases, Phase1: treatment step-up in which treatment was stepped-up every 12 weeks until “Total Control” was achieved or the highest dose of study drug was reached and Phase 2: treatment at constant dose. A broad range of subjects were included in the study and were stratified into 3 groups according to baseline asthma therapy over the 6 months prior to randomization; Stratum 1: ICS naïve or no ICS in last 6 months; Stratum 2: using low doses of inhaled corticosteroid (ICS) in the previous 6 months (≤500mcg BDP daily or equivalent, i.e. ≤250mcg of FP); Stratum 3: using moderate doses of ICS in the previous 6 months (>500mcg-1000mcg BDP daily or equivalent, i.e. >250-500mcg of FP). SAM40027 assessed two pre-defined levels of asthma control: “Well-Controlled” (primary efficacy endpoint) and “Total Control”. July 29, 2014 Page 41 of 67
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ADVAIR DISKUS ADVAIR - GlaxoSmithKline

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