GSK Medicine: Study Number: Title: Rationale: Study Period: Objectives Indication: Study Investigators/Centers: Research Methods Data Source:

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1 GSK Medicine: Study Number: Title: OCSIGEN study Longitudinal follow-up of a cohort of patients with asthma treated with inhaled corticosteroids in primary care Rationale: In the Post-Licensing File of 20 December 200 for proprietary drugs containing fluticasone propionate, signed on April 2 nd 2003, GlaxoSmithKline undertook to conduct an observational study to assess how inhaled corticosteroids (ICS) were used in real-world conditions. This comprised two panels, one in a primary care setting (general practitioner; GP) and the other in a specialist care setting (chest physician; CP) in France. National and international consensus guidelines (Global Initiative for Asthma, GINA) provide recommendations for asthma management as a function of disease severity. In order to propose appropriate asthma controller therapy, asthma severity should thus be assessed regularly. Treatment decisions are based on the level of asthma control assessed over a few weeks, on the basis of symptoms, daily activity and lung function, and taking into account the treatment received during this period. The appropriateness of asthma controller therapy in real-world conditions can thus only be evaluated as a function of asthma severity and control. According the request of French health Authorities, the study was put in place in order to assess the appropriateness of ICS treatment of asthma under real world conditions of care in France. Study Period: : inclusion from May 2004 to March CP panel: September 2005 to April 2009 October 2007 : Inclusion reports from both panels, January 2008 : -year report, May 2008 : CP panel -year report, June 2009: final report, March 200: CP panel final report, several exchanges with French health Authorities between May 2008 and June 20, evaluation by French health Authorities between July and December 202 Objectives: Principal objective: to describe the conditions of use of fluticasone propionate and other ICS in real-world practice (general practice and speciality care), according to asthma severity and control in individual patients ages 5 years and older. Secondary objective: to study factors related to the management of patients with asthma. Indication: Asthma. Study Investigators/Centers: Research Methods: To cover the whole range of asthma care in France, the study had two distinct settings, one in primary care and the other in secondary care. For this reason, the study consisted of two independent panels, conducted by different physician groups, one by GPs and one by CPs. The two panels used different procedures for patient recruitment and data collection, and recruited over different, albeit overlapping, periods. However, the same variables were analysed in the same way from both panels. Participating GPs and CPs were selected at random from a list of all licensed physicians. Subjects were recruited during spontaneous consultation for asthma in participating practices. All subjects consulting for asthma during the recruitment period were invited to participate in the study. Subjects were evaluated at the inclusion consultation and at all follow-up consultations for asthma occurring during the two-year follow-up period. At each consultation, current symptoms and treatment were documented. From the data obtained on recent symptoms and current treatments, asthma severity, asthma control and appropriateness of treatment were determined. These three variables were compared between two subgroups of patients, one treated with fluticasone propionate and one with other ICS. Data Source: : data were extracted from the Thalès electronic database. Thalès is a computerised network of,200 GPs who collect exhaustive anonymous data on patient consultations and prescriptions which are entered into a centralised electronic database, allowing subsequent follow-up of outcomes. CP panel: data were entered by investigator into an electronic case report form after the inclusion consultation and after each follow-up consultation. Symptoms and severity data have been collected by GPs. Study Design: Observational, prospective, pharmacoepidemiological study with two years follow-up. Study Population:Diagnosis of asthma Aged at least fifteen years Consultation at least twice in the previous year Prescription of an ICS in the previous six months Consulting specifically for asthma during the recruitment period Providing oral informed consent Diagnosis of COPD, chronic bronchitis, professional pulmonary disease or emphysema Refusal to participate in the study Study Exposures, Outcomes: Study groups: two study groups were constituted, one prescribed fluticasone propionate, the other prescribed another

2 ICS. Choice of treatment: the choice of ICS (fluticasone propionate or other) was made at the investigator s discretion prior to and independently of participation in the study. Modification of treatment: asthma treatment could be modified at any time during the study and for whatever reason at the investigator s discretion. Outcome measures: (i) asthma severity Asthma severity was evaluated using the following algorithm, which was designed by the Scientific Committee of the study and subsequently validated by the French Health Authorities: Asthma severity was assessed at each consultation and classified as intermittent, mild persistent, moderate persistent or severe persistent, based on the GINA 2004 clinical (C) and therapeutic (T) classifications. The algorithm took into account all consultations for each patient, and assessed the overall asthma severity level. The assessment of asthma severity over the two-year period did not take into account whether treatment seemed appropriate for the severity grade. (ii) asthma control Asthma control was assigned on the basis of symptoms reported in the previous three works as defined in the 2004 ANAES guidelines. Control was defined as either acceptable or unacceptable. This parameter was assessed at inclusion and at the last consultation recorded in the study. In the CP panel only, asthma control was also determined using patient reported outcome measures Asthma Control Test Asthma Control Questionnaire (iii) appropriateness of treatment Appropriateness of treatment was assessed in terms of compliance with national guidelines in force at the time of the study (ANAES 2004) and was evaluated by analysing therapeutic strategies implemented by participating physicians between inclusion and the first follow-up visit. Appropriate level of treatment intensity: therapeutic (T) severity classification superior or equivalent to clinical (C) severity classification Inadequate level of treatment intensity: therapeutic (T) classification inferior to clinical (C) classification Excessive level of treatment: intensity: therapeutic (T) classification at least two grades superior to clinical (C) classification without an apparent clinical rationale Other relevant variables documented: Type and dose (defined as beclomethasone equivalents, according to the 2004 GINA guidelines) of ICS prescribed Changes to ICS treatment during follow-up Presence of asthma risk factors Lung function (peak expiratory flow rate) Data Analysis Methods: with the management of patients with asthma (type of ICS prescribed) were evaluated using multivariate regression analysis. Two models were investigated. The first deterministic model included four variables, namely gender, age group, smoking status and asthma severity. The second exploratory model included, together with asthma severity as a covariate, all variables significantly associated with treatment group that had been identified in a preliminary bivariate analysis adjusted for severity. Limitations: Information on consultations for asthma by other physicians is not documented in the Thalès database, and treatment changes made by other physicians are thus not documented. The participation of CPs being voluntary, this may have led to selection of physicians whose treatment practice is not representative of all CPs in France. To respect the observational nature of the study, no follow-up visits were organised specifically for the needs of the study. This is a potential source of significant loss of subjects to follow-up. Study Results: 2

3 Study participants N (87.6%) 748 (2.4%) 666 (3.4%) 6 (70.0%) 924 (82.8%) CP panel 44 (47.7%) 483 (52.3%) N (98.%) 500 (88.3%) 465 (93.0%) 206 (44.3%) 259 (56.7%) Demographics/Baseline Characteristics Subjects included in the CP panel were similar to those included in the with respect to age, gender and disease duration. However, the CP panel comprised fewer current smokers than the (8.2% versus 6.7%) and more subjects with documented atopic asthma (69.4% versus 5.8%). GP Panel Age (years; mean ± SD) Age (years; median [range]) Gender (% women) Duration of asthma (years; mean ± SD) Duration of asthma (years; median [range]) Smoking status (% current smoker) Type of asthma (% atopic asthma) Asthma severity assessed by the investigator (N = 44) 52.3 ± [5 92]253 (57.4%)8.8 ± 4.65 [ 75]70 (5.9%) 236 (53.5%) 25 (5.7%) 39 (8.8%) 49 (33.8%) 228 (5.7%) 54.8 ± [5 93] 278 (57.6%) 7.7 ± [ 80] 84 (7.4%) 243 (50.3%) 35 (7.2%) 7 (4.7%) 238 (49.3%) 39 (28.8%) 3

4 CP Panel Age (years; mean ± SD) Age (years; median [range]) Gender (% women) Duration of asthma (years; mean ± SD) Duration of asthma (years; median [range]) Smoking status (% current smoker) Type of asthma (% atopic asthma) Asthma severity assessed by the investigator ICS treatment 47.4 ± [5-8] 9 (57.8%) 8.9 ± [ 6] 22 (0.7%) 49 (73.0%) 2 (.0%) 7 (8.3%) 63 (30.6%) 24 (60.2%) 49.4 ± [6 85] 67 (64.5%) 8.9 ± [ 70] 6 (6.2%) 69 (66.5%) (0.4%) 26 (0.0%) 32 (5.0%) 00 (38.6%) Low dose Intermediate dose High dose ICS alone Free ICS/LABA combination FIxed ICS/LABA combination Prescribed ICS at last follow-up visit CP panel Low dose Intermediate dose High dose ICS alone Free ICS/LABA combination FIxed ICS/LABA combination (N = 44) 6 (3.6%) 44 (32.7%) 28 (63.7%) 28 (6.3%) 48 (0.9%) 365 (82.8%) 330 (74.8%) 6 (7.8%) 58 (28.2%) 32 (64.%) 5 (7.3%) 22 (0.7%) 69 (82.0%) 49 (30.8%) 287 (59.4%) 47 (9.7%) 53 (3.7%) 22 (25.3%) 208 (43.%) 323 (66.9%) 78 (3.0%) 20 (46.3%) 6 (23.6%) 39 (5.%) 74 (28.6%) 46 (56.4%) Prescribed ICS at last follow-up visit 20 (97.5%) 244 (94.2%) Outcome: asthma severity The majority of subjects were classified as having moderate or severe persistent asthma at inclusion (80% overall for the and 90% overall for the CP panel). Subjects treated with fluticasone propionate were more frequently classified as having severe persistent asthma than subjects treated with other ICS. (N = 44) 5.7% [3.5% - 7.8%] 8.8% [6.2% -.5%] 33.8% [29.4% %] 5.7% [47.0% %] 7.2% [4.9% - 9.6%] 4.7% [.5% - 7.9%] 49.3% [44.8% %] 28.8% [24.7% %] 4

5 CP panel.0% [0% - 2.3%] 8.3% [4.5% - 2%] 30.6% [24.3% %] 60.2% [53.5% %] 0.4% [0% -.%] 0.0% [6.4% - 3.7%] 5.0% [44.9% - 57.%] 38.6% [32.7% %] Outcome: asthma control According to the ANAES criteria, asthma control at inclusion was considered unacceptable in around three-quarters of subjects. No differences were observed in the proportion of subjects with acceptable control, which was similar between subjects in the and subjects in the CP panel and between subjects treated with fluticasone propionate and subjects treated with another ICS. The proportion of subjects whose asthma control was acceptable both at inclusion and at last follow-up ranged from 0% to 6%, according to the group and panel. In the CP panel, asthma control was also evaluated using patient-reported outcome measures. Asthma control at inclusion was acceptable in 57% of subjects according to the ACT and in 38% according to the ACQ. : control at inclusion (ANAES) Evolution of control between inclusion and last visit at both visits at inclusion/unacceptable at last follow-up visit at inclusion/acceptable at last follow-up visit Uncceptable at both visits CP panel: control at inclusion (ANAES) Evolution of control between inclusion and last visit at both visits at inclusion/unacceptable at last follow-up visit at inclusion/acceptable at last follow-up visit Uncceptable at both visits Control at inclusion (ACT) Control at inclusion (ACQ) (N = 44) 23.4% [9.4% %] 76.6% [72.7% %] (N = 44) 43 (9.8%) 94 (2.3%) 60 (3.8%) 244 (55.3%) 23.4% [7.6% %] 76.6% [70.8% %] (N = 203) 25 (2.%) 23 (.3%) 37 (8.2%) 8 (58.%) (N = 82) 99 (54.4%) 83 (45.6%) (N = 80) 70 (38.9%) 0 (6.%) 25.% [2.2% %] 75.0% [7.% %] 66 (3.7%) 55 (.4%) 3 (23.4% 249 (5.6%) 24.4% [9.% %] 75.6% [70.3% %] (N = 247) 39 (5.8%) 2 (8.5%) 44 (7.8%) 43 (57.9%) (N = 232) 36 (58.6%) 96 (4.4%) (N = 238) 89 (37.4%) 49 (62.6%) 5

6 Outcome: appropriateness of treatment For the majority of subjects, the intensity of ICS treatment at inclusion was considered appropriate for the severity of the underlying asthma. The proportion of subjects whose treatment was considered to be appropriate was higher for the CP panel than for the, and higher for subjects who were prescribed fluticasone propionate than for subjects prescribed another ICS. Subjects treated with other ICS were more frequently treated at an inadequate intensity. Inadequate Appropriate Excessive CP panel Inadequate Appropriate Excessive (N = 44) 25.9% [2.8% %] 64.2% [59.7% %] 0.0% [7.2% - 2.8%] 4.6% [9.7% - 9.4%] 79.% [73.6% %] 6.3% [3.0% - 9.6%] 4.6% [37.2% %] 50.7% [46.3% %] 7.7% [5.3% - 0.0%] 3.7% [26.0% %] 62.5% [56.7% %] 5.8% [2.9% - 8.6%] Factors associated with type of ICS treatment In both the deterministic and the exploratory models and in both the GP and CP panels, asthma severity as determined by the study algorithm, was strongly associated with the type of ICS prescribed (p <0.000). Subjects with more severe asthma were more likely to be prescribed fluticasone propionate than another ICS. In the, a weaker association (p = 0.008) was also observed with age as a continuous variable, with younger subjects being more likely to be prescribed fluticasone propionate. Deterministic model Gender (women versus men) Age group (by quartile) <35 years (reference) 35 to 48 years 49-6 years >6 years Smoking status (smokers versus non-smokers) (reference) Exploratory model Age (continuous variable) (reference) Odds ratio [95% CI] 0,993 [0,757 -,302] 0,790 [0,538 -,6] 0,69 [0,470 -,04] 0,58 [0,39-0,864] 0,778 [0,536 -,30] 0,820 [0,428 -,572] 0,927 [0,530 -,62] 2,54 [,432-4,44] 0,990 [0,983-0,997] 0,837 [0,437 -,603] 0,923 [0,529 -,60] 2,52 [,438-4,427] p 0,96 0,05 0,9 < 0,000 0,008 < 0,000 6

7 CP panel Odds ratio [95% CI] p Deterministic model Gender (women versus men) Age group (by quartile) <35 years (reference) 35 to 48 years 49-6 years >6 years Smoking status (smokers versus non-smokers) (reference) or intermittent Exploratory model (reference) or intermittent [ ].240 [ ] [ ] [ ].672 [ ] [ ] [ ] [ ] [ ] < < Conclusion: In this study performed in primary and specialist care in France, fluticasone propionate accounted for 44.7% of all ICS use in the patients recruited into the (n=924) and 44.3% in the CP patients recruited into the panel (n=577). Treatment with fluticasone propionate was rated as appropriate for the severity of asthma in 64% () and 79% (CP panel) of cases based upon available data and the severity algorithm. Asthma control was deemed unacceptable in three-quarters of subjects (both panels), illustrating the need for a more dynamic approach to asthma management as recommended in the GINA guidelines. Treatment with fluticasone propionate was appropriate for the severity of asthma in a higher proportion of subjects than was the case for other ICS (, 64% vs 5%, CP panel, 79% vs 62%). Less than 0% of subjects were apparently using ICS at an excessively high treatment intensity. was more frequently used in subjects with more severe asthma than, and more frequently used at a higher dose consistent with the greater severity. Otherwise, no other substantial differences in clinical or demographic characteristics were observed between subjects prescribed fluticasone propionate and those prescribed other ICS in this study of patients treated by GP and CP healthcare settings in France. 7