ahead cosmos and compass studies. the ahead study

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: 1 2 3 4 5

Week: –2 0 4 13 26

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

CharacteristicsFlu/salm + SABA

n=1155SMART n=1154

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, g/day 720 705

Long-acting 2-agonists, n (%) 622 (54) 645 (56)

Mean SABA use, inh./day 2.3 2.2

Mean % nights with awakenings 32 32

Bousquet et al. AHEAD trial. Respir Med 2008; accepted.

SMART = Symbicort Maintenance And Reliever TherapySymbicort = 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 (%)

0 30 60 90 120 150 1800

5

10

15 1st exacerbation (primary variable)

0 30 60 90 120 150 18000

5

3

2

1

4

2nd exacerbation

1st exacerbation, SMART vs. flu/salm+SABA: 18% difference in exacerbation risk, P=0.12

Cumulative Rate of Severe Exacerbations

Exacerbations/patient

SMARTFlu/salm + SABA


0 30 60 90 120 150 180

0.0

0.1

0.2

0.3

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*0.090.13Events/patient/yearª

34*39 (3)59 (5)No.(%) patients

Hospitalization/

ER treatment

21*0.250.31Events/patient/yearª

18108 (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

86

100

25

50

75

150

100

125

Exacerbation subtypes

0

10

30

50

70

51

73

0

90

Total exacerbations

No. of events

25

50

75

150 137 *

173

100

125

0

175

*P <0.05

Cumulative Rate of Hospitalizations/ER Treatments Due to Asthma


Hospitalization/ER treatment/patient


0.0

0.1

0.2

P<0.05

0 30 60 90 120 150 180

SMART reduced rate by 31% vs. flu/salm + SABA

As-needed Use and Symptom Score During Exacerbations

00

11

22

33

44

55

-12-12 -9-9 -6-6 -3-3 00 33 66 99 1212

SMART Flu/salm + SABA

1515

Days relative to start of exacerbationDays 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 *

00

11

22

33

44

55

-12-12 -9-9 -6-6 -3-3 00 33 66 99 1212

SMART Seretide + SABA

1515

Days relative to start of exacerbationDays relative to start of exacerbation

* Number of events: SMART, 137; flu/salm +SABA, 173

4.1

3.1

2.7

3.1

Additional Treatments for Severe Exacerbations(descriptive statistics)

-80

-60

-40

-20

0

20Oral steroids

added

60% fewer days with SMART

171-68 days171-68 days

% difference SMART vs. flu/salm + SABA

1009-833 days1009-833 days

Beta2-agonistsadded

Xanthinesadded

94-39 days94-39 days



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**0.100.21Events/patient/year ª

Hospitalization/ ER treatment

41**0.270.46Events/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 (%)

0

20

40

Flu/salm + SABA SMARTRun-in Treatment Run-in Treatment

NS

0

20

40

60

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 (%)

0

20

40

Flu/salm + SABA SMARTRun-in Treatment Run-in Treatment

NS

Day-to-Day Asthma Control

P=0.56 4647As-needed inh.- free days, %

P=0.11-20-19Awakenings, %

P=0.42 23 22Evening PEF, L/min

P=0.92 -0.90 -0.90Total daily symptom score (0-6)

P=0.7336 37Symptom free days, %

-1.3 P=0.36

SMART n=1151

Flu/salm + SABA

n=1153

P=0.67 27 28Morning PEF, L/min

P=0.37 37 38Asthma control days, %

-1.2Total daily as-needed inh.

SMART vs.

Flu/salm + SABA P value

Adjusted mean change

Daily Mean Use of As-needed Inhalations

0.4

0.8

1.2

1.6

2.0

2.4

0 20 40 60 80 100 120 140 180

Inhalations/24h

160

SMART

Flu/salm + SABA


P=NS

Percentage of Days with Different Levels of As-needed Use

As-needed inhalations

10

20

30

40

50

60

0 21 3 4 5 6 7 8 >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

90th

25th

10th

75th

Median

Average daily no. of as-needed inh.

0

2

3

4

1


0.51 0.51

50% of patients in both groups used < 0.51 inh./day as-needed

25% of patients in both groups used <1 inh./week as-needed

Corticosteroid Load Load

*Adapted from GINA 2006, page 29

106139No. of courses

Oral corticosteroid use/group

12382000 Adjusted (BDP equivalent)*

792 1000 Not adjusted (FP vs. BUD)

Mean ICS dose, maintenance plus as needed (g/day)

SMARTn=1151

Flu/salm + SABAn=1153Level of use

Distribution of Mean Daily Budesonide Dose in the SMART Group

Mean budesonide dose (µg/day)

640 641-800 801-960 961-1120 1121-1280 >1281

10

20

30

40

50

60

70

Patients (%)

0

No extraNo extraprnprn

<<1 inh./day1 inh./dayprnprn



>4 inh./day>4 inh./dayprnprn


Distribution of Mean Daily ICS Dose in BDP Equivalents* vs. Fluticasone/Salmeterol Group

1000 1001-1250

1251-1500

1501-1750

1751-2000

>2000

10

20

30

40

50

60

70

Patients (%)

0

Flu/salm 1000/daily = 2000 µg/dailyBDP 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 + SABAn=1153

SMARTn=1151

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 (<0.5) 5 (<0.5)

No. (%) of pts. with DAEs

All events 20 (2) 11 (1)

Asthma 3 (<0.5) 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

0 4 12 26 52Weeks

Dose titration phase (at scheduled or unscheduled visits)

R

Seretide 2 inh. 50/100 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;26:819-28.

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 2 inh. 160/4.5 µgµg

4 inh. 160/4.5 4 inh. 160/4.5 µg µg Titration(doctor)

(up to 4 different inhalers) (1 inhaler)



SMARTFlu/salm+SABA

(n=1067)(n=1076)

Mean SABA use, inh./day 2.62.7

Mean FEV1, % predicted*

Males, n (%) 451 (42)429 (40)

Mean age, years (range) 45 (12-80)45 (12-84)

7373

Long-acting 2-agonists, % 38 38

Mean ICS at entry, g/day 888881

Characteristic

Mean reversibility in FEV1, % 12.5 12.5

Smoking pack-years 5 5

*Pre-bronchodilator

SMART=Symbicort Maintenance And Reliever Therapy


Patient Flow

Enrolled: 2509

Randomized: 2143

907 (84%)

930 (87%)930 (87%)Completed on treatment:

Flu/salm: 1076 Bud/form: 1067


Risk of Having a First Severe Exacerbation

0 80 160 240 320 Time (days)

Patients with exacerbation (%)

Risk reduction:25% (CI: 7, 39%)

SMARTFlu/salm+SABA

5

15

20

25

10

Titration phase

P=0.01

0



Event rateFlu/salm 0.31SMART 0.24

Titration phase

Events/patient/year

0.08

0.16

0.24

0.32

NNT=14

Decrease in rate: 22% (CI: 9, 44%)

P<0.01

Time (days)0 80 160 240 320

SMARTFlu/salm+SABA


COSMOS: ICS Dose and Exacerbation Rate

1250

1000

500

250

1500

750

Titration phase

0.08

0.16

0.24

0.32

0 60 120 180 300240 360 0 60 120 180 300240 360

Titration phase

Time post-randomization (days)

Flu/salm Bud/form maintenance + as neededBud/form maintenance only

Total ICS dose mg/day (BDP equivalents) Cumulative exacerbation rate

Difference in rate=

0.24 vs 0.31

Difference in rate= 0.03 vs 0.04


Severe Exacerbations

Total exacerbations

SMARTFlu/salm+SABA

Exacerbation subtypes

Unscheduled

visits only

10

30

50

70

39

62

Oral steroid courses

without

hospital/ER visits

40

120

200

280

174

217

Hospitalizations/

ER visits

10

30

50

70

42

50

*Poisson regression analysis

0

100

200

300

P<0.01*

255

329

400


16%

37%

* Flu/salm (7.2 days/event) vs. SMART (5.9 days/event)

34%

24%

Exacerbation Burden (descriptive statistics)

-40

-30

-20

-10

0

10Unscheduled

visitsOral steroid

daysHospital

daysER visits

154 to 117154 to 117 2978 to 19802978 to 1980 45 to 3845 to 38 94 to 5994 to 59**

Reduction (%) with SMART vs. Flu/salm+SABA


Both Regimens Provide Sustained Increases inPre- and Post-bronchodilator FEV1

P=0.07 (pre-terbutaline)

SMART

Flu/salm+SABA

2.25

2.35

2.45

2.55

2.65

Mean FEV1 (L)

P<0.05 (post-terbutaline)

0 4 12 26 52 Weeks

Titration phase


Self-reported Relief Medication Use (estimated for two weeks prior to each visit)

Treatment Flu/salm: 0.9 inh./dayBud/form: 0.6 inh./day

Reliever use (mean inh./day)

1.2

0.8

0.4

0

SMART

Flu/salm

(as-needed salbutamol)

4 12 26 52Weeks

Baseline Flu/salm: 2.7 inh./dayBud/form: 2.6 inh./day

P<0.001

0

Titration phase


COSMOS: ICS Dose and Rescue Use

1250

1000

500

250

1500

750

Titration phase

0.25

0.50

0.75

1.0

0 60 120 180 300240 360 0 60 120 180 300240 360

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


Patients with Low As-needed Use at 12 Months

0

20

40

60

80

66%(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 SMARTFlu/salm Flu/salm

*A criterion for well-controlled asthma in the GOAL study (Bateman et al. Am J Respir Crit Care Med 2004;170(8):836-44 )


Maintenance & As-needed Use (Assessed at the final visit)

High

0

20

40

60

80

Patients (%)

Well-controlled (<4 inh./week as needed)

Not well-controlled(>4 inh./week as needed)

SMART SMARTFlu/salm Flu/salm

Maintenance ICS level*

Medium

Low

*As defined by GINA 2002


Symptom Control Questionnaire

ACQ5 overall score (0–6)

1.0

1.2

1.4

1.6

1.8

2.0

0 4 12 26 52

P=0.07

SMART

Flu/salm+SABA

Weeks

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.


0 60 120 180 240 300 360

Bud/form (maintenance + as needed)

Flu/salm

1400

1200

1000

600

800

200

400

0

BDP equivalent total daily ICS dose (µg)

Bud/form (maintenance only)

Titration phase

Mean Total ICS Dose Over Time


Final Prescribed Maintenance ICS Dose (% of patients on dose)

~1-2% of subjects in both groups used a non-protocolled dose (not shown)

10

30

50

70

320

Low*

(BUD g/day)

SMART

31% 31%

68% 68%

200

Low*

500

Medium*

1000

High*

Flu/salm

10

30

50

70

27% 27%

14% 14%

58% 58%

(FP g/day) 640

Medium*

*As defined by GINA 2002


Overall Steroid Load

Inhaled dose in micrograms g/day)

0

100

300

500

700

Flu/salm SMART

FP 583 g/day BUD 653 g/day

91 g prn

562 g regular

Days with oral steroid use*

500

1500

2500

3500

Flu/salm

SMART

2978

1980

aDue to asthma exacerbation


Total Inhaler Prescriptions(Mean number of prescribed study inhalers/patient/year)

0

4

8

12

Flu/salm +albuterol

SMART

12.712.7

5.016

11.6

20

Flu/salm (100/250/500 strengths) + albuterol prn

SMART (160/4.5 strength) for maintenance + as needed

16.616.6


Health-related Quality of Life

0

0.2

0.4

0.6

0.8

Symptoms Activity Emotional Environmental Overall

Flu/salm+SABA

SMART

Adjusted mean change in AQLQs scores


Cost Difference SMART vs. Flu/salm+SABA

21

-50

8

-92

-120

-80

-40

0

40GERMANYa FRANCE ITALY UKb

Co

st d

iffe

ren

ce/p

atie

nt-

year

(€)

-1

-73

-15

-118

Direct costsTotal costs

Cost increase with SMART

Cost decrease with SMART

aDifferences in direct and total costs were statistically significant only in Germany

b1 £=1.45 Euro (Dec 2004)


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

Overview of Exposure

SMART(n=1064)

Flu/salm+SABA(n=1071)


Number of Patients with the Most Frequently Reported Adverse Events (>3%)

Nasopharyngitis 110 (10) 105 (10)

Bronchitis 86 (8) 77 (7)

Upper respiratory tract infection 77 (7) 79 (7)

Sinusitis 53 (5) 31 (3)

SMART(n=1064)

n (%)Preferred term

Flu/salm+SABA(n=1071)

n (%)


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. Adapted from Kuna et al. Int J Clin Pract Int J Clin Pract 2007;61(5):725-36.2007;61(5):725-36.

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: 1 2 3 4 5

Week: -2 0 8 16 24

Six-month, double-blind, double-dummy

Regular ICS ≥500 µg R

Enrolled: n=4399

Randomized: n=3335


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


*Pre-bronchodilator

SMART Bud/form(n=1107)(n=1105)

Mean SABA use, inh./day during run-in

2.32.3

Mean FEV1, % predicted*

Males, n (%) 479 (43)448 (41)

Mean age, years (range) 38 (11-79)38 (12-83)

7273

Long-acting 2-agonists, %

Mean ICS at entry, g/day 740750

Characteristics

Mean reversibility in FEV1, % 25 24

Flu/salm(n=1123)

Mean % nights with awakeningsduring run-in

3433

2.3

484 (43)

38 (12-83)

73

744

23

32

47 47 46


Severe Exacerbations

A deterioration in asthma leading to:

Emergency room treatment/hospitalization

Oral steroids for 3 days

Primary variable: time to first severe exacerbation


Time to First Severe Exacerbation

15

10

5

0400 60 80 100 120 140 16020

Patients with severe

exacerbations (%)


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



Exacerbations/patient0.20

0.15

0.10

0.05

0400 60 80 100 120 140 16020


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


Total Severe ExacerbationsP

atie

nts

with

eve

nt(s

) (%

)

15

10

5

00 20 40 60 80 100 120 140 160 180

15

10

5

0

15

10

5

00 20 40 60 80 100 120 140 160 180

0 20 40 60 80 100 120 140 160 180


Flu/salm: 208 events

SMART: 125 events

Bud/form: 173 events


Total number of events Subtypes of severe events

Oral steroids only Hospitalizations/

ER treatments

Flu/salm Bud/form SMART

6472

106102 101

61

P<0.001

125

173

208 P<0.01

200

150

100

50

100

150

50

100

150

50

250

Severe Exacerbations by Subtype


Reduction in Exacerbation Risk and Rate

ªExtrapolated from the six-month studyExtrapolated 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 ***0.320.38 28**0.23Events/patient/year┼

SMART

vs.

bud/form

No.(%) patients

Events/patient/year┼ 39 **0.100.16 12 0.10

Treatment group

29

9

15

32*

Bud/form

vs. flu/salm


0.20

0.15

0.10

0.05

0400 60 80 100 120 140 16020


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


x

Mean am PEF (L/min)

Mean reliever use (inh./day)

360

340

320

300

280

260

240

220

200

5

4

3

2

1

0

Mean Profile of Severe Exacerbations Daily PEF and reliever use 14 days prior to and after events

Bud/form SMARTn=94n=126n=138

Flu/salmRun-in values for whole

population

-12 -6 0 6 12 -12 -6 0 6 12

Day relative to start of exacerbation

x

xxx

xxx


0

20

40

60

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



Reliever use(Inh./day)

2.8

2.0

1.2

0.4

0 40 80 120 160

Morning PEF (L/min)

380

370

360

350

340

330

0 40 80 120 160

Sustained Improvements in PEF and Reliever Use

SMART vs both groups (NS)

SMART vs. both groups (NS)


Seretide = flu/salm; Symbicort = bud/formSeretide = flu/salm; Symbicort = bud/form

Absolute FEV1 Values

Mean FEV1 (L)

2.70

2.60

2.50

2.40

0 8 16 24

Flu/salm + SABA

Bud/form + SABA

SMART

Weeks

NS


Average Daily Reliever Use for All Patients

Average number of reliever (inh./day)

Percentiles

16

14

12

10

8

6

4

2

0Bud/form SMARTFlu/salm

90th

10th 25th

75th

Median

Median values quoted; points = outliers above 90th percentile

Median during run-in 2.0 inh./day across groups

0.5 0.5 0.6


Occasional High Use of Reliever Therapy

501 544

No. of patients with >4 inh./day

491 > 1 day

> 10 days

SMARTSymbicort(n=1103)(n=1099)Level of use

Flu/sal(n=1118)

93 129

No. of pts. with >8 inh/day

112 > 1 day

> 10 days

217 245 263

30 33 21

Adapted from Kuna et al, International Journal of Clinical Practice 2007.

501 544 491 > 1 day

> 10 days

SMART(n=1103)(n=1099)Level of use (n=1118)

93 129 112

217 245 263

30 33 21

Corticosteroid Load

483 640

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)

86 139

Oral corticosteroid use/group

148 No. of courses

Days with use

755 1000 1000

1132 1044 619

*Adapted from GINA


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

10No. 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)


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