AHEAD COSMOS and COMPASS Studies

The AHEAD Study

Run-in AHEAD: Study Design 2 inh. budesonide/formoterol 160/4.5 µg b.i.d. plus as-needed (n=1154) 1 inh. fluticasone/salmeterol 50/500 µg b.i.d. plus terbutaline 0.4 mg as-needed (n=1155) Visit: Week: – Six-month, double-blind, double-dummy Enrolled: 3346 Randomized: 2309 Randomization *Only if taken as maintenance treatment before study entry Regular ICS ≥500 µg plus LABA* R Bousquet et al. AHEAD trial. Respir Med 2008; accepted.

Patient Characteristics Characteristics Flu/salm + SABA n=1155 SMART n=1154 Males, n (%)444 (38)443 (38) Mean age, years (range)39 (12-80)40 (12-80) Mean FEV 1, % predicted*71 70 Mean reversibility in FEV 1, % 24 Mean ICS at entry,  g/day Long-acting  2 -agonists, n (%) 622 (54)645 (56) Mean SABA use, inh./day Mean % nights with awakenings32 Bousquet et al. AHEAD trial. Respir Med 2008; accepted. SMART = Symbicort Maintenance And Reliever Therapy Symbicort = budesonide/formoterol (bud/form) Seretide = fluticasone/salmeterol (fu/salm) *Pre-bronchodilator

Time to First and Second Severe Exacerbations SMART Flu/salm + SABA Days since randomization Patients with exacerbation (%) st exacerbation (primary variable) nd exacerbation 1 st exacerbation, SMART vs. flu/salm+SABA: 18% difference in exacerbation risk, P=0.12

Cumulative Rate of Severe Exacerbations Exacerbations/patient SMART Flu/salm + SABA Days since randomization P<0.05 SMART reduced rate by 21% vs. Flu/salm + SABA

Reduction in Exacerbation Risk and Rate by Event Type *P <0.05; a Extrapolated from 6-month study 31* Events/patient/yearª 34*39 (3)59 (5)No.(%) patients Hospitalization/ ER treatment 21* Events/patient/yearª (9)130 (11)No. (%) patients All exacerbations SMART n=1151 Flu/salm + SABA n=1153 % Reduction SMART vs. flu/salm + SABA Treatment group

Severe Exacerbations by Type SMART Flu/salm + SABA Hospitalizations/ ER visits Oral steroid courses Exacerbation subtypes Total exacerbations No. of events * *P <0.05

Cumulative Rate of Hospitalizations/ ER Treatments Due to Asthma Days since randomization Hospitalization/ER treatment/patient SMART Flu/salm + SABA P< SMART reduced rate by 31% vs. flu/salm + SABA

As-needed Use and Symptom Score During Exacerbations SMART Flu/salm + SABA 15 Days relative to start of exacerbation Total asthma symptom score Total asthma symptom score * Total number of as-needed inhalations Total number of as-needed inhalations * SMART Seretide + SABA 15 Days relative to start of exacerbation * Number of events: SMART, 137; flu/salm +SABA,

Additional Treatments for Severe Exacerbations (descriptive statistics) Oral steroids added 60% fewer days with SMART days % difference SMART vs. flu/salm + SABA days Beta 2 -agonists added Xanthines added days 59% fewer days with SMART 17% fewer days with SMART

Reduction in Exacerbation Rates in Patients Ever Using >4 Inh. As-Needed/day (mechanism of action analysis) **P <0.01 from post-hoc analysis of patients with at least 1 study day with high as-needed use. a Extrapolated from data in patients after the first day with greater than 4 as-needed inh. of reliever therapy 53** Events/patient/year ª Hospitalization/ ER treatment 41** Events/patient/yearª All exacerbations SMART 305 (26%) Flu/salm + SABA 333 (29%) Subgroup N (%) % reduction SMART vs. flu/salm + SABA Subgroup with high use

Change in Awakenings Due to Asthma Awakenings (%) Flu/salm + SABA SMART Run-inTreatmentRun-inTreatment NS

Flu/salm + SABA SMART As-needed free days (%) Run-in Treatment Run-in Treatment NS Change in As-needed Inhalation-free Days

* Asthma control days = symptom- & rescue-free days plus awakening-free nights Change in Asthma Control Days* 60 Asthma control days (%) Flu/salm + SABASMART Run-inTreatmentRun-inTreatment NS

Day-to-Day Asthma Control P= As-needed inh.- free days, % P= Awakenings, % P= Evening PEF, L/min P= Total daily symptom score (0-6) P= Symptom free days, % -1.3P=0.36 SMART n=1151 Flu/salm + SABA n=1153 P= Morning PEF, L/min P= Asthma control days, % -1.2 Total daily as-needed inh. SMART vs. Flu/salm + SABA P value Adjusted mean change

Daily Mean Use of As-needed Inhalations Inhalations/24h 160 SMART Flu/salm + SABA Days since randomization P=NS

Percentage of Days with Different Levels of As-needed Use As-needed inhalations >8 Mean % of days 0 SMART Flu/salm + SABA No as-needed use on 59% of days in both groups >4 inh. as needed: Flu/salm + SABA: 3.6 % SMART: 2.7 %

Distribution of Average Daily Reliever Use Percentiles 90 th 25 th 10 th 75 th Median Average daily no. of as-needed inh SMARTFlu/salm + SABA % of patients in both groups used < 0.51 inh./day as-needed 25% of patients in both groups used <1 inh./week as-needed

Load Corticosteroid Load * Adapted from GINA 2006, page No. of courses Oral corticosteroid use/group Adjusted (BDP equivalent) * Not adjusted (FP vs. BUD) Mean ICS dose, maintenance plus as needed (  g/day) SMART n=1151 Flu/salm + SABA n=1153 Level of use

Distribution of Mean Daily Budesonide Dose in the SMART Group Mean budesonide dose (µg/day) > Patients (%) 0 No extra prn <1 inh./day prn <2 inh./day prn <3 inh./day prn >4 inh./day prn <4 inh./day prn

Distribution of Mean Daily ICS Dose in BDP Equivalents* vs. Fluticasone/Salmeterol Group > Patients (%) 0 Flu/salm 1000/daily = 2000 µg/daily BDP equivalents >90% of SMART patients use a lower daily ICS dose vs. the prescribed dose of flu/salm *Adapted from GINA 2006, page 29 Mean daily inhaled ICS dose (BDP equiv. µg/day)

Summary of Adverse Events AE = adverse event; SAE = serious adverse event; DAE = discontinuation due to adverse event *Includes one death due to typhoid fever Flu/salm + SABA n=1153 SMART n=1151 No. (%) of pts. with AEs All events460 (40)451 (39) Asthma7 (1)8 (1) No. (%) of pts. with SAEs All events31 (3)30* (3) Asthma5 (<0.5) No. (%) of pts. with DAEs All events20 (2)11 (1) Asthma 3 (<0.5)

The COSMOS Study

COSMOS Study Design Symbicort 2 inh. 160/4.5 µg + Symbicort as needed Symbicort 4 inh. 160/4.5 µg + Symbicort as needed Run-in: 2 weeks Randomized, open-label effectiveness study (N=2,143) ICS  500 µg/day  LABA Weeks Dose titration phase (at scheduled or unscheduled visits) R Seretide 2 inh. 50/100 µg + salbutamol as needed Seretide 2 inh. 50/500 µg + salbutamol as needed Seretide 2 inh. 50/250 µg + salbutamol as needed Inh.=inhalations; Seretide=fluticasone/salmeterol (flu/salm); Symbicort=budesonide/formoterol (bud/form) Adapted from Vogelmeier et al. Eur Respir J 2005;26:

COSMOS Examined Two Treatment Concepts Daily asthma medication Bud/form prn (patient) Salbutamol prn (patient) prn=as-needed use Flu/salm group Bud/form group 2 inh. 50/100 µg 2 inh. 50/500 µg 2 inh. 50/250 µg Titration (doctor) 2 inh. 160/4.5 µg 4 inh. 160/4.5 µg Titration (doctor) (up to 4 different inhalers) (1 inhaler) Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Patient Characteristics SMARTFlu/salm+SABA (n=1067) (n=1076) Mean SABA use, inh./day Mean FEV 1, % predicted* Males, n (%) 451 (42)429 (40) Mean age, years (range) 45 (12-80) 45 (12-84) 73 Long-acting  2 -agonists, % 38 Mean ICS at entry,  g/day Characteristic Mean reversibility in FEV 1, % 12.5 Smoking pack-years55 *Pre-bronchodilator SMART=Symbicort Maintenance And Reliever Therapy Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Patient Flow Enrolled: 2509 Randomized: (84%) 930 (87%) Completed on treatment : Flu/salm: 1076 Bud/form: 1067 Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Risk of Having a First Severe Exacerbation Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Cumulative Rate of Severe Exacerbations Adapted from Vogelmeier et al. Eur Respir J 2005;26:

COSMOS: ICS Dose and Exacerbation Rate Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Severe Exacerbations Total exacerbations SMART Flu/salm+SABA Exacerbation subtypes Unscheduled visits only Oral steroid courses without hospital/ER visits Hospitalizations/ ER visits * Poisson regression analysis P<0.01* Adapted from Vogelmeier et al. Eur Respir J 2005;26:

16% 37% * Flu/salm (7.2 days/event) vs. SMART (5.9 days/event) 34% 24% Exacerbation Burden (descriptive statistics) Unscheduled visits Oral steroid days Hospital days ER visits 154 to to to to 59 * Reduction (%) with SMART vs. Flu/salm+SABA Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Both Regimens Provide Sustained Increases in Pre- and Post-bronchodilator FEV 1 P=0.07 (pre-terbutaline) SMART Flu/salm+SABA Mean FEV 1 (L) P<0.05 (post-terbutaline) Weeks Titration phase Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Self-reported Relief Medication Use (estimated for two weeks prior to each visit) Treatment Flu/salm: 0.9 inh./day Bud/form: 0.6 inh./day Reliever use (mean inh./day) SMART Flu/salm (as-needed salbutamol) Weeks Baseline Flu/salm: 2.7 inh./day Bud/form: 2.6 inh./day P< Titration phase Adapted from Vogelmeier et al. Eur Respir J 2005;26:

COSMOS: ICS Dose and Rescue Use Titration phase Titration phase Time post-randomization (days) Flu/salm Bud/form maintenance + as needed Bud/form maintenance only Total ICS dose  g/day (BDP equivalents) As-needed rescue (inh./day) Difference overall 38% P>0.001 Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Patients with Low As-needed Use at 12 Months % (n=688) 76% (n=787) 34% (n=350) 24% (n=247) Patients (%) Odds of being well-controlled were increased by 68% with SMART (P<0.01) Well-controlled (<4 inh./week as needed)* Not well-controlled (>4 inh./week as needed)* SMART Flu/salm * A criterion for well-controlled asthma in the GOAL study (Bateman et al. Am J Respir Crit Care Med 2004;170(8): ) Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Maintenance & As-needed Use (Assessed at the final visit) High Patients (%) Well-controlled (<4 inh./week as needed) Not well-controlled (>4 inh./week as needed) SMART Flu/salm Maintenance ICS level* Medium Low *As defined by GINA 2002 Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Symptom Control Questionnaire ACQ 5 overall score (0–6) P=0.07 SMART Flu/salm+SABA Weeks Titration phase ACQ 5 was a short form of the asthma control questionnaire used to assess symptoms. The ACQ 5 excluded control measures related to as-needed medication use and lung function. Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Bud/form (maintenance + as needed) Flu/salm BDP equivalent total daily ICS dose (µg) Bud/form (maintenance only) Titration phase Mean Total ICS Dose Over Time Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Final Prescribed Maintenance ICS Dose (% of patients on dose) ~1-2% of subjects in both groups used a non-protocolled dose (not shown) Low* (BUD  g/day) SMART31% 68% 200 Low* 500 Medium* 1000 High* Flu/salm % 14% 58% (FP  g/day) 640 Medium* * As defined by GINA 2002 Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Overall Steroid Load Inhaled dose in micrograms  g/day) Flu/salm SMART FP 583  g/day BUD 653  g/day 91  g prn 562  g regular Days with oral steroid use * Flu/salm SMART a Due to asthma exacerbation Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Total Inhaler Prescriptions (Mean number of prescribed study inhalers/patient/year) Flu/salm + albuterol SMART Flu/salm (100/250/500 strengths) + albuterol prn SMART (160/4.5 strength) for maintenance + as needed 16.6 Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Health-related Quality of Life SymptomsActivityEmotionalEnvironmentalOverall Flu/salm+SABA SMART Adjusted mean change in AQLQs scores Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Cost Difference SMART vs. Flu/salm+SABA GERMANY a FRANCE ITALY UK b Cost difference/patient-year (€) Direct costs Total costs Cost increase with SMART Cost decrease with SMART a Differences in direct and total costs were statistically significant only in Germany b 1 £=1.45 Euro (Dec 2004) Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Mean exposure time (days) Discontinuations due to adverse events, n (%) 27 (3)28 (3) Discontinuations due to other reasons, n (%) 107 (10)136 (13) Number of patients completing the study treatment Overview of Exposure SMART (n=1064) Flu/salm+SABA (n=1071) Adapted from Vogelmeier et al. Eur Respir J 2005;26:

Number of Patients with the Most Frequently Reported Adverse Events (>3%) Nasopharyngitis110 (10)105 (10) Bronchitis86 (8)77 (7) Upper respiratory tract infection77 (7)79 (7) Sinusitis53 (5)31 (3) SMART (n=1064) n (%) Preferred term Flu/salm+SABA (n=1071) n (%) Adapted from Vogelmeier et al. Eur Respir J 2005;26:

The COMPASS Study

Study Objective  To compare the efficacy and safety of budesonide/formoterol (bud/form) maintenance and reliever therapy (SMART) with:  Double maintenance dose of bud/form  Fluticasone/salmeterol (flu/salm) at its most frequently prescribed dose Adapted from Kuna et al. Int J Clin Pract 2007;61(5): SMART = Symbicort Maintenance And Reliever Therapy

Run-in COMPASS: Study Design Flu/salm 25/125 µg 2 inh. bd + Bricanyl as reliever (n=1123) Bud/form 320/9 µg 1 inh. bd + terbutaline as reliever (n=1105) Bud/form 160/4.5 µg 1 inhalation bd + bud/form as reliever (SMART) (n=1107) Visit: Week: Six-month, double-blind, double-dummy Regular ICS ≥500 µg R Enrolled: n=4399 Randomized: n=3335 Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Patients  Age  12 years  ≥1 exacerbation in the last year  ≥500 µg/day budesonide, fluticasone, ≥1000 µg other ICS  ≥ 50% predicted FEV 1 (pre-bronchodilator)  ≥12% reversibility in FEV 1 Randomization criteria:  Terbutaline use on ≥5 of the last 7 days of the run-in   10 inh/day of terbutaline on all days of the run-in

Patient Characteristics * Pre-bronchodilator SMARTBud/form (n=1107) (n=1105) Mean SABA use, inh./day during run-in 2.3 Mean FEV 1, % predicted * Males, n (%) 479 (43)448 (41) Mean age, years (range) 38 (11-79) 38 (12-83) Long-acting  2 -agonists, % Mean ICS at entry,  g/day Characteristics Mean reversibility in FEV 1, % Flu/salm (n=1123) Mean % nights with awakenings during run-in (43) 38 (12-83) Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Severe Exacerbations A deterioration in asthma leading to:  Emergency room treatment/hospitalization  Oral steroids for  3 days Primary variable: time to first severe exacerbation Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Time to First Severe Exacerbation Patients with severe exacerbations (%) Days since randomization P<0.05 NS P<0.01 SMART decreased instantaneous risk by:  33% vs. flu/salm+SABA  26% vs. bud/form+SABA Flu/salm+SABA Bud/form+SABA SMART Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Cumulative Rate of Severe Exacerbations Exacerbations/patient Days since randomization P<0.001 P<0.01 NS SMART reduced rate of exacerbations by:  39% vs. flu/salm+SABA  28% vs. bud/form+SABA Flu/salm+SABA Bud/form+SABA SMART Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Total Severe Exacerbations Patients with event(s) (%) Days since randomization Flu/salm: 208 events SMART: 125 events Bud/form: 173 events Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Total number of events Subtypes of severe events Oral steroids only Hospitalizations/ ER treatments Flu/salmBud/form SMART P< P< Severe Exacerbations by Subtype Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Reduction in Exacerbation Risk and Rate Extrapolated from the six-month study ªExtrapolated from the six-month study No. (%) patients 31* 50 (5)70 (6) Hospitalization/ER treatment 33 ** 126 (11) 138 (12) All exacerbations % reduction Flu/salm Bud/form ***P<0.001; **P<0.01; *P<0.05 SMART vs. flu/salm SMART 3 26* 48 (4) 94 (9) 39 *** ** 0.23 Events/patient/year┼ SMART vs. bud/form No.(%) patients Events/patient/year┼ 39 ** Treatment group * Bud/form vs. flu/salm Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Days since randomization Events/patient Cumulative Rate of Hospitalizations/ ER Treatments Due to Asthma P<0.05 both bud/form groups vs. flu/salm group Flu/salm+SABA Bud/form+SABA SMART Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

x Mean am PEF (L/min) Mean reliever use (inh./day) Mean Profile of Severe Exacerbations Daily PEF and reliever use 14 days prior to and after events Bud/form SMART n=94 n=126n=138 Flu/salm Run-in values for whole population Day relative to start of exacerbation x x x x x x x Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Flu/salm+SABA Bud/form+SABA SMART Asthma Control Days Asthma control days (%) Run-in Treatment Run-in Treatment Run-in Treatment NS Asthma control days = symptom & rescue-free days Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Days since randomization Reliever use (Inh./day) Morning PEF (L/min) Seretide+SABA Symbicort+SABA Symbicort SMART Sustained Improvements in PEF and Reliever Use SMART vs both groups (NS) SMART vs. both groups (NS) Adapted from Kuna et al. Int J Clin Pract 2007;61(5): Seretide = flu/salm; Symbicort = bud/form

Absolute FEV 1 Values Mean FEV 1 (L) Flu/salm + SABA Bud/form + SABA SMART Weeks NS Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Average Daily Reliever Use for All Patients Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Occasional High Use of Reliever Therapy No. of patients with >4 inh./day 491 > 1 day > 10 days SMARTSymbicort ( n=1103) (n=1099) Level of use Flu/sal (n=1118) No. of pts. with >8 inh/day 112 > 1 day > 10 days Adapted from Kuna et al, International Journal of Clinical Practice > 1 day > 10 days SMART ( n=1103) (n=1099) Level of use (n=1118)

Corticosteroid Load Mean ICS dose (  g/day) 500 Not adjusted (FP vs. BUD) BDP equivalents* SMARTBud/form ( n=1103) (n=1099) Level of use Flu/salm (n=1118) Oral corticosteroid use/group 148 No. of courses Days with use * Adapted from GINA Adapted from Kuna et al. Int J Clin Pract 2007;61(5):

Summary of Adverse Events 457 (41) 439(40) No. (%) of pts. with AEs 11 (1)13 (1) No. (%) of pts. with DAEs No. (%) of pts. with SAEs 1 0 No. of deaths SAE = serious adverse event ; DAE = discontinuation due to adverse event 10 (1) 428 (38) 1 7(1) 12 (1) All events Asthma 15 (1) All events Asthma 7 (1) 8 (1) 5 (<0.5) SMARTBud/form ( n=1103) (n=1099) Flu/salm (n=1119) All events Asthma 14 (1) 27 (2)20 (2) 31(3)39(4) 32 (3) Adapted from Kuna et al. Int J Clin Pract 2007;61(5):