Addition of long‐acting beta2‐agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children

Francine M Ducharme; Muireann Ni Chroinin; Ilana Greenstone; Toby J Lasserson

doi:10.1002/14651858.CD005535.pub2

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Figure 1

Flow diagram for literature search results April 2004 to May 2008.

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Figure 2

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Figure 3

Forest plot of comparison: 1 Long‐acting beta2 vs placebo: both groups receiving similar dose ICS, outcome: 1.1 # patients with exacerbations requiring oral steroids.

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Figure 4

Funnel plot of outcome: 2.9 Sensitivity analysis: exacerbations requiring oral steroids by data publication status (data available from published source).

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Figure 5

Forest plot of comparison: 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, outcome: 1.2 # patients with exacerbations requiring hospitalisation.

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Figure 6

Forest plot of comparison: 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, outcome: 1.3 Serious adverse event including respiratory.

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Analysis 1.1

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 1 # patients with exacerbations requiring oral steroids.

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Analysis 1.2

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 2 # patients with exacerbations requiring hospitalisation.

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Analysis 1.3

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 3 Serious adverse event including respiratory.

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Analysis 1.4

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 4 Total # withdrawals.

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Analysis 1.5

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 5 # withdrawals due to poor asthma control or exacerbation.

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Analysis 1.6

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 6 # withdrawals due to adverse events.

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Analysis 1.7

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 7 # withdrawals due to serious non‐respiratory event.

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Analysis 1.8

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 8 FEV1 (L) at endpoint.

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Analysis 1.9

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 9 Change in FEV1 at endpoint stratifying on baseline FEV1.

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Analysis 1.10

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 10 Change in FEV1 predicted endpoint stratifying on baseline FEV1.

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Analysis 1.11

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 11 FEV1 % predicted at endpoint.

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Analysis 1.12

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 12 Change in FEV1 (L or % predicted) stratifying on trial duration.

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Analysis 1.13

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 13 Morning PEF (L/min) at endpoint.

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Analysis 1.14

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 14 Change in morning PEF (L/min) at endpoint stratifying on baseline FEV1.

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Analysis 1.15

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 15 Evening PEF (L/min) at endpoint.

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Analysis 1.16

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 16 Change in evening PEF at endpoint.

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Analysis 1.17

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 17 Change in PEF variability at endpoint.

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Analysis 1.18

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 18 Change in 24‐hour symptom score at endpoint.

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Analysis 1.19

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 19 Change in daytime symptom score at endpoint.

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Analysis 1.20

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 20 Change in night‐time symptom score at endpoint.

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Analysis 1.21

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 21 % symptom‐free days.

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Analysis 1.22

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 22 Change in % symptom‐free days at endpoint.

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Analysis 1.23

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 23 Change in # of symptom‐free nights at endpoint.

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Analysis 1.24

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 24 % symptom‐free nights at 12 +/‐ 4 weeks.

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Analysis 1.25

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 25 Change in % symptom‐free nights at endpoint.

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Analysis 1.26

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 26 Change in asthma control days %.

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Analysis 1.27

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 27 Change in # overall daily rescue inhalations at endpoint.

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Analysis 1.28

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 28 Change in # daytime rescue inhalations at endpoint.

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Analysis 1.29

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 29 # daytime rescue inhalations (puffs per day) at endpoint.

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Analysis 1.30

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 30 # night‐time rescue inhalations (puffs per night) at endpoint.

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Analysis 1.31

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 31 Change in # night‐time rescue inhalations at endpoint.

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Analysis 1.32

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 32 Change in mean rescue‐free days.

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Analysis 1.33

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 33 Rescue medication‐free days.

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Analysis 1.34

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 34 Change in % rescue medication‐free days.

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Analysis 1.35

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 35 Change in % nights with no awakening.

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Analysis 1.36

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 36 % nights with awakening.

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Analysis 1.37

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 37 Change in night‐time awakening (number of nights) at endpoint.

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Analysis 1.38

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 38 Change in quality of life (AQLQ score) at endpoint.

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Analysis 1.39

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 39 Total # adverse events.

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Analysis 1.40

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 40 # patients with headache.

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Analysis 1.41

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 41 # patients with hoarseness.

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Analysis 1.42

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 42 # patients with oral thrush.

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Analysis 1.43

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 43 # patients with tremor.

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Analysis 1.44

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 44 # patients with tachycardia or palpitations.

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Analysis 1.45

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 45 Deaths.

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Analysis 1.46

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 46 # patients with adverse cardiovascular events.

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Analysis 1.47

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 47 # Worsening asthma.

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Analysis 1.48

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 48 Change in height (cm) as SD scores at 24 +/‐ 4 weeks.

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Analysis 1.49

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 49 PC20 Methacholine‐adjusted odds ratio increase from baseline.

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Analysis 1.50

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 50 ACTH induced cortisol < 18 microg/dl at endpoint.

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Analysis 1.51

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 51 am cortisol < 5 microg/dl at endpoint.

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Analysis 1.52

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 52 Change in % PC20 at endpoint.

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Analysis 1.53

Comparison 1 Long‐acting beta2 versus placebo: both groups receiving similar dose ICS, Outcome 53 PC20 histamine.

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Analysis 2.1

Comparison 2 Additional comparisons for same dose, Outcome 1 # patients with exacerbations requiring oral steroids by baseline predicted FEV1.

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Analysis 2.2

Comparison 2 Additional comparisons for same dose, Outcome 2 # patients with exacerbations requiring oral steroids children versus adults.

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Analysis 2.3

Comparison 2 Additional comparisons for same dose, Outcome 3 # patients with exacerbations requiring oral steroids by dose of ICS in both groups.

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Analysis 2.4

Comparison 2 Additional comparisons for same dose, Outcome 4 # patients with exacerbations requiring oral steroids by combination inhaler or separate inhaler for LABA.

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Analysis 2.5

Comparison 2 Additional comparisons for same dose, Outcome 5 # patients with exacerbations requiring oral steroids by whether LABA dose is usual or higher than usual.

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Analysis 2.6

Comparison 2 Additional comparisons for same dose, Outcome 6 # patients with exacerbations requiring oral steroids by type of LABA.

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Analysis 2.7

Comparison 2 Additional comparisons for same dose, Outcome 7 # patients with exacerbations requiring oral steroids by trial duration.

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Analysis 2.8

Comparison 2 Additional comparisons for same dose, Outcome 8 # patients with exacerbations requiring oral steroids study unsupported by pharmaceutical industry excluded.

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Analysis 2.9

Comparison 2 Additional comparisons for same dose, Outcome 9 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of bias of selection bias (adequate allocation sequence generation).

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Analysis 2.10

Comparison 2 Additional comparisons for same dose, Outcome 10 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of bias of selection bias (adequate allocation concealment).

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Analysis 2.11

Comparison 2 Additional comparisons for same dose, Outcome 11 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of detection bias (adequate blinding).

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Analysis 2.12

Comparison 2 Additional comparisons for same dose, Outcome 12 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of bias of attrition bias (complete follow up of study participants).

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Analysis 2.13

Comparison 2 Additional comparisons for same dose, Outcome 13 Sensitivity analysis: exacerbations requiring oral steroids by data publication status (data available from published source).

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Analysis 2.14

Comparison 2 Additional comparisons for same dose, Outcome 14 Change in FEV1 at endpoint stratifying on age (children versus adults).

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Analysis 2.15

Comparison 2 Additional comparisons for same dose, Outcome 15 Change in FEV1 at endpoint stratifying on LABA (formoterol versus salmeterol).

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Analysis 2.16

Comparison 2 Additional comparisons for same dose, Outcome 16 Change in FEV1 at endpoint stratifying on baseline FEV1.

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Analysis 3.1

Comparison 3 WMD archive, Outcome 1 Change in morning PEF (L/min) at endpoint stratifying on baseline FEV1.

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Analysis 3.2

Comparison 3 WMD archive, Outcome 2 Change in evening PEF (L/min) at endpoint.

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Analysis 3.3

Comparison 3 WMD archive, Outcome 3 Change in % symptom‐free days at endpoint.

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Analysis 3.4

Comparison 3 WMD archive, Outcome 4 Change in mean % rescue free days at 12 +/‐ 4 weeks.

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Analysis 3.5

Comparison 3 WMD archive, Outcome 5 Change in FEV1 at endpoint (L) stratifying on baseline FEV1.

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Analysis 3.6

Comparison 3 WMD archive, Outcome 6 Change in # daytime rescue inhalations (puffs per day) at endpoint.

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Analysis 3.7

Comparison 3 WMD archive, Outcome 7 Change in FEV1 at endpoint (% predicted) stratifying on baseline FEV1.

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Analysis 3.8

Comparison 3 WMD archive, Outcome 8 Change in # overall daily rescue inhalations at endpoint.

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Analysis 3.9

Comparison 3 WMD archive, Outcome 9 Change in quality of life (AQLQ score) at endpoint.

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Table 1. Search history

Year

Detail

All years to April 2004

Citations identified: 594

Of these, 545 reports were excluded for the following mutually exclusive reasons:

(1) duplicate references (N = 208)
(2) not a randomised controlled trial (N = 68) or an ongoing trial (N = 14)
(3) participants were not asthmatics (N = 4)
(4) no consistent intervention with inhaled corticosteroids in all participants (N = 41)
(5) intervention was not daily inhaled long‐acting ß2‐agonists (N = 19)
(6) control intervention was not inhaled corticosteroids alone (N = 63)
(7) duration of intervention was less than 30 days (N = 45)
(8) outcome measures did not reflect asthma control (N = 8)
(9) the treatment and intervention groups compared the same medications either in combination or with different delivery devices (N = 30)
(10) co‐intervention with a non‐permitted agent (N = 1)
(11) patients were steroid‐naive on study entry (N = 20)
(12) control group had a higher dose of inhaled corticosteroid than the intervention group (N = 21)
(13) the dose of inhaled corticosteroid did not remain stable during the trial (N = 3)

Due to the large number of citations considered, the reasons for exclusion are provided only for published randomised controlled trials

33 treatment‐control comparisons derived from 28 trials met the entry criteria of the review

Table 1. Search history

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Table 2. Control group risk status for primary outcome

Study ID	Control group % event rate	Control group N	Duration (wk)
Akpinarli 1999	0	16	6
Kavaru 2000	0	90	12
Weiler 2005	0	90	4
SFA100314	1	124	4
SFA100316	1	118	4
SAS40024	2	100	4
Shapiro 2000	2	84	12
Malone 2005	3	102	12
Nathan 2006	3	91	12
Noonan 2006a	4	55	12
Noonan 2006b	4	54	12
SAS40037	4	161	16
SAS40036	4	159	16
Li 1999	6	16	12
Simons 1997	6	16	4
Fitzgerald 1999	7	91	24
Aubier 1999b	8	83	28
Aubier 1999a	9	82	28
Norhaya 1999	10	30	4
Verberne 1998	18	57	54
Russell 1995	18	99	12
O'Byrne 2001b	20	312	52
Kemp 1998	23	254	12
Boyd 1995	23	64	12
Langton Hewer 1995	25	12	8
O'Byrne 2001a	25	322	52
Wallin 2003	26	19	12
Pauwels 1997b	28	214	52
van der Molen 1997	28	114	24
Pauwels 1997a	38	213	52

Table 2. Control group risk status for primary outcome

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Comparison 1. Long‐acting beta2 versus placebo: both groups receiving similar dose ICS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 # patients with exacerbations requiring oral steroids Show forest plot	30	6808	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.68, 0.87]

1.1 Mean baseline FEV1 >/= 80% of predicted	8	1713	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.56, 0.86]
1.2 Mean baseline FEV1 61% to 79% of predicted	18	4095	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.70, 0.94]
1.3 Mean baseline FEV1 not reported	4	1000	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.24, 1.65]
2 # patients with exacerbations requiring hospitalisation Show forest plot	24	7297	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.70, 1.82]

2.1 Mean baseline FEV1 >/= 80% of predicted	3	193	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.18, 5.39]
2.2 Mean baseline FEV1 61% to 79% of predicted	18	5685	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.67, 1.84]
2.3 Mean baseline FEV1 not reported	3	1419	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 72.71]
3 Serious adverse event including respiratory Show forest plot	57	16213	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.87, 1.30]

3.1 Mean baseline FEV1 >/= 80% of predicted	14	4219	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.64, 1.21]
3.2 Mean baseline FEV1 61% to 79% of predicted	32	8397	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.89, 1.62]
3.3 Mean baseline FEV1 not reported	11	3597	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.74, 1.87]
4 Total # withdrawals Show forest plot	58	14718	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.75, 0.87]

4.1 Mean baseline FEV1 >/= 80% of predicted	16	2501	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.67, 1.04]
4.2 Mean baseline FEV1 61% to 79% of predicted	35	9644	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.75, 0.90]
4.3 Mean baseline FEV1 not reported	7	2573	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.60, 0.85]
5 # withdrawals due to poor asthma control or exacerbation Show forest plot	38	9505	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.41, 0.61]

5.1 Mean baseline FEV1 >/= 80% of predicted	6	596	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.20, 1.17]
5.2 Mean baseline FEV1 61% to 79% of predicted	27	6879	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.42, 0.66]
5.3 Mean baseline FEV1 not reported	5	2030	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.24, 0.66]
6 # withdrawals due to adverse events Show forest plot	52	14038	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.86, 1.26]

6.1 Mean baseline FEV1 >/= 80% of predicted	9	1647	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.41, 1.34]
6.2 Mean baseline FEV1 61% to 79% of predicted	35	9199	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.90, 1.45]
6.3 Mean baseline FEV1 not reported	9	3192	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.62, 1.36]
7 # withdrawals due to serious non‐respiratory event Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.1 Mean baseline FEV1 61% to 79% of predicted	2		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 FEV1 (L) at endpoint Show forest plot	10	2045	Mean Difference (IV, Fixed, 95% CI)	0.12 [0.07, 0.17]

8.1 Mean baseline FEV1 >/‐ 80% of predicted	2	615	Mean Difference (IV, Fixed, 95% CI)	0.10 [0.03, 0.17]
8.2 Mean baseline FEV1 61% to 79% of predicted	6	914	Mean Difference (IV, Fixed, 95% CI)	0.15 [0.07, 0.22]
8.3 Mean baseline FEV1 not reported	2	516	Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.02, 0.26]
9 Change in FEV1 at endpoint stratifying on baseline FEV1 Show forest plot	32	9784	L (Random, 95% CI)	0.11 [0.09, 0.13]

9.1 Mean baseline FEV1 >= 80% of predicted	5	1036	L (Random, 95% CI)	0.09 [0.03, 0.14]
9.2 Mean baseline FEV1 61% to 79% of predicted	24	7917	L (Random, 95% CI)	0.12 [0.09, 0.14]
9.3 Mean baseline FEV1 predicted not reported	3	831	L (Random, 95% CI)	0.13 [0.05, 0.21]
10 Change in FEV1 predicted endpoint stratifying on baseline FEV1 Show forest plot	8		% (Random, 95% CI)	3.73 [2.66, 4.80]

10.1 Mean baseline FEV1 >= 80% of predicted	6		% (Random, 95% CI)	4.06 [2.96, 5.16]
10.2 Mean baseline FEV1 61% to 79% of predicted	1		% (Random, 95% CI)	3.46 [1.40, 5.52]
10.3 Mean baseline FEV1 predicted not reported	1		% (Random, 95% CI)	‐0.40 [‐5.03, 4.23]
11 FEV1 % predicted at endpoint Show forest plot	4	939	Mean Difference (IV, Fixed, 95% CI)	5.34 [3.29, 7.38]

11.1 Mean baseline FEV1 >‐ 80% of predicted	2	87	Mean Difference (IV, Fixed, 95% CI)	2.67 [‐2.21, 7.55]
11.2 Mean baseline FEV1 61% to 79% of predicted	2	852	Mean Difference (IV, Fixed, 95% CI)	5.90 [3.65, 8.16]
12 Change in FEV1 (L or % predicted) stratifying on trial duration Show forest plot	14	4008	Std. Mean Difference (IV, Random, 95% CI)	0.34 [0.26, 0.42]

12.1 Change in FEV1 (L) or (% predicted) at 6 +/‐ 2 weeks of treatment	2	299	Std. Mean Difference (IV, Random, 95% CI)	0.41 [0.18, 0.64]
12.2 Change in FEV1 (L) or (% predicted) at 12 +/‐ 4 weeks of treatment	11	2003	Std. Mean Difference (IV, Random, 95% CI)	0.36 [0.24, 0.49]
12.3 Change in FEV1 (L) or (% predicted) at 24 +/‐ 4 weeks of treatment	2	352	Std. Mean Difference (IV, Random, 95% CI)	0.30 [0.09, 0.51]
12.4 Change in FEV1 (L) or (% predicted) at 52 +/‐ 4 weeks of treatment	3	1354	Std. Mean Difference (IV, Random, 95% CI)	0.28 [0.12, 0.44]
13 Morning PEF (L/min) at endpoint Show forest plot	8	1787	Mean Difference (IV, Random, 95% CI)	26.21 [13.31, 39.10]

13.1 Mean baseline FEV1 >/= 80%	1	29	Mean Difference (IV, Random, 95% CI)	86.0 [17.11, 154.89]
13.2 Mean baseline FEV1 61% to 79% of predicted	5	1127	Mean Difference (IV, Random, 95% CI)	19.14 [2.93, 35.34]
13.3 Mean baseline FEV1 not reported	2	631	Mean Difference (IV, Random, 95% CI)	34.26 [17.83, 50.70]
14 Change in morning PEF (L/min) at endpoint stratifying on baseline FEV1 Show forest plot	53	14365	L/min (Random, 95% CI)	19.64 [17.08, 22.20]

14.1 Mean baseline FEV1 >/= 80% of predicted	12	3364	L/min (Random, 95% CI)	11.96 [8.68, 15.24]
14.2 Mean baseline FEV1 61% to 79% of predicted	32	8348	L/min (Random, 95% CI)	23.41 [19.84, 26.98]
14.3 Mean baseline FEV1 not reported	9	2653	L/min (Random, 95% CI)	17.09 [12.99, 21.18]
15 Evening PEF (L/min) at endpoint Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

15.1 Mean baseline FEV1 61% to 79% of predicted	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Change in evening PEF at endpoint Show forest plot	33	8248	L/min (Random, 95% CI)	17.89 [14.82, 20.95]

16.1 Mean baseline FEV1 > /= 80% of predicted	7	1345	L/min (Random, 95% CI)	13.37 [5.98, 20.76]
16.2 Mean baseline FEV1 61% to 79% of predicted	23	6058	L/min (Random, 95% CI)	19.70 [16.36, 23.03]
16.3 Mean baseline FEV1 not reported	3	845	L/min (Random, 95% CI)	13.85 [5.05, 22.64]
17 Change in PEF variability at endpoint Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

17.1 Mean baseline FEV1 61% to 79% of predicted	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Change in 24‐hour symptom score at endpoint Show forest plot	6	1473	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐0.34, ‐0.12]

18.1 Mean baseline FEV1 61% to 79% of predicted	6	1473	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐0.34, ‐0.12]
19 Change in daytime symptom score at endpoint Show forest plot	8	1767	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐0.42, ‐0.23]

19.1 Mean baseline FEV1 >/= 80%	1	54	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.80, 0.27]
19.2 Mean baseline FEV1 61% to 79% of predicted	7	1713	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐0.43, ‐0.23]
20 Change in night‐time symptom score at endpoint Show forest plot	5	1319	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.22 [‐0.33, ‐0.11]

20.1 Mean baseline FEV1 >/= 80%	1	54	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.53 [‐1.08, 0.01]
20.2 Mean baseline FEV 1 61‐79% of predicted	4	1265	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.21 [‐0.32, ‐0.10]
21 % symptom‐free days Show forest plot	6	2169	Mean Difference (IV, Random, 95% CI)	7.31 [0.50, 14.12]

21.1 Mean baseline FEV1 >/= 80% of predicted	1	627	Mean Difference (IV, Random, 95% CI)	4.60 [0.69, 8.51]
21.2 Mean baseline FEV1 61% to 79% of predicted	4	1460	Mean Difference (IV, Random, 95% CI)	10.35 [0.05, 20.65]
21.3 Mean baseline FEV1 not reported	1	82	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐4.47, 2.47]
22 Change in % symptom‐free days at endpoint Show forest plot	16	4186	Mean Difference (IV, Random, 95% CI)	11.88 [8.25, 15.50]

22.1 Mean baseline FEV1 >/= 80% of predicted	1	203	Mean Difference (IV, Random, 95% CI)	3.20 [‐8.08, 14.48]
22.2 Mean baseline FEV1 61% to 79% of predicted	13	3344	Mean Difference (IV, Random, 95% CI)	13.37 [9.31, 17.44]
22.3 Mean baseline FEV1 not reported	2	639	Mean Difference (IV, Random, 95% CI)	6.57 [1.11, 12.03]
23 Change in # of symptom‐free nights at endpoint Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

23.1 Mean baseline FEV1 61% to 79% of predicted	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24 % symptom‐free nights at 12 +/‐ 4 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

24.1 Mean baseline FEV1 61% to 79% of predicted	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
25 Change in % symptom‐free nights at endpoint Show forest plot	4	1052	Std. Mean Difference (IV, Random, 95% CI)	0.51 [0.28, 0.74]

25.1 Mean baseline FEV1 61% to 79% of predicted	4	1052	Std. Mean Difference (IV, Random, 95% CI)	0.51 [0.28, 0.74]
26 Change in asthma control days % Show forest plot	4	813	Mean Difference (IV, Fixed, 95% CI)	15.81 [10.85, 20.77]

26.1 Mean baseline FEV1 61% to 79% of predicted	4	813	Mean Difference (IV, Fixed, 95% CI)	15.81 [10.85, 20.77]
27 Change in # overall daily rescue inhalations at endpoint Show forest plot	14	4654	Mean Difference (IV, Random, 95% CI)	‐0.58 [‐0.80, ‐0.35]

27.1 Mean baseline FEV1 >/= 80% of predicted	2	1272	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.29, ‐0.05]
27.2 Mean baseline FEV1 61% to 79% of predicted	12	3382	Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.05, ‐0.41]
28 Change in # daytime rescue inhalations at endpoint Show forest plot	13		puffs per day (Random, 95% CI)	‐0.68 [‐0.94, ‐0.42]

28.1 Mean baseline FEV 1 >/= 80% of predicted	3		puffs per day (Random, 95% CI)	‐0.27 [‐0.62, 0.07]
28.2 Mean baseline FEV1 61% to 79% of predicted	10		puffs per day (Random, 95% CI)	‐0.82 [‐1.18, ‐0.46]
28.3 Mean baseline FEV1 not reported	0		puffs per day (Random, 95% CI)	0.0 [0.0, 0.0]
29 # daytime rescue inhalations (puffs per day) at endpoint Show forest plot	2	277	Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.24, ‐0.22]

29.1 Mean baseline FEV1 61% to 79% of predicted	2	277	Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.24, ‐0.22]
30 # night‐time rescue inhalations (puffs per night) at endpoint Show forest plot	2	546	Mean Difference (IV, Random, 95% CI)	‐0.44 [‐0.81, ‐0.07]

30.1 Mean baseline FEV1 61% to 79% of predicted	2	546	Mean Difference (IV, Random, 95% CI)	‐0.44 [‐0.81, ‐0.07]
31 Change in # night‐time rescue inhalations at endpoint Show forest plot	7	2219	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.48, ‐0.11]

31.1 Mean baseline FEV1 >/= 80% of predicted	1	168	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.20, ‐0.02]
31.2 Mean baseline FEV1 61% to 79% of predicted	6	2051	Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.57, ‐0.10]
32 Change in mean rescue‐free days Show forest plot	6	1698	% (Fixed, 95% CI)	17.05 [13.75, 20.35]

32.1 Mean baseline FEV1 61% to 79% of predicted	5	1381	% (Fixed, 95% CI)	17.63 [14.03, 21.23]
32.2 Mean baseline FEV1 not reported	1	317	% (Fixed, 95% CI)	14.0 [5.77, 22.23]
33 Rescue medication‐free days Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

33.1 Mean baseline FEV1 61% to 79% of predicted	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
34 Change in % rescue medication‐free days Show forest plot	2	667	Mean Difference (IV, Random, 95% CI)	6.43 [1.20, 11.66]

34.1 Mean baseline FEV1 61% to 79% of predicted	1	475	Mean Difference (IV, Random, 95% CI)	5.20 [‐1.78, 12.18]
34.2 Mean baseline FEV1 not reported	1	192	Mean Difference (IV, Random, 95% CI)	8.0 [0.10, 15.90]
35 Change in % nights with no awakening Show forest plot	5	1158	Mean Difference (IV, Fixed, 95% CI)	1.01 [‐1.06, 3.08]

35.1 Mean baseline FEV1 61% to 79% of predicted	5	1158	Mean Difference (IV, Fixed, 95% CI)	1.01 [‐1.06, 3.08]
36 % nights with awakening Show forest plot	2	913	Mean Difference (IV, Fixed, 95% CI)	‐1.37 [‐2.75, 0.02]

36.1 Mean baseline FEV1 >/= 80% of predicted	1	627	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐3.19, 0.19]
36.2 Mean baseline FEV1 61% to 79% of predicted	1	286	Mean Difference (IV, Fixed, 95% CI)	‐1.10 [‐3.51, 1.31]
37 Change in night‐time awakening (number of nights) at endpoint Show forest plot	5	1308	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.21, 0.01]

37.1 Mean baseline FEV1 61% to 79% of predicted	5	1308	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.21, 0.01]
38 Change in quality of life (AQLQ score) at endpoint Show forest plot	3		Mean Difference (Random, 95% CI)	0.26 [0.04, 0.47]

38.1 Mean baseline FEV1 61% to 79% of predicted	3		Mean Difference (Random, 95% CI)	0.26 [0.04, 0.47]
39 Total # adverse events Show forest plot	41	10622	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.97, 1.04]

39.1 Mean baseline FEV1 >/= 80% of predicted	7	1424	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [1.01, 1.19]
39.2 Mean baseline FEV1 61% to 79% of predicted	25	6555	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.94, 1.02]
39.3 Mean baseline FEV1 not reported	9	2643	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.92, 1.10]
40 # patients with headache Show forest plot	37	10020	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.87, 1.13]

40.1 Mean baseline FEV1 >/= 80% of predicted	4	779	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.78, 1.33]
40.2 Mean baseline FEV1 61% to 79% of predicted	26	6644	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.81, 1.13]
40.3 Mean baseline FEV1 not reported	7	2597	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.70]
41 # patients with hoarseness Show forest plot	6	1602	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.44, 3.10]

41.1 Mean baseline FEV1 61% to 79% of predicted	5	1284	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.36, 2.88]
41.2 Mean baseline FEV1 not reported	1	318	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.24, 103.33]
42 # patients with oral thrush Show forest plot	9	1379	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [0.71, 3.86]

42.1 FEV1 >/= 80% predicted	3	356	Risk Ratio (M‐H, Fixed, 95% CI)	4.04 [0.46, 35.52]
42.2 Mean baseline FEV1 61% to 79% of predicted	6	1023	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.52, 3.46]
43 # patients with tremor Show forest plot	16	3833	Risk Ratio (M‐H, Random, 95% CI)	1.74 [0.72, 4.20]

43.1 Mean baseline FEV1 >/= 80% of predicted	2	530	Risk Ratio (M‐H, Random, 95% CI)	5.30 [0.26, 109.66]
43.2 Mean baseline FEV1 61% to 79% of predicted	14	3303	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.64, 4.15]
44 # patients with tachycardia or palpitations Show forest plot	12	3491	Risk Ratio (M‐H, Fixed, 95% CI)	2.11 [0.83, 5.37]

44.1 Mean baseline FEV1 >/= 80% of predicted	1	116	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
44.2 Mean baseline FEV1 61% to 79% of predicted	10	2464	Risk Ratio (M‐H, Fixed, 95% CI)	2.13 [0.77, 5.88]
44.3 Mean baseline FEV1 not reported	1	911	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [0.18, 22.03]
45 Deaths Show forest plot	3	1673	Risk Ratio (M‐H, Fixed, 95% CI)	2.46 [0.48, 12.65]

45.1 Mean baseline FEV1 61% to 79% of predicted	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	2.90 [0.12, 70.57]
45.2 Mean baseline FEV1 not reported	2	1337	Risk Ratio (M‐H, Fixed, 95% CI)	2.31 [0.34, 15.63]
46 # patients with adverse cardiovascular events Show forest plot	4	792	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.32, 2.54]

46.1 Mean baseline FEV1 >/= 80% of predicted	1	116	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.49]
46.2 Mean baseline FEV1 61% to 79% of predicted	3	676	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.35, 3.24]
47 # Worsening asthma Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

47.1 Mean baseline FEV1 61% to 79% of predicted	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
48 Change in height (cm) as SD scores at 24 +/‐ 4 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

48.1 Mean baseline FEV1 >/= 80% of predicted	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
49 PC20 Methacholine‐adjusted odds ratio increase from baseline Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

49.1 Mean baseline FEV1 61% to 79% of predicted	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
50 ACTH induced cortisol < 18 microg/dl at endpoint Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

50.1 Mean baseline FEV1 61% to 79% of predicted	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
51 am cortisol < 5 microg/dl at endpoint Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

51.1 Mean baseline FEV1 61% to 79% of predicted	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
52 Change in % PC20 at endpoint Show forest plot	1	39	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.68, 1.28]

52.1 Mean baseline FEV1 >/= 80% of predicted	1	39	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.68, 1.28]
53 PC20 histamine Show forest plot	1		Doub'g doses (Fixed, 95% CI)	Totals not selected

53.1 Mean baseline FEV1 >/= 80% of predicted	1		Doub'g doses (Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Long‐acting beta2 versus placebo: both groups receiving similar dose ICS

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Comparison 2. Additional comparisons for same dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 # patients with exacerbations requiring oral steroids by baseline predicted FEV1 Show forest plot	30		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

1.1 Mean baseline FEV1 >/= 80% of predicted	8	1713	Risk Ratio (IV, Fixed, 95% CI)	0.70 [0.57, 0.87]
1.2 Mean baseline FEV1 61% to 79% of predicted	17	3764	Risk Ratio (IV, Fixed, 95% CI)	0.83 [0.72, 0.96]
1.3 Mean baseline FEV1 not reported	5	1331	Risk Ratio (IV, Fixed, 95% CI)	0.49 [0.21, 1.16]
2 # patients with exacerbations requiring oral steroids children versus adults Show forest plot	30		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

2.1 Children	6	605	Risk Ratio (IV, Fixed, 95% CI)	0.89 [0.58, 1.39]
2.2 Adults	24	6203	Risk Ratio (IV, Fixed, 95% CI)	0.77 [0.68, 0.88]
3 # patients with exacerbations requiring oral steroids by dose of ICS in both groups Show forest plot	30	6808	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.72 [0.62, 0.83]

3.1 Low dose of ICS (<= 400 mcg/day of BDP‐eq)	12	3398	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.63 [0.51, 0.78]
3.2 Moderate dose of ICS (401 to 800 mcg/day of BDP‐eq)	6	1067	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.68 [0.48, 0.97]
3.3 High dose of ICS (>800 mcg/day of BDP‐eq)	7	1366	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.94 [0.58, 1.54]
3.4 Unspecified dose of ICS or range of dose only mentioned	5	977	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.89 [0.65, 1.22]
4 # patients with exacerbations requiring oral steroids by combination inhaler or separate inhaler for LABA Show forest plot	30		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

4.1 Combination inhaler	13	2718	Risk Ratio (IV, Fixed, 95% CI)	0.81 [0.50, 1.32]
4.2 Separate inhaler	16	4053	Risk Ratio (IV, Fixed, 95% CI)	0.78 [0.69, 0.89]
4.3 Not reported	1	37	Risk Ratio (IV, Fixed, 95% CI)	0.21 [0.03, 1.64]
5 # patients with exacerbations requiring oral steroids by whether LABA dose is usual or higher than usual Show forest plot	30		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

5.1 LABA at usual dose	27	6427	Risk Ratio (IV, Fixed, 95% CI)	0.74 [0.65, 0.84]
5.2 LABA at higher than usual dose	3	381	Risk Ratio (IV, Fixed, 95% CI)	1.10 [0.79, 1.52]
6 # patients with exacerbations requiring oral steroids by type of LABA Show forest plot	30		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

6.1 Formoterol	9	2923	Risk Ratio (IV, Fixed, 95% CI)	0.74 [0.64, 0.85]
6.2 Salmeterol	21	3885	Risk Ratio (IV, Fixed, 95% CI)	0.89 [0.72, 1.10]
7 # patients with exacerbations requiring oral steroids by trial duration Show forest plot	30		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

7.1 <= 16 weeks	21	3645	Risk Ratio (IV, Fixed, 95% CI)	0.91 [0.72, 1.14]
7.2 > 16 weeks	9	3163	Risk Ratio (IV, Fixed, 95% CI)	0.74 [0.64, 0.85]
8 # patients with exacerbations requiring oral steroids study unsupported by pharmaceutical industry excluded Show forest plot	30		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

8.1 Charity funded	1	23	Risk Ratio (IV, Fixed, 95% CI)	1.09 [0.28, 4.32]
8.2 Funded by pharmaceutical industry	29	6785	Risk Ratio (IV, Fixed, 95% CI)	0.78 [0.69, 0.88]
9 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of bias of selection bias (adequate allocation sequence generation) Show forest plot	26	6513	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.69, 0.87]

10 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of bias of selection bias (adequate allocation concealment) Show forest plot	20	5042	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.66, 0.91]

11 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of detection bias (adequate blinding) Show forest plot	30	6808	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.68, 0.87]

12 Sensitivity analysis: exacerbations requiring oral steroids: studies with low risk of bias of attrition bias (complete follow up of study participants) Show forest plot	2	391	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.10, 3.89]

13 Sensitivity analysis: exacerbations requiring oral steroids by data publication status (data available from published source) Show forest plot	14	3161	Risk Ratio (IV, Fixed, 95% CI)	0.77 [0.67, 0.88]

14 Change in FEV1 at endpoint stratifying on age (children versus adults) Show forest plot	32		L (Random, 95% CI)	Subtotals only

14.1 Children	9		L (Random, 95% CI)	0.08 [0.05, 0.11]
14.2 Adults	23		L (Random, 95% CI)	0.13 [0.10, 0.15]
15 Change in FEV1 at endpoint stratifying on LABA (formoterol versus salmeterol) Show forest plot	32	9784	L (Random, 95% CI)	0.11 [0.09, 0.13]

15.1 Formoterol	17	4057	L (Random, 95% CI)	0.09 [0.07, 0.12]
15.2 Salmeterol	15	5727	L (Random, 95% CI)	0.14 [0.10, 0.18]
16 Change in FEV1 at endpoint stratifying on baseline FEV1 Show forest plot	32		L (Random, 95% CI)	Subtotals only

16.1 <= 16 weeks	25		L (Random, 95% CI)	0.12 [0.09, 0.14]
16.2 > 16 weeks	7		L (Random, 95% CI)	0.10 [0.06, 0.13]

Comparison 2. Additional comparisons for same dose

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Comparison 3. WMD archive

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in morning PEF (L/min) at endpoint stratifying on baseline FEV1 Show forest plot	42		Mean Difference (IV, Random, 95% CI)	Totals not selected

2 Change in evening PEF (L/min) at endpoint Show forest plot	25		Mean Difference (IV, Random, 95% CI)	Totals not selected

3 Change in % symptom‐free days at endpoint Show forest plot	13	2935	Mean Difference (IV, Random, 95% CI)	13.34 [9.43, 17.24]

3.1 Mean baseline FEV1 >/= 80% of predicted	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Mean baseline FEV1 61% to 79% of predicted	11	2296	Mean Difference (IV, Random, 95% CI)	14.98 [11.03, 18.92]
3.3 Mean baseline FEV1 not reported	2	639	Mean Difference (IV, Random, 95% CI)	6.57 [1.11, 12.03]
4 Change in mean % rescue free days at 12 +/‐ 4 weeks Show forest plot	6	1698	Mean Difference (IV, Fixed, 95% CI)	17.05 [13.75, 20.35]

4.1 Mean baseline FEV1 61% to 79% of predicted	5	1381	Mean Difference (IV, Fixed, 95% CI)	17.63 [14.03, 21.23]
4.2 Mean baseline FEV1 not reported	1	317	Mean Difference (IV, Fixed, 95% CI)	14.0 [5.77, 22.23]
5 Change in FEV1 at endpoint (L) stratifying on baseline FEV1 Show forest plot	26		Mean Difference (IV, Random, 95% CI)	Totals not selected

6 Change in # daytime rescue inhalations (puffs per day) at endpoint Show forest plot	12		Mean Difference (IV, Random, 95% CI)	Totals not selected

7 Change in FEV1 at endpoint (% predicted) stratifying on baseline FEV1 Show forest plot	7		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8 Change in # overall daily rescue inhalations at endpoint Show forest plot	10	3088	Mean Difference (IV, Random, 95% CI)	‐0.74 [‐1.07, ‐0.42]

8.1 Mean baseline FEV1 >/= 80% of predicted	2	1272	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.29, ‐0.05]
8.2 Mean baseline FEV1 61% to 79% of predicted	8	1816	Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.76, ‐0.37]
9 Change in quality of life (AQLQ score) at endpoint Show forest plot	3	1354	Mean Difference (IV, Random, 95% CI)	0.33 [0.05, 0.60]

Comparison 3. WMD archive

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