AHEAD COSMOS and COMPASS

1
AHEAD COSMOS
and
COMPASS
Studies
2
The AHEAD Study
3
AHEAD Study Design
Six-month, double-blind, double-dummy
2 inh. budesonide/formoterol 160/4.5 µg b.i.d.
plus as-needed (n1154)
Run-in
Regular ICS 500 µg plus LABA
1 inh. fluticasone/salmeterol 50/500 µg b.i.d.
plus terbutaline 0.4 mg as-needed (n1155)
Enrolled 3346
Randomized 2309
Visit 1 2 3
4
5 Week 2 0 4
13 26

Randomization
Only if taken as maintenance treatment before
study entry
Bousquet et al. AHEAD trial. Respir Med 2008
accepted.
4
Patient Characteristics
Characteristics Flu/salm SABA n1155 SMART n1154
Males, n () 444 (38) 443 (38)
Mean age, years (range) 39 (12-80) 40 (12-80)
Mean FEV1, predicted 71 70
Mean reversibility in FEV1, 24 24
Mean ICS at entry, mg/day 720 705
Long-acting b2-agonists, n () 622 (54) 645 (56)
Mean SABA use, inh./day 2.3 2.2
Mean nights with awakenings 32 32
SMART Symbicort Maintenance And Reliever
Therapy Symbicort budesonide/formoterol
(bud/form) Seretide fluticasone/salmeterol
(fu/salm)
Pre-bronchodilator
Bousquet et al. AHEAD trial. Respir Med 2008
accepted.
5
Time to First and Second Severe Exacerbations
Patients with exacerbation ()
15
5
1st exacerbation (primary variable)
2nd exacerbation
4
10
3
2
5
1
0
0
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Days since randomization
1st exacerbation, SMART vs. flu/salmSABA 18
difference in exacerbation risk, P0.12
6
Cumulative Rate of Severe Exacerbations
Exacerbations/patient
0.3
SMART reduced rate by 21 vs. Flu/salm SABA
SMART
Flu/salm SABA
0.2
Plt0.05
0.1
0.0
0
30
60
90
120
150
180
Days since randomization
7
Reduction in Exacerbation Risk and Rate by Event
Type
P lt0.05 a Extrapolated from 6-month study
8
Severe Exacerbations by Type
P lt0.05
9
Cumulative Rate of Hospitalizations/ ER
Treatments Due to Asthma
Hospitalization/ER treatment/patient
0.2
SMART reduced rate by 31 vs. flu/salm SABA
SMART
Flu/salm SABA
0.1
Plt0.05
0.0
0
30
60
90
120
150
180
Days since randomization
10
As-needed Use and Symptom Score During
Exacerbations
Total asthma symptom score
Total number of as-needed inhalations
SMART
SMART
5
5
Seretide SABA
Flu/salm SABA
4.1
4
4
3.1
3.1
3
3
2.7
2
2
1
1
0
0
-12
-9
-6
-3
0
3
6
9
12
15
-12
-9
-6
-3
0
3
6
9
12
15
Days relative to start of exacerbation
Days relative to start of exacerbation
Number of events SMART, 137 flu/salm SABA,
173
11
(descriptive statistics)
Additional Treatments for Severe Exacerbations
difference SMART vs. flu/salm SABA
20
Xanthines added
Oral steroids added
Beta2-agonists added
0
1009-833 days
171-68 days
94-39 days
-20
17 fewer days with SMART
-40
-60
60 fewer days with SMART
59 fewer days with SMART
-80
12
Reduction in Exacerbation Rates in Patients Ever
Using gt4 Inh. As-Needed/day (mechanism of action
analysis)
reduction SMART vs. flu/salm SABA
Subgroup with high use
SMART 305 (26)
Flu/salm SABA 333 (29)
Subgroup N ()
All exacerbations
41
0.27
0.46
Events/patient/yearª
Hospitalization/ ER treatment
53
0.10
0.21
Events/patient/year ª
P lt0.01 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
13
Change in Awakenings Due to Asthma

Awakenings ()
NS
40
20
0
Run-in
Treatment
Run-in
Treatment
Flu/salm SABA
SMART
14
Change in As-needed Inhalation-free Days
As-needed free days ()
NS
60
40
20
0
Treatment
Run-in
Treatment
Run-in
SMART
Flu/salm SABA
15
Change in Asthma Control Days
Asthma control days ()
NS
60
40
20
0
Run-in
Treatment
Run-in
Treatment
Flu/salm SABA
SMART
Asthma control days symptom- rescue-free
days plus awakening-free nights
16
Day-to-Day Asthma Control
SMART vs. Flu/salm SABA P value
Adjusted mean change
SMART n1151
Flu/salm SABA n1153
P0.92
-0.90
-0.90
Total daily symptom score (0-6)
P0.73
36
37
Symptom free days,
-1.3
P0.36
-1.2
Total daily as-needed inh.
P0.56
46
47
As-needed inh.- free days,
P0.11
-20
-19
Awakenings,
P0.37
37
38
Asthma control days,
P0.67
27
28
Morning PEF, L/min
P0.42
23
22
Evening PEF, L/min
17
Daily Mean Use of As-needed Inhalations
18
Percentage of Days with Different Levels of
As-needed Use
Mean of days
60
No as-needed use on 59 of days in both groups
50
40
30
20
gt4 inh. as needed Flu/salm SABA 3.6 SMART
2.7
10
0
0
2
1
3
4
5
6
7
8
gt8
As-needed inhalations
19
Distribution of Average Daily Reliever Use
Average daily no. of as-needed inh.
4
Percentiles
90th
3
75th
Median
25th
10th
2
50 of patients in both groups used lt 0.51
inh./day as-needed 25 of patients in both
groups used lt1 inh./week as-needed
1
0.51
0.51
0
SMART
Flu/salm SABA
20
Corticosteroid Load
SMART n1151
Flu/salm SABA n1153
Level of use
Mean ICS dose, maintenance plus as needed (mg/day)
792
1000
Not adjusted (FP vs. BUD)
1238
2000
Adjusted (BDP equivalent)
Oral corticosteroid use/group
106
139
No. of courses
Adapted from GINA 2006, page 29

21
Distribution of Mean Daily Budesonide Dose in the
SMART Group
Patients ()
70
lt1 inh./day prn
60
50
40
30
lt2 inh./day prn
20
lt3 inh./day prn
No extra prn
lt4 inh./day prn
10
gt4 inh./day prn
0
640
641-800
801-960
961-1120
1121-1280
gt1281
Mean budesonide dose (µg/day)
22
Distribution of Mean Daily ICS Dose in BDP
Equivalents vs. Fluticasone/Salmeterol Group
Patients ()
Mean daily inhaled ICS dose (BDP equiv. µg/day)
70
60
50
40
Flu/salm 1000/daily 2000 µg/daily BDP
equivalents gt90 of SMART patients use a lower
daily ICS dose vs. the prescribed dose of flu/salm
30
20
10
0
1000
gt2000
1001- 1250
1251- 1500
1501- 1750
1751- 2000
Adapted from GINA 2006, page 29
23
Summary of Adverse Events
Flu/salm SABA n1153 SMART n1151
No. () of pts. with AEs
All events 460 (40) 451 (39)
Asthma 7 (1) 8 (1)
No. () of pts. with SAEs
All events 31 (3) 30 (3)
Asthma 5 (lt0.5) 5 (lt0.5)
No. () of pts. with DAEs
All events 20 (2) 11 (1)
Asthma 3 (lt0.5) 3 (lt0.5)
AE adverse event SAE serious adverse event
DAE discontinuation due to adverse event
Includes one death due to typhoid fever
24
The COSMOS Study
25
COSMOS Study Design
Inh.inhalations Seretidefluticasone/salmeterol
(flu/salm) Symbicortbudesonide/formoterol
(bud/form)
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
26
COSMOS Examined Two Treatment Concepts
Daily asthma medication
Bud/form group
Flu/salm group
(up to 4 different inhalers)
(1 inhaler)
prnas-needed use
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
27
Patient Characteristics
SMARTSymbicort Maintenance And Reliever Therapy
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
28
Patient Flow
Enrolled 2509
Randomized 2143
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
29
Risk of Having a First Severe Exacerbation
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
30
Cumulative Rate of Severe Exacerbations
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
31
COSMOS ICS Dose and Exacerbation Rate
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
32
Severe Exacerbations
Flu/salmSABA
SMART
Plt0.01
Exacerbation subtypes
400
329
300
70
280
70
255
62
217
50
200
50
50
42
200
174
39
30
30
120
100
10
10
40
0
Oral steroid courses without hospital/ER visits
Unscheduled visits only
Hospitalizations/ ER visits
Total exacerbations
Poisson regression analysis
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
33
Exacerbation Burden (descriptive statistics)
Reduction () with SMART vs. Flu/salmSABA
10
Unscheduled visits
Oral steroid days
Hospital days
ER visits
0
154 to 117
2978 to 1980
45 to 38
94 to 59
-10
-20
-30
-40
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
34
Both Regimens Provide Sustained Increases inPre-
and Post-bronchodilator FEV1
Mean FEV1 (L)
2.65
2.55
P0.07 (pre-terbutaline)
2.45
Flu/salmSABA
2.35
SMART
2.25
Weeks
0
4
12
26
52
Titration phase
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
35
Self-reported Relief Medication Use (estimated
for two weeks prior to each visit)
Reliever use (mean inh./day)
1.2
Flu/salm (as-needed salbutamol)
0.8
Plt0.001
SMART
0.4
0
Weeks
4
12
26
52
0
Treatment Flu/salm 0.9 inh./day Bud/form 0.6
inh./day
Baseline Flu/salm 2.7 inh./day Bud/form 2.6
inh./day
Titration phase
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
36
COSMOS ICS Dose and Rescue Use
Total ICS dose mg/day (BDP equivalents)
As-needed rescue (inh./day)
1500
1.0
1250
0.75
Difference overall 38 Pgt0.001
1000
750
0.50
500
Flu/salm
Bud/form maintenance as needed
0.25
Bud/form maintenance only
250
0
60
120
180
300
240
360
0
60
120
180
300
240
360
Titration phase
Titration phase
Time post-randomization (days)
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
37
Patients with Low As-needed Use at 12 Months
Odds of being well-controlled were increased by
68 with SMART (Plt0.01)
Patients ()
(n787)
76
80
(n688)
66
60
(n350)
40
34
(n247)
24
20
0
Flu/salm
SMART
Flu/salm
SMART
Well-controlled (lt4 inh./week as needed)
Not well-controlled (gt4 inh./week as needed)
A criterion for well-controlled asthma in the
GOAL study (Bateman et al. Am J Respir Crit Care
Med 2004170(8)836-44 )
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
38
Maintenance As-needed Use (Assessed at the
final visit)
As defined by GINA 2002
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
39
Symptom Control Questionnaire
ACQ5 overall score (06)
2.0
1.8
Flu/salmSABA
1.6
SMART
1.4
P0.07
1.2
1.0
Weeks
0
4
12
26
52
Titration phase
ACQ5 was a short form of the asthma control
questionnaire used to assess symptoms.
The ACQ5 excluded control measures related to
as-needed medication use and lung function.
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
40
Mean Total ICS Dose Over Time
BDP equivalent total daily ICS dose (µg)
Flu/salm
Bud/form (maintenance as needed)
1400
Bud/form (maintenance only)
1200
1000
800
600
400
200
0
0
60
120
180
240
300
360
Titration phase
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
41
Final Prescribed Maintenance ICS Dose ( of
patients on dose)
As defined by GINA 2002
1-2 of subjects in both groups used a
non-protocolled dose (not shown)
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
42
Overall Steroid Load
Inhaled dose in micrograms (mg/day)
Days with oral steroid use
3500
700
2978
2500
500
1980
1500
300
100
500
0
Flu/salm
SMART
Flu/salm
SMART
aDue to asthma exacerbation
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
43
Total Inhaler Prescriptions(Mean number of
prescribed study inhalers/patient/year)
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
44
Health-related Quality of Life
Adjusted mean change in AQLQs scores
Flu/salmSABA
SMART
0.8
0.6
0.4
0.2
0
Symptoms
Activity
Emotional
Environmental
Overall
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
45
Cost Difference SMART vs. Flu/salmSABA
aDifferences in direct and total costs were
statistically significant only in Germany
b1 1.45 Euro (Dec 2004)
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
46
Overview of Exposure

Mean exposure time (days) 332 325
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 930 907
SMART (n1064)
Flu/salmSABA (n1071)
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
47
Number of Patients with the Most Frequently
Reported Adverse Events (gt3)

Nasopharyngitis Nasopharyngitis 110 (10) 105 (10) 105 (10)
Bronchitis Bronchitis 86 (8) 77 (7) 77 (7)
Upper respiratory tract infection Upper respiratory tract infection 77 (7) 79 (7) 79 (7)
Sinusitis Sinusitis 53 (5) 31 (3) 31 (3)
SMART (n1064)n ()
Flu/salmSABA (n1071)n ()
Preferred term
Adapted from Vogelmeier et al. Eur Respir J
200526819-28.
48
The COMPASS Study
49
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

SMART Symbicort Maintenance And Reliever Therapy
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
50
COMPASS Study Design
Six-month, double-blind, double-dummy
Flu/salm 25/125 µg 2 inh. bd Bricanyl as
reliever (n1123)
Run-in
Regular ICS 500 µg
Bud/form 320/9 µg 1 inh. bd terbutaline as
reliever (n1105)
R
Enrolled n4399
Randomized n3335
Bud/form 160/4.5 µg 1 inhalation bd bud/form as
reliever (SMART) (n1107)
Visit 1 2 3
4
5 Week -2 0 8
16
24

Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
51
Patients

• Age ?12 years
• 1 exacerbation in the last year
• 500 µg/day budesonide, fluticasone, 1000 µg
  other ICS
• 50 predicted FEV1 (pre-bronchodilator)
• 12 reversibility in FEV1
• 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

52
Patient Characteristics
SMART
Bud/form
Flu/salm
Characteristics
(n1107)
(n1105)
(n1123)
Males, n ()
479 (43)
448 (41)
484 (43)
Mean age, years (range)
38 (11-79)
38 (12-83)
38 (12-83)
Mean FEV1, predicted
72
73
73
Mean reversibility in FEV1,
25
24
23
Mean ICS at entry, mg/day
740
750
744
Long-acting b2-agonists,
47
46
47
Mean SABA use, inh./day during run-in
2.3
2.3
2.3
Mean nights with awakenings during run-in
34
33
32
Pre-bronchodilator
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
53
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
200761(5)725-36.
54
Time to First Severe Exacerbation
Patients with severe exacerbations ()
15
NS
Plt0.01
10
Plt0.05

• SMART decreased instantaneous risk by
• 33 vs. flu/salmSABA
• 26 vs. bud/formSABA

5
0
Days since randomization
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
55
Cumulative Rate of Severe Exacerbations
Exacerbations/patient
NS
Plt0.001
Plt0.01

• SMART reduced rate of exacerbations by
• 39 vs. flu/salmSABA
• 28 vs. bud/formSABA

40
0
60
80
100
120
140
160
20
Days since randomization
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
56
Total Severe Exacerbations
Flu/salm 208 events
15
10
5
0
0
20
40
60
80
100
120
140
160
180
Bud/form 173 events
15
Patients with event(s) ()
10
5
0
0
20
40
60
80
100
120
140
160
180
SMART 125 events
15
10
5
0
0
20
40
60
80
100
120
140
160
180
Days since randomization
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
57
Severe Exacerbations by Subtype
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
58
Reduction in Exacerbation Risk and Rate
Treatment group
reduction
SMART

• Bud/form
• vs. flu/salm

• SMART
• vs. flu/salm

SMART vs. bud/form
Bud/form
Flu/salm
All exacerbations
33
126 (11)
26
94 (9)
138 (12)
No. () patients
9
39
0.32
28
0.23
0.38
Events/patient/year
15
Hospitalization/ER treatment
31
50 (5)
70 (6)
3
No.() patients
29
48 (4)
12
Events/patient/year
0.16
39
0.10
0.10
32
Plt0.001 Plt0.01 Plt0.05
ªExtrapolated from the six-month study
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
59
Cumulative Rate of Hospitalizations/ER
Treatments Due to Asthma
Events/patient
Plt0.05 both bud/form groups vs. flu/salm group
40
0
60
80
100
120
140
160
20
Days since randomization
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
60
Mean Profile of Severe Exacerbations
Daily PEF and
reliever use 14 days prior to and after events
Mean am PEF (L/min)
Mean reliever use (inh./day)
360
5
x
340
x
x
4
320
300
3
280
x
x
x
x
2
260
240
1
220
200
0
Day relative to start of exacerbation
Run-in values for whole population
Bud/form
SMART
Flu/salm
x
n94
n126
n138
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
61
Asthma Control Days
Asthma control days ()
NS
60
40
20
0
Run-in
Run-in
Run-in
Treatment
Treatment
Treatment
Flu/salmSABA
Bud/formSABA
SMART
Asthma control days symptom rescue-free days
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
62
Sustained Improvements in PEF and Reliever Use
Reliever use(Inh./day)
Morning PEF (L/min)
SMART vs both groups (NS)
2.8
380
370
2.0
360
350
SMART vs. both groups (NS)
1.2
340
330
0.4
0
40
80
120
160
0
40
80
120
160
Days since randomization
Seretide flu/salm Symbicort bud/form
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
63
Absolute FEV1 Values
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
64
Average Daily Reliever Use for All Patients
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
65
Occasional High Use of Reliever Therapy
Adapted from Kuna et al, International Journal of
Clinical Practice 2007.
66
Corticosteroid Load
SMART
Bud/form
Flu/salm
Level of use
(n1103)
(n1099)
(n1118)
Mean ICS dose (mg/day)
483
640
500
Not adjusted (FP vs. BUD) BDP equivalents
1000
755
1000
Oral corticosteroid use/group
86
139
148
No. of courses Days with use
1132
1044
619
Adapted from GINA
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.
67
Summary of Adverse Events
SMART
Bud/form
Flu/salm
(n1103)
(n1099)
(n1119)
No. of deaths
1
0
1
No. () of pts. with SAEs
32 (3)
31(3)
39(4)

All events Asthma
12 (1)
7(1)
15 (1)
No. () of pts. with DAEs
11 (1)
13 (1)
10 (1)
All events Asthma
7 (1)
8 (1)
5 (lt0.5)
No. () of pts. with AEs
439(40)
457 (41)
428 (38)
All events Asthma
14 (1)
27 (2)
20 (2)
SAE serious adverse event DAE
discontinuation due to adverse event
Adapted from Kuna et al. Int J Clin Pract
200761(5)725-36.