Beclomethasone versus budesonide for chronic asthma

Nick P Adams; Janine C Bestall; Paul Jones

doi:10.1002/14651858.CD003530

. 2002 Jan 21;2002(1):CD003530. doi: 10.1002/14651858.CD003530

Beclomethasone versus budesonide for chronic asthma

Nick P Adams ^1,^✉, Janine C Bestall ², Paul Jones ³

Editor: Cochrane Airways Group

PMCID: PMC8717128 PMID: 11869673

Abstract

Background

Beclomethasone dipropionate (BDP) and budesonide (BUD) are used widely in the treatment of chronic asthma. The two drugs have different in vitro pharmacokinetic characteristics. It is unclear whether this translates into clinically significant differences in efficacy or safety when treating children and adults with chronic asthma.

Objectives

To assess clinical outcomes in studies which have compared inhaled BDP and BUD in the treatment of chronic asthma.

Search methods

We searched the Cochrane Airways Group Trial Register (1999) and reference lists of articles. We contacted trialists and pharmaceutical companies for additional studies and searched abstracts of major respiratory society meetings (1997‐1999).

Selection criteria

Prospective, randomised trials comparing BDP to BUD in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality.

Data collection and analysis

One reviewer extracted data; authors were contacted to clarify missing information. Quantitative analyses where undertaken using Review Manager 4.0.3 with MetaView 3.1.

Main results

24 studies met the criteria for inclusion (1174 participants). Methodological quality was variable. A meta‐analysis of crossover studies did not demonstrate a significant difference between BDP and BUD for FEV1, morning PEF, evening PEF, asthma symptoms or rescue beta2 agonist use, over a dose range of 400 to 1000 mcg/d. The majority of crossover trials had significant design flaws related to a lack of washout and/or failure to exclude carryover effects so the results must be viewed with caution. A single crossover study with adequate washout showed that BUD 400 mcg/d delivered via Turbohaler dry powder inhaler (DPI) may be more effective than BDP 400 mcg/d delivered via Rotahaler DPI in reducing histamine bronchial hyper‐responsiveness: Weighted Mean Difference (WMD) 0.43 log10 PC20 FEV1 (95% Confidence Intervals (CI) 0.05, 0.81 log10 PC20 FEV1). A meta‐analysis of two parallel group, dose down‐titration studies (231 patients) showed that less BUD delivered via a Turbohaler DPI was required to maintain control in adults asthmatics compared to BDP delivered via metered dose inhaler with or without a spacer: WMD 444 mcg/d (95% CI 332, 556 mcg/d).

Authors' conclusions

There is limited high quality randomised controlled trial data comparing the relative efficacy of BDP and BUD. Current guidelines (BTS 1997; GINA 1995; NHLBI 1997) assume BDP and BUD to have equal efficacy, such that for each defined level of asthma severity, the recommended doses BDP and BUD are the same. Although there is some data to suggest that BUD via Turbohaler is more effective than BDP via either Rotahaler or MDI (with and without spacer), these comparisons are confounded by use of different delivery devices, and are not sufficient to warrant a change in guideline recommendations.

Plain language summary

The effects of beclomethasone or budesonide for chronic asthma

Beclomethasone and budesonide are commonly used to treat people with asthma in the long‐term. Despite the large amount of research which has been conducted with these two steroids, very little can be concluded as to how effective they are, because the quality of the research to date has not been strong enough. The available research does not therefore provide a clear answer as to whether beclomethasone or budesonide are better for treating asthma.

Background

Beclomethasone dipropionate (BDP) was the first inhaled corticosteroid (ICS) marketed for use in the treatment of chronic asthma in 1972. Budesonide had been available since the early 1980's. Extensive clinical experience has been gained with these compounds in the treatment of chronic asthma, both are regarded as having a highly favourable therapeutic index when compared to oral corticosteroids, i.e. offering large advantages in terms of their efficacy at the cost of few side‐effects.

In vitro studies assessing pharmacodynamic properties have shown differences between BDP and BUD. Receptor affinity is a measure of the strength with which an active molecule binds to the glucocorticoid receptor. This is 1.5 fold higher for 17‐beclomethasone monopropionate (17‐BMP), the bronchially active metabolite of BDP, compared to BUD (Boobis 1998). However when assessing drugs in terms of their relative in vitro potency, i.e. the concentration of drug required producing a standard effect, BUD appears more potent than BDP. This has been shown in early experimental studies for the MacKenzie skin‐blanching test (Johansson 1982), and more recently in terms of several in vitro assays of anti‐inflammatory action including eosinophil survival, basophil histamine release and expression of vascular cell adhesion molecule‐1 (Stellato 1999). It is noteworthy that in these in vitro assays, the maximum effect of BDP and BUD (i.e. their intrinsic activity) was similar, and at very high concentrations (on the 'plateau' of the dose response curve) the quantitative effects of the two drugs were closely matched.

Do differences in the in vitro pharmacodynamic actions of BDP and BUD translate into differences in clinical efficacy? This may depend on dose. At low inhaled dose, more likely to be on the 'steep' portion of the dose response curve for each drug, differences in potency might lead to differences in clinical efficacy. Conversely, at higher inhaled dose (approaching or on the 'plateau' of the dose response curve for each drug) differences in clinical efficacy may not be apparent. A retrospective analysis of prescription records for BDP and BUD in primary care in New Zealand has recently been published (Pethica 1998). The investigators concluded that BDP was more 'potent' than BUD because the mean daily‐prescribed dose of BDP over a one‐year period was 635 mcg/d compared to a mean daily BUD dose 979 mcg/d. This study has a number of limitations however including the fact that drug exposure could not validated and other known and unknown biases may have been operating in this non‐randomised, retrospective cross‐sectional study.

The purpose of this review is to assess the relative clinical efficacy and safety of BDP and BUD delivered at equal nominal dose in the treatment of chronic asthma by systematically reviewing the prospective randomised trials that have compared these inhaled corticosteroids.

Objectives

To assess clinical outcomes in studies which have compared inhaled beclomethasone (BDP) and inhaled budesonide (BUD) in the treatment of chronic asthma.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised studies. Double, single and non‐blinded studies were considered. Studies could be of either parallel group or crossover design.

Types of participants

Studies of both children and adults were included, but patients under two years of age were excluded. To be eligible, participants had to have a diagnosis of chronic asthma. Studies conducted in both primary and secondary care settings were considered.

Types of interventions

BDP versus BUD delivered by oral inhalation. Each drug had to be delivered at the same nominal daily dose. Nominal dose was calculated as the valve dose multiplied by the number of actuations per day. Each drug could be delivered by different device including pressurised metered dose aerosol inhaler (MDI), MDI+spacer or dry powder device (DPI). Studies using nebuliser devices were excluded.

Types of outcome measures

All outcomes were considered. Those identified as important a priori were as follows:

Efficacy related  1. Clinic measured FEV1 and PEF, diary card morning and evening PEF, diurnal variability in PEF  2. Symptoms  3. Rescue beta2 agonist use  4. Histamine and methacholine bronchial hyper‐responsiveness (BHR)  5. Asthma exacerbations: hospital admission, emergency room attendance, unscheduled primary care visits, days off school or work  6. Health‐related quality of life (HRQOL)    Safety related  1. Hypothalamo‐pituitary‐adrenal (HPA) axis function reflected in serum and urinary cortisol measures and clinical adrenal insufficiency   2. Oropharyngeal side effects (hoarseness, sore throat, oral Candidiasis)

Search methods for identification of studies

Electronic searches

Stage 1: a search was carried out of the Cochrane Airways Group Trials Register (1999). The following search terms were applied:

steroid* OR glucocorticoid* OR corticosteroid* OR beclomethasone OR budesonide OR fluticasone OR triamcinolone OR flunisolide OR Becotide OR Becloforte OR Pulmicort OR Flixotide

Abstracts from this search were imported into a bibliographic database termed the Inhaled Steroid Register. This was hand‐searched by two reviewers (NPA and JB). Duplicate publications were removed.

Stage 2: two further registers were created by undertaking searches of the Inhaled Steroid Register using the following terms:

beclomethasone OR Becotide OR Becloforte: the Beclomethasone Register

budesonide OR Pulmicort : the Budesonide Register

Each register was hand‐searched for RCTs meeting the inclusion criteria. Citations were excluded based on abstract if it was clear that the study was a) not concerned with the treatment of asthma in humans b) not an RCT c) did not include a treatment arm with inhaled corticosteroid (ICS). Where uncertainty existed, the publication was retrieved in full text form.

Searching other resources

Reference lists of all included trails and relevant narrative reviews were searched for additional RCTs. Authors of identified trials, Glaxo Wellcome (UK) and Astra Zeneca (Sweden) were contacted and were asked about any further published or unpublished trials that may have been conducted. There were no language restrictions. The British Journal of Clinical Research and the European Journal of Clinical Research, which are not electronically indexed on MEDLINE or EMBASE, were hand searched for relevant studies. The proceedings of the British Thoracic Society (1997/1998), European Respiratory Society (1997/1998) and the American Thoracic Society (1997‐1999) were searched for relevant trials.

Data collection and analysis

Selection of studies

The decision to exclude studies prior to full paper retrieval was made by one reviewer (NPA). Papers retrieved in full text form were assessed independently by two reviewers (NPA and JB); disagreement as to which papers to include was resolved by consensus.

Data extraction and management

One reviewer (NPA) extracted data for each outcome from the published results of included trials. In the case of continuous outcomes such as FEV1 measures:

1. Where outcomes were evaluated at a number of time points only data from the last evaluable time point was used.  2. Data were extracted from graphical plots when presented in this form; attempt was made to verify such data by contacting authors.  3. If an intention‐to‐treat analysis was not used by the investigators, and it was not explicit in the presentation of results how many subjects (N) were in each group at the time of last evaluation of that outcome, the appropriate N value for each intervention group was calculated by subtracting the number of patients who withdrew in each intervention group from those randomised to each intervention group.

Authors were written to (by mail, fax and/or electronic mail) to clarify details of randomisation and/or request missing outcome data. Attempt was made to send requests to correct current addresses by searching MEDLINE, EMBASE and hospital World Wide Web (WWW) sites for up‐to‐date contact details.

Assessment of risk of bias in included studies

Two reviewers (NPA and JB) who were blinded to the author's names, institution and funding sources independently assessed each study for methodological quality. The trials were scored using the Cochrane approach:

Grade A: adequate allocation concealment  Grade B: unclear allocation concealment  Grade C: clearly inadequate concealment

The methodological quality of included studies was also assessed using a 5 point scoring instrument (Jadad 1996):

a) Was the study described as randomised? (yes=1 no=0)  b) Was the study described as double blind? (yes=1 no=0)  c) Was there a description of withdrawals and dropouts? (yes=1 no=0)  d) Was the method of randomisation well described and appropriate? (yes=1 no=0)  e) Was the method of double blinding well described and appropriate? (yes=1 no=0)  f) deduct 1 point if method of randomisation or blinding inappropriate

Inter‐rater agreement was measured using the kappa statistic. Disagreement was resolved by consensus.

Assessment of heterogeneity

Heterogeneity of effect size across studies pooled was calculated using a chi square test, with P< 0.05 used as the cut‐off level for significance. Sensitivity analyses were performed on the basis of methodological quality. Results were re‐analysed using studies of only the highest quality scores (Jadad 3 to 5). Subgroup analyses based upon patient age, delivery device and study duration were planned.

Data synthesis

A weighted treatment effect across trials was calculated using the Cochrane statistical package RevMan 4.0.3 with MetaView 3.1. For continuous outcomes, a weighted mean difference (WMD) or standardised mean difference (SMD) was calculated as appropriate. For dichotomous outcomes a relative risk (RR) was calculated. Pooled treatments effects are expressed with their 95% confidence intervals (95% CI). A fixed effect model was used throughout. A number of a priori conditions were established regarding the comparisons made:

1. Studies were distinguished as those in which patients were a) not treated with regular oral corticosteroid (OCS), b) dependent upon regular oral steroid treatment prior to study. Trials involving OCS‐dependent patients in which the efficacy of inhaled corticosteroid (ICS) is being assessed may have an 'OCS down‐titration' design using reduction in the use of oral steroid as an outcome measure, whilst maintaining a given level of asthma control. However, studies in which patients were not treated with regular OCS are more likely to have a design aimed at detecting improvements in asthma control. It is inappropriate to combine trials with these different designs and objectives.

2. The results of parallel and crossover trials were not pooled.

3. It was anticipated that measures of bronchial hyper‐responsiveness (PD20 FEV1, PC20 FEV1) would often be reported as geometric means. Presentation of results in this way indicates that data has been logarithmically transformed prior to analysis by investigators to take account of a skewed distribution. Data for such outcomes was only pooled across studies where the mean and standard deviation of logged values (from which geometric means are derived) could be calculated.

Results

Description of studies

Results of the search

Stage 1 electronic search: 6494 citations retrieved, 2162 original citations

Stage 2 electronic search:

BDP register BUD register

Electronic citations 1149 1036

Citations excluded from abstract description:  Not RCT 379 331  Not chronic asthma in humans 190 195  Not concerned with ICS treatment 177 129  Clearly not concerned with BDP v BUD 113 40

Papers retrieved in full text 290 341

Excluded after full paper retrieval:  Not RCT 94 46  Not involving BDP v BUD comparison at 176 275  equal nominal daily dose

Included studies 20  (same studies identified from both registers)

One study (Greefhorst 1992) was identified after searching the bibliographies of included studies, three studies (Dal Negro 1997, Hamalainen 1998, Micheletto 1997) were identified by searching the proceedings of respiratory society meetings.

Included studies

24 publications were identified met the inclusion criteria for the review representing 24 studies. Publication dates ranged from 1982 to 1998. Details of the trials are in the table of Characteristics of Included Studies. Four studies were identified that were published in abstract form only (Dal Negro 1997, Greefhorst 1992, Hamalainen 1998, Micheletto 1997). No outcome data for these studies is available. The studies have been included as further information may be available at a future date when the review is updated. Two further publications (Hernandez 1995, Lee 1995) require translation and are awaiting assessment. We would also like to draw the reader's attention to the six further citations (Baxter‐Jones 2000, Brand 2001, Dal Negro 1999b, Jager 2000, Kraszko 1999, Reichel 2001) listed under Studies awaiting assessment. Due to unforeseen delays in the publication of this review, a number of potentially relevant trials have been identified after an up dated search of the electronic sources from April 1999 ‐ August 2001. These studies will be fully evaluated and included as appropriate in a future update at the earliest possible opportunity.

Study Populations

The majority of studies were conducted in Europe (Belgium, Denmark, Finland, France, Germany, Ireland, Italy, Sweden, The Netherlands, UK). One study (Springer 1987) was conducted in Israel. One study (Baran 1987) was conducted in a residential centre for asthmatic children; in one study (Greefhorst 1992) the setting was unclear. All other studies were conducted in a hospital outpatient clinic setting. Six studies were in children, 18 in adults.

Diagnosis of asthma

In 17 studies (71%) there was no clear indication of the criteria upon which a diagnosis of asthma was made and appears to have been at the discretion of the investigators. In one study (Boe 1989) diagnosis was based upon ATS 1962 criteria. In three studies (Bisgaard 1988, Ebden 1986, Petrie 1990) diagnosis was supported by demonstrable reversibility of clinic PEF or FEV1 following inhaled beta2 agonist; in three studies (Brambilla 1994, Svendsen 1992, Tjwa 1995) diagnosis was supported by demonstration of a 15% or greater reversibility in FEV1 following inhaled beta2 agonist or variability in FEV1 in combination with bronchial hyper‐responsiveness (BHR) to methacholine or histamine.

Treatment with oral corticosteroids

In three early studies (Rafferty 1985, Stiksa 1982a, Stiksa 1982b) requirement for oral corticosteroid (OCS) for asthma control in the form of prednisolone was an inclusion criterion. In one study (Stiksa 1985) a proportion of enrolled patients were OCS‐treated, although this was not a specific inclusion criterion. In 20 studies regular OCS treatment was either a specific exclusion criterion or it was clear from baseline demographic characteristics that patients were not receiving regular OCS prior to the study.

Asthma severity and asthma control

Asthma severity may be defined in terms of the amount of medication required to achieve a certain level of asthma control, or in terms of the frequency of symptoms experienced and/or the degree to which FEV1 (% predicted) is depressed before commencing regular prophylactic therapy. Asthma control is best considered the degree to which patients symptoms are uncontrolled and/or the degree to which their FEV (% predicted) is depressed, irrespective of the amount/type of prophylactic medication prescribed. The characteristics of the included studies in terms of these factors have been listed in Table 1, Table 2 and Table 3. Baseline FEV1 (% predicted) and symptom frequency were reported infrequently, so, in the majority of studies, it was not possible to determine the level of asthma control at randomisation.

1. Trial recruiting non‐OCS, non‐ICS treated asthmatics: baseline asthma control.

Study ID	B.L. FEV1 (% pred)	B.L. symp freq
Bisgaard 1988	not stated	not stated
Keelan 1984	not stated	symptoms 'insufficiently controlled' by bronchodilators and/or anti‐allergy therapy
Nicolaizik 1994	not stated	symptoms 'inadequately controlled'

B.L: baseline

Study ID	B.L. ICS dose	B.L. FEV1 (% pred)	B.L. symp freq
Baran 1987	not stated	not stated	not stated
Bjorkander 1982	not stated	>70	not stated
Boe 1989	ICS 400‐800 mcg/d	not stated	not stated
Brambilla 1994	BDP 1000‐2000 mcgd	not stated	recurrent acute exacerbations of dyspoea and wheezing
Dal Negro 1997	BDP 1000 mcg/d	not stated	not stated
Ebden 1986	not stated	not stated	not clearly stated but in opinion of investigator patients were poorly controlled
Field 1982	not stated	not stated	not stated
Greefhorst 1992	not stated	not stated	not stated
Hamalainen 1998	BDP or BUD 800‐1000 mcg/d	not stated	not stated
Michleletto 1997	BDP 1000 mcg/d	not stated	not stated
Pedersen 1988	BDP or BUD 800‐1200 mcg/d	not stated	not stated
Petrie 1990	BDP or BUD 800‐1600 mcg/d	mean 72%, range 34‐114)	not stated
Selroos 1994	BDP 1000 mcg/d	not stated but mean PEFR 75‐77% predicted	not stated
Springer 1987	BDP 400 mcg/d	not stated	not stated
Svendsen 1993	ICS 300‐500 mcg/d	<70	stated by authors that asthma was 'poorly controlled'
Tjwa 1995	ICS 150‐800 mcg/d	40‐85	not stated
Willey 1982	BDP 400 mcg/d or greater	not stated	symptom frequency not stated, but at least 2 courses or oral steroids in last 12 months for exacerbations

B.L: baseline

Study ID	Missing data
Bisgaard 1988	Morning PEFR  Evening PEFR  Daily beta3 agonist use  No numerical data presented for above outcomes
Boe 1989	FEV1  FVC  Morning PEFR  Evening PEFR  Daily asthma symptom score  No numerical data for above outcomes
Dal Negro 1997	FEV1  Unclear if error bars plotted represent standard deviation values or standard error    FVC  FEF25‐75  FEF 50  Rescue use beta2 agonist  Daily wheeze score  Outcomes reported as medians with ranges
Ebden 1986	Rescue use beta2 agonist  Daily wheeze score  Outcomes reported as medians with ranges
Greefhorst 1992	Morning PEFR  Evening PEFR  No SD values for above outcomes  Asthma symptom score  Rescue beta2 agonist use  No numerical data available
Hamalainen 1998	Morning PEFR  Morning plasma cortisol  No standard deviation values available for above outcomes
Keelan 1984	FEV1  FVC  Morning PEFR  Evening PEFR  Asthma symptom score  Beta2 agonist use  Serum cortisol (time not specified)  No numerical data presented for above outcomes
Micheletto 1997	FEV1  Serum ECP  Unclear if error bars plotted represent standard deviation values or standard error for above outcomes    FVC  Clinic PEFR  FEF 25‐75  Morning PEFR  Evening PEFR  Daily beta2 agonist use  Morning serum cortisol  No numerical data available for above outcomes
Nicolaizik 1994	Serum cortisol  Serum ACTH  24 hour urinary free cortisol  Above outcomes expressed using medians and analyses using non‐parametric tests  Histamine BHR (PC20 FEV1)  No SD values for log transformed data available
Petrie 1990	FEV1  Morning PEFR  Evening PEFR  Daily beta2 agonist use (puffs/day)  No numerical data presented for above outcomes  Questionnaire concerning delivery device: ease of use, carrying convenience, overall preference  No SD values presented for above outcomes
Svendsen 1993	FEV1  FVC  Morning PEFR  Evening PEFR  Clinic PEFR  Histamine BHR (PC20 FEV1)  Sleep disturbance, wheeze and activity restriction score  Rescue beta2 agonist use (puffs/day)  Plasma cortisol (time not stated)  Plasma cortisol 30 min post 250 mcg iv tetracosactrin  No SD values available for any of the above outcomes

Date	Event	Description
21 July 2008	Amended	Converted to new review format.
14 November 1999	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV1 (% predicted)	2	74	Mean Difference (IV, Fixed, 95% CI)	‐5.04 [‐11.98, 1.89]
1.1 400 mcg/d or less	2	74	Mean Difference (IV, Fixed, 95% CI)	‐5.04 [‐11.98, 1.89]
1.2 500‐800 mcg/d	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 FEV1 (litres)	6	227	Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐0.43, ‐0.03]
2.1 400 mcg/d or less	5	174	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.50, ‐0.04]
2.2 500‐800 mcg/d	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 1000 mcg/d or greater	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.51, 0.29]
3 FEV1 (% predicted, litre measures combined)	8	301	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.38, 0.07]
3.1 400 mcg/d or less	7	248	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.40, 0.10]
3.2 500‐800 mcg/d	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 1000 mcg/d or greater	1	53	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.68, 0.40]
4 FVC (% predicted)	1	54	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐8.79, 9.99]
4.1 400 mcg/d or less	1	54	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐8.79, 9.99]
4.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 FVC (litres)	5	203	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]
5.1 400 mcg/d or less	4	150	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.32, 0.22]
5.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 1000 mcg/d or greater	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.08 [‐0.54, 0.38]
6 FVC (% predicted, litre measures combined)	6	257	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.29, 0.20]
6.1 400 mcg/d or less	5	204	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.31, 0.24]
6.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 1000 mcg/d or greater	1	53	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.63, 0.45]
7 Clinic PEFR (% predicted)	1	20	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐14.55, 10.55]
7.1 400 mcg/d or less	1	20	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐14.55, 10.55]
7.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Morning PEFR (% predicted)	1	54	Mean Difference (IV, Fixed, 95% CI)	‐2.90 [‐16.86, 11.06]
8.1 400 mcg/d or less	1	54	Mean Difference (IV, Fixed, 95% CI)	‐2.90 [‐16.86, 11.06]
8.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Morning PEFR (L/min)	6	220	Mean Difference (IV, Fixed, 95% CI)	‐2.99 [‐28.43, 22.45]
9.1 400 mcg/d or less	5	168	Mean Difference (IV, Fixed, 95% CI)	‐3.02 [‐32.36, 26.32]
9.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 1000 mcg/d or greater	1	52	Mean Difference (IV, Fixed, 95% CI)	‐2.90 [‐52.00, 48.20]
10 Morning PEFR (% predicted, L/min measures combined)	7	274	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.28, 0.20]
10.1 400 mcg/d or less	6	222	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.31, 0.22]
10.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.3 1000 mcg/d or greater	1	52	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.57, 0.51]
11 Evening PEFR (L/min)	5	211	Mean Difference (IV, Fixed, 95% CI)	‐5.47 [‐31.50, 20.56]
11.1 400 mcg/d or less	4	158	Mean Difference (IV, Fixed, 95% CI)	‐7.12 [‐38.59, 24.35]
11.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.3 1000 mcg/d or greater	1	53	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐48.21, 44.41]
12 Daytime breathlessness score	2	74	Std. Mean Difference (IV, Fixed, 95% CI)	0.26 [‐0.20, 0.72]
12.1 400 mcg/d or less	2	74	Std. Mean Difference (IV, Fixed, 95% CI)	0.26 [‐0.20, 0.72]
12.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Morning breathlessness score	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.34 [‐0.85, 0.17]
13.1 400 mcg/d or less	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.34 [‐0.85, 0.17]
13.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Daytime wheeze score	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.29 [‐0.40, 0.99]
14.1 400 mcg/d or less	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.29 [‐0.40, 0.99]
14.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Morning wheeze score	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.66, 0.36]
15.1 400 mcg/d or less	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.66, 0.36]
15.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Daytime cough score	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.39 [‐0.31, 1.09]
16.1 400 mcg/d or less	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.39 [‐0.31, 1.09]
16.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Morning cough score	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.61, 0.40]
17.1 400 mcg/d or less	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.61, 0.40]
17.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Daily asthma symptom score	5	164	Std. Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.22, 0.39]
18.1 400 mcg/d or less	5	164	Std. Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.22, 0.39]
18.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 Symptoms (daytime breathlessness, morning breathlessness, daily symptom scores combined)	7	256	Std. Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.18, 0.31]
19.1 400 mcg/d or less	7	256	Std. Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.18, 0.31]
19.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
20 Night‐time breathlessness score	2	74	Std. Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.34, 0.57]
20.1 400 mcg/d or less	2	74	Std. Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.34, 0.57]
20.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
21 Evening breathlessness score	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐0.86, 0.16]
21.1 400 mcg/d or less	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐0.86, 0.16]
21.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
21.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22 Night‐time wheeze score	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.53, 0.85]
22.1 400 mcg/d or less	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.53, 0.85]
22.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23 Evening wheeze score	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐0.73, 0.28]
23.1 400 mcg/d or less	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐0.73, 0.28]
23.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24 Night‐time cough score	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.43 [‐0.27, 1.13]
24.1 400 mcg/d or less	1	32	Std. Mean Difference (IV, Fixed, 95% CI)	0.43 [‐0.27, 1.13]
24.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
25 Evening cough score	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.70, 0.32]
25.1 400 mcg/d or less	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.70, 0.32]
25.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
25.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
26 Symptoms (night‐time breathlessness, evening breathlessness scores combined)	3	134	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.43, 0.25]
26.1 400 mcg/d or less	3	134	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.43, 0.25]
26.2 500‐800 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
26.3 1000 mcg/d or greater	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
27 Daytime use of rescue beta2 agonist (puffs/day)	1	32	Mean Difference (IV, Fixed, 95% CI)	0.48 [‐0.13, 1.09]
27.1 400 mcg/d or less	1	32	Mean Difference (IV, Fixed, 95% CI)	0.48 [‐0.13, 1.09]
27.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
28 Morning use of rescue beta2 agonist (puffs)	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.64, 0.44]
28.1 400 mcg/d or less	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.64, 0.44]
28.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
28.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
29 Night‐time use of rescue beta2 agonist (puffs/night)	1	32	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.52, 0.42]
29.1 400 mcg/d or less	1	32	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.52, 0.42]
29.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
29.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
30 Evening use of rescue beta2 agonist (puffs)	1	60	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐3.65, 1.65]
30.1 400 mcg/d or less	1	60	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐3.65, 1.65]
30.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
30.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
31 Histamine BHR (log 10 PC20 FEV1)	1	20	Mean Difference (IV, Fixed, 95% CI)	0.43 [0.05, 0.81]
31.1 400 mcg/d or less	1	20	Mean Difference (IV, Fixed, 95% CI)	0.43 [0.05, 0.81]
31.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.3 1000 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
32 Morning plasma cortisol (nmol/L)	3	118	Mean Difference (IV, Fixed, 95% CI)	24.32 [‐15.78, 64.41]
32.1 400 mcg/d or less	2	66	Mean Difference (IV, Fixed, 95% CI)	22.29 [‐37.29, 81.86]
32.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
32.3 1000 mcg/d or greater	1	52	Mean Difference (IV, Fixed, 95% CI)	26.0 [‐28.21, 80.21]
33 Plasma cortisol 30 min post 250 mcg tetracosactrin (nmol/L)	2	76	Mean Difference (IV, Fixed, 95% CI)	26.84 [‐24.79, 78.48]
33.1 400 mcg/d or less	1	24	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐254.22, 254.22]
33.2 500‐800 mcg/d or greater	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
33.3 1000 mcg/d or greater	1	52	Mean Difference (IV, Fixed, 95% CI)	28.00 [‐24.74, 80.74]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Daily dose inhaled corticosteroid (mcg)	2	231	Mean Difference (IV, Fixed, 95% CI)	444.22 [332.46, 555.98]
1.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 1‐5 months	1	129	Mean Difference (IV, Fixed, 95% CI)	470.00 [315.00, 625.00]
1.3 6 months or longer	1	102	Mean Difference (IV, Fixed, 95% CI)	416.30 [255.01, 577.59]
2 FEV1 (litres)	2	231	Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.23, 0.20]
2.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 1‐5 months	1	129	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.30, 0.20]
2.3 6 months or longer	1	102	Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.33, 0.47]
3 Morning PEFR	1	129	Mean Difference (IV, Fixed, 95% CI)	‐18.0 [‐54.76, 18.76]
3.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 1‐5 months	1	129	Mean Difference (IV, Fixed, 95% CI)	‐18.0 [‐54.76, 18.76]
3.3 6 months or longer	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Evening PEFR (L/min)	1	129	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐49.29, 33.29]
4.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 1‐5 months	1	129	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐49.29, 33.29]
4.3 6 months or longer	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Daily PEFR (L/min)	1	102	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐58.72, 59.92]
5.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 1‐5 months	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 6 months or longer	1	102	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐58.72, 59.92]
6 Rescue beta2 agonist use (puffs/day)	1	129	Mean Difference (IV, Fixed, 95% CI)	0.5 [‐0.43, 1.43]
6.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 1‐5 months	1	129	Mean Difference (IV, Fixed, 95% CI)	0.5 [‐0.43, 1.43]
6.3 6 months or longer	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Withdrawal due to asthma exacerbation (No. of patients)	1	146	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.44, 7.10]
7.1 1‐4 weeks	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 1‐5 months	1	146	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.44, 7.10]
7.3 6 months or longer	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Sore throat/erythematous throat/Candidiasis (No. of patients)	1	146	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.92, 2.37]
8.1 1‐4 weeks	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 1‐5 months	1	146	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.92, 2.37]
8.3 6 months or longer	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Hoarseness (No. of patients)	2	248	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.74, 1.76]
9.1 1‐4 weeks	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 1‐5 months	1	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.61, 1.55]
9.3 6 months or longer	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	3.90 [0.93, 16.27]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Morning PEFR (L/min)	3	144	Mean Difference (IV, Fixed, 95% CI)	3.15 [‐30.72, 37.01]
2 Evening PEFR (L/min)	3	144	Mean Difference (IV, Fixed, 95% CI)	4.68 [‐29.03, 38.38]
3 Daytime breathlessness score	3	144	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.36, 0.29]
4 Night‐time breathlessness score	3	144	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.08 [‐0.41, 0.24]
5 Sleeping difficulty due to asthma score	3	144	Std. Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.25, 0.40]
6 Rescue beta2 agonist use (puffs/d)	3	144	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.70, 0.96]

Methods	Setting: Belgium, residential centre for asthmatic children  Length of intervention: 3 weeks  Design: crossover, no washout  Randomisation: yes, method not stated   Allocation concealment: unclear  Masking: double blind  Excluded: not stated  Withdrawals: stated (none)  Baseline characteristics: no tabulated demographic data  Jadad score: 3
Participants	21 children: 15M 6F  Age range: 4‐14  Inclusion criteria:  Children suffering from chronic asthma and using inhaled corticosteroids to control their disease  No other criteria given  Exclusion criteria:  None stated
Interventions	BDP: 50 mcg 2puffs 2xdaily (200 mcg/d) via MDI BUD: 50 mcg 2puffs 2xdaily (200 mcg/d) via Inhalet spacer
Outcomes	FEV1  FVC  Morning PEFR  Evening PEFR  Daytime breathlessness score  Night‐time breathlessness score  Daily cough score  Sleeping difficulties score  8 am plasma cortisol   Incidence of oropharyngeal Candidiasis  Both active treatment arms demonstrated significant improvements compared to non‐randomised placebo arm for morning PEFR, evening PEFR and symptom scores.
Notes	No reply from author to clarify details of randomisation method  Not stated if carryover effects were tested for.  Significant improvements in morning PEFR, evening PEFR and symptoms compared to non‐randomised placebo treatment period at end of study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: multicentre Denmark, hospital outpatient clinic  Length of intervention: 3 months  Design: parallel group, dose escalation  Randomisation: yes, method not stated  Allocation concealment: unclear  Masking: double blind  Excluded: not stated  Withdrawals: stated   Baseline characteristics: comparable  Jadad score: 4
Participants	41 children   Age range: 7‐15 years (of those completing trial)  Inclusion criteria:  Children with bronchial asthma  "airway obstruction reversible by > 20%"  All children recruited were using regular beta2 agonists.  None of the children recruited had used oral steroids within the previous 6 months, but this was not an explicit exclusion criterion.  Exclusion criteria:   None stated
Interventions	BDP: step‐wise increased doses (200, 400, 800 mcg daily) via aerosol MDI BUD: step‐wise increased doses (200, 400, 800 mcg daily) via aerosol MDI
Outcomes	24 hour urinary free cortisol excretion (corrected for creatinine)  Plasma cortisol 30 min post 125 mcg iv tetracosactrin (nmol/L)  Morning PEFR (% predicted)  Evening PEFR (% predicted)  Rescue beta2 agonist use  Withdrawal due to asthma exacerbation (No. of patients)
Notes	Dose escalation design: patients were randomised to receive either BDP or BUD. Successive doses (200 mcg/d, 400 mcg/d, 800 mcg/d) were given for 4 week periods in succession, with no washout between each dose. Patients were not randomised to receive each dose.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: Sweden, hospital outpatient clinic  Length of intervention: 2 weeks  Design: crossover, 1 week washout  Randomised: yes, method not stated  Allocation concealment: unclear  Masking: not stated  Excluded: not stated  Withdrawals: none, but 5 patients excluded from analysis due to requirement for oral steroids during washout period  Baseline characteristics: no details  Jadad score: 2
Participants	17 adults randomised, 12 completed the study: 3M 9F  Age range: 27‐66 years  Inclusion criteria:  Stable chronic asthma of moderate severity   Demonstrated requirement for treatment with BDP over last year and were steroid dependent i.e. relapsed if steroid medication was withdrawn  % predicted FEV1 70 or greater  Exclusion criteria:  None stated
Interventions	BDP: 100mcg 1 puff 4xdaily (400mcg/day) via MDI BUD: 100mcg 1 puff 4xdaily (400mcg/day) via MDI
Outcomes	FEV1   FVC   Morning PEFR   Evening PEFR  Daily use of beta2 agonists (puffs/day)   Daily asthma symptom score   Morning plasma cortisol   Morning plasma cortisol 30 min post 250mg tetracosactrin
Notes	No reply from author to clarify details of randomisation method  Published paper reported two studies. The second study was excluded (see Excluded studies).  Significantly higher FEV1 and morning PEFR in BDP treated subjects, and higher evening PEFR in BUD treated subjects, compared to placebo washout
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: multicentre study Sweden, hospital outpatient clinic  Length of intervention: 4 weeks  Design: crossover, no washout  Randomisation: yes, random number table  Allocation concealment: unclear  Masking: double blind  Excluded: not stated  Withdrawals: stated  Baseline characteristics: no details  Jadad score: 4
Participants	128 adults: 67M 61F  Age range 18‐77 years  Inclusion criteria:   Asthma as defined by ATS criteria  Requirement for inhaled steroids in a dose range of 400‐800 mcg/d  Exclusion criteria:  Cardiovascular disease or diabetes mellitus
Interventions	Four treatment allocations:  1) BDP 200 micrograms 2xdaily (400 mcg/day)  2) BUD 200 micrograms 2xdaily (400 mcg/day)  3) BDP 500 micrograms 2xdaily (1000 mcg/day)  4) BUD 400 micrograms 2xdaily (800 mcg/day)  All via MDI
Outcomes	FEV1  FVC  Morning PEFR  Evening PEFR  Daily asthma symptom score
Notes	No reply from author to clarify if allocation concealment was employed  Not stated if carryover effects were tested for.  Significant improvements in morning/evening PEFR, beta2 agonist use, symptoms in BDP and BUD groups compared to non‐randomised placebo.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: multicentre study France, hospital outpatient clinic  Length of intervention: 12 weeks  Design: parallel group, dose down‐titration  Randomisation: yes, method not stated  Allocation concealment: unclear  Masking: none  Excluded: not stated  Withdrawals: stated   Baseline characteristics: comparable  Jadad score: 2
Participants	146 adults   Inclusion criteria:  Recurrent acute exacerbations of breathlessness and wheezing  15% or greater variability in FEV1   Bronchial responsiveness to methacholine or histamine (PD20 FEV1 2mg or less)  Receiving inhaled BDP 1000‐2000 mcg/d for at least 6 months  Exclusion criteria:  Airways disease other than asthma  Smoker > 5 packs cigarettes per year   Significant co‐existent disease
Interventions	BDP: 800 to 2000 mcg total daily dose via MDI BUD: 800 to 1600 mcg total daily dose via Turbohaler DPI
Outcomes	FEV1   Morning PEFR   Evening PEFR   Number of puffs of inhaled corticosteroid per day   Number asthma exacerbations/week  Number night awakenings requiring beta2 agonist use/week  Daily beta2 agonist use (puffs/day)   Withdrawal due to asthma exacerbation  Incidence of local oral side effects
Notes	Reply from author but unable to clarify details of randomisation procedure.  Dose down titration study design: patients were randomised to receive either BDP or BUD at a dose considered to be equivalent to their pre‐study dose of BDP. BDP 250 mcg/puff via MDI was considered equivalent to BUD 200 mcg/actuation via Turbuhaler DPI.   During the study daily dose of ICS was reduced according to pre‐defined criteria based on experience of asthma symptoms in the week prior to assessment.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: multicentre study Italy, hospital outpatient clinic  Length of intervention period: 8 weeks  Randomisation: yes, method not stated  Allocation concealment: unclear  Design: parallel group  Masking: not stated  Excluded: not stated  Withdrawals: stated  Baseline characteristics: no demographic data presented  Jadad score: 1
Participants	79 adult adults  Inclusion criteria:  Adult patients with stable asthma (not defined)  Regular treatment with BDP 1000 mcg/d  No further details  Exclusion criteria:  No details
Interventions	BDP: 200 mcg 4xdaily (800 mcg/d) via Pulvinal DPI BUD: 200 mcg 4xdaily (800 mcg/d) via Turbuhaler DPI
Outcomes	FEV1   FVC  FEF25‐75  MEF50  Morning PEFR  Asthma symptom score
Notes	Study in abstract form only.  No reply from trial sponsors to clarify details of randomisation procedure, further inclusion/exclusion criteria, patient withdrawals or outcomes data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: Wales, hospital outpatient clinic  Length of intervention: 6 weeks  Design: crossover, no washout  Randomisation: yes, method not stated  Allocation concealment: unclear  Masking: double blind  Excluded: not stated  Withdrawals: stated  Baseline characteristics: no details  Jadad score: 3
Participants	28 adults: 20M 8F  Age range: 19‐72 years  Inclusion criteria  Patients with chronic asthma whose "attending physician considered their asthma to be poorly controlled and require further treatment"  15% reversibility in PEFR after inhaled beta2 agonist  Good inhaler technique  Exclusion criteria:  Use of oral steroids within 2 months of the study
Interventions	BDP: 250 mcg 3puffs 2xdaily (1500 mcg/day) via MDI BUD: 200 mcg 4 puffs 2xdaily (1600 mcg/day) via MDI+ collapsible spacer
Outcomes	FEV1   FVC   Morning PEFR   Evening PEFR   Daily beta2 agonist (puffs/day)  Daytime wheeze score   Morning serum cortisol   Serum cortisol 30 minutes post 250mcg tetracosactrin
Notes	Reply from author but unable to clarify details of randomisation procedure or if carryover effects were excluded.  Majority of patients demonstrated a significant improvement in at least one efficacy outcome compared to baseline
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: UK, paediatric outpatient clinic   Length of intervention: 4 weeks  Design: crossover, no washout  Randomisation: yes, method not stated   Allocation concealment: unclear  Masking: double blind  Excluded: not stated  Withdrawals: stated   Baseline characteristics: no details   Jadad score: 3
Participants	31 children: 19M 12F  Age range: 4‐14 years  Inclusion criteria:  "fairly severe asthma requiring regular inhaled corticosteroids"  Exclusion criteria: not stated
Interventions	BDP: 400 mcg/day in 4 divided doses children remained on delivery device used before trial (either aerosol MDI or Rotahaler DPI) BUD: 200 mcg 2xdaily (400 mcg/day) via aerosol MDI with tube spacer
Outcomes	FEV1 (% predicted)   FVC (% predicted)   Morning PEFR (% predicted)   Evening PEFR (% predicted)   FEF 50 (% predicted)  FEF 25 (% predicted)  Daily symptom score
Notes	Reply from authors but unable to clarify details of randomisation procedure.  Not stated if carryover effects were tested for.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: muticentre study, The Netherlands, primary care or hospital outpatient setting unclear   Length of intervention period: 6 weeks  Randomisation: yes, method not stated  Allocation concealment: unclear  Design: crossover, no washout  Masking: none  Excluded: not stated  Withdrawals: not stated  Baseline characteristics: no demographic data presented  Jadad score: 1
Participants	145 adults  Inclusion criteria:  Adult asthmatic patients already treated with inhaled corticosteroids  No further details  Exclusion criteria:  No details
Interventions	BDP: 200 mcg 2xdaily (400 mcg/d) via Rotahaler DPI BUD: 200 mcg 2xdaily (400 mcg/d) via Turbuhaler DPI
Outcomes	Morning PEFR  Evening PEFR  Asthma symptom score  Rescue beta2 agonist use
Notes	Study in abstract form only.  No reply from author to clarify details of randomisation method used, further inclusion/exclusion criteria, patient withdrawals or data for outcomes.  Not stated if carryover effects were tested for.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: multicentre study Germany, hospital outpatient clinic  Length of intervention period: 8 weeks  Randomisation: yes, method not stated  Allocation concealment: unclear  Design: crossover, no washout   Masking: none  Excluded: not stated  Withdrawals: not stated  Baseline characteristics: no demographic data presented  Jadad score: 1
Participants	79 adults: 39M 40F  Mean (SD) age: 51 (15) years  Inclusion criteria:  Adults with asthma currently treated with inhaled BDP 1000 mcg/day via MDI  Non smokers  No further details  Exclusion criteria:  No details
Interventions	BDP: 200 mcg 4 actuations/day (800 mcg/d) via Easyhaler DPI BUD: 200 mcg 4 actuations/day (800 mcg/d) via Turbuhaler DPI
Outcomes	Morning PEFR  Morning serum cortisol
Notes	Study in abstract form only.   No reply from author to clarify details of randomisation method used, further inclusion/exclusion criteria, patient withdrawals or data for outcomes.  Not stated if carryover effects were tested for.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: Ireland, hospital outpatient clinic  Length of intervention: 4 weeks  Design: crossover, no washout  Randomisation: yes, method not stated   Allocation concealment: unclear  Masking: double‐blind  Excluded: not stated  Withdrawals: stated  Baseline characteristics: no tabulated demographic data presented  Jadad score: 3
Participants	36 adults: 21M 15F  Age range: 15‐65 years  Inclusion criteria:  Adults with asthma insufficiently controlled by bronchodilators and /or anti‐allergic therapy and who required 400 micrograms of BDP per day.  Exclusion criteria:  Bronchopulmonary disease other than asthma, or other disease  Use of oral steroids or ACTH preparation within last month
Interventions	BDP: 50 mcg 2 puffs 4xdaily (400 mcg/day) via MDI and placebo via MDI+spacer BUD: 50 mcg 2 puffs 4xdaily (400 mcg/day) via MDI+ spacer and placebo via MDI
Outcomes	FEV1   FVC   Morning PEFR  Evening PEFR  Asthma symptom score   Beta2 agonist use   Serum cortisol (time not specified)
Notes	No reply from author to clarify details of randomisation procedure.  Not stated if carryover effects were tested for.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: Italy, hospital outpatient clinic  Length of intervention period: 8 weeks  Randomisation: yes, method not stated  Allocation concealment: unclear  Design: parallel group  Masking: unclear  Excluded: not stated  Withdrawals: not stated  Baseline characteristics: no details  Jadad score: 1
Participants	32 adults  Age range: not stated  Inclusion criteria:  Adult patients with stable asthma receiving inhaled BDP 1000 mcg/day  No other details  Exclusion criteria:  Not stated
Interventions	BDP: 200 mcg 4xdaily (800 mcg/day) via Pulvinal DPI BUD: 200 mcg 4xdaily (800 mcg/day) via Turbuhaler DPI
Outcomes	FEV1  FVC  Clinic PEFR  FEF 25‐75  Morning PEFR  Evening PEFR  Daily beta2 agonist use  Serum ECP  Morning serum cortisol
Notes	Study in abstract form only.   No reply from trial sponsors to clarify details of randomisation procedure, further inclusion/exclusion criteria, patient withdrawals or data for outcomes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: UK, hospital outpatient clinic  Length of intervention: 2 weeks  Design: crossover, no washout  Randomisation: yes, method not stated  Allocation concealment: unclear  Masking: none  Excluded: not stated  Withdrawals: stated   Baseline characteristics: no tabulated demographic data presented  Jadad score: 2
Participants	14 children: 11M 3F  Age range: 8 to 14 years  Inclusion criteria:  Asthma inadequately controlled on inhaled sodium cromoglycate and beta2 agonists and/or optimal doses of slow release oral theophyllines  Reliable in medication compliance, diary card recording, use of MDI  Exclusion criteria:  Any steroid medication within the last month or regular corticosteroid treatment in the last 12 months.  Significant bronchopulmonary disease other than asthma
Interventions	BDP: 50 mcg 4 puffs 2xdaily (400 mcg/day) via MDI BUD: 50 mcg 4 puffs 2xdaily (400 mcg/day) via MDI
Outcomes	FEV1   FVC   Morning PEFR   Evening PEFR  Daily symptom score   Weekly use of beta2 agonists   Bronchial responsiveness to histamine PC20 FEV1, PD20 FEV1)   Serum cortisol (area under curve for 12 hours, 20min interval samples)  Serum growth hormone (area under curve for 12 hours, 20min samples)  12pm serum ACTH   8am serum ACTH   24 hour urinary free cortisol
Notes	Reply from authors but unable to clarify details of randomisation procedure  Not stated if carryover effects were tested for.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: Denmark, hospital outpatient clinic  Length of intervention: 6 weeks  Design: crossover, no washout  Randomisation: yes, computer generated algorithm  Allocation concealment: yes, using sealed envelopes  Masking: none  Excluded: not stated  Withdrawals: stated  Baseline characteristics: no tabulated demographic data presented  Jadad score: 3
Participants	31 children: 15M 16F  Age range: 5‐15 years  Inclusion criteria:  Children with asthma receiving high dose inhaled corticosteroids (either BDP or BUD)  Exclusion criteria:  Receipt of oral or parenteral steroids in last 6 months
Interventions	BDP: total daily dose 800‐1200 mcg via either aerosol MDI or MDI+spacer BUD: total daily dose 800‐1200 mcg via either aerosol MDI or MDI+spacer  Children continued with the same dose of inhaled steroid throughout the trial, which was their dose at baseline on entering the study
Outcomes	24 hour urinary free cortisol
Notes	Author confirmed method of random order generation and use of allocation concealment.  Carryover effects were tested for and excluded.  Children continued using the delivery device that they had been using prior to study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

PERMALINK

Beclomethasone versus budesonide for chronic asthma

Nick P Adams

Janine C Bestall

Paul Jones

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Assessment of heterogeneity

Data synthesis

Results

Description of studies

Results of the search

Included studies

1. Trial recruiting non‐OCS, non‐ICS treated asthmatics: baseline asthma control.

2. Trials recruiting non‐OCS, but ICS‐treated asthmatics: baseline asthma control.

3. Trials recruiting OCS‐treated asthmatics: baseline asthma control.

Risk of bias in included studies

Effects of interventions

4. Outcome data not included in meta‐analysis.

ASTHMA NOT TREATED WITH ORAL STEROIDS

CROSSOVER STUDIES

Spirometry

Peak expiratory flow rate (PEF)

Symptoms

Rescue beta‐2 agonist use

Bronchial hyper‐responsiveness (BHR)

Hypothalamo‐pituitary adrenal axis (HPA) function

Local oral side effects

Sensitivity analyses

Subgroup analyses

PARALLEL GROUP STUDIES: DOSE‐DOWN TITRATION DESIGN

PARALLEL GROUP STUDIES: DOSE ESCALATION DESIGN

ASTHMATICS TREATED WITH ORAL STEROIDS

CROSSOVER STUDIES: OCS‐SPARING STUDY DESIGN

CROSSOVER STUDIES: NON OCS‐SPARING STUDY DESIGN

Discussion

RELATIVE EFFICACY

RELATIVE SAFETY

STUDY POWER

Authors' conclusions

Implications for practice.

Implications for research.

Feedback

Data entry error

Summary

Reply

Contributors

What's new

History

Acknowledgements

Data and analyses

Comparison 1. BDP v BUD crossover design studies, no OCS: all doses.

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

Methods	Setting: multicentre study UK, hospital outpatient clinic   Length of intervention: 4 weeks  Design: crossover, no washout  Randomisation: yes, method not stated  Allocation concealment: unclear  Masking: none  Excluded: stated   Withdrawals: stated   Baseline characteristics: no tabulated demographic data presented  Jadad score: 2
Participants	40 adults  Age range of study completers: 26‐76 years  Inclusion criteria:  Adults with chronic stable asthma  15% or greater reversibility in PEFR following beta2 agonists or > 20% variability in daily PEFR during 2 week run in period  All patients receiving 800‐1600 mcg inhaled BDP or BUD on entry to study.  Exclusion criteria:  Respiratory tract infection within last 2 weeks
Interventions	BDP: 100 mcg 4puffs 2xdaily ( 800mcg/day) via Diskhaler DPI BUD: 200 mcg 2 puffs 2xdaily (800 mcg/day) via Turbohaler DPI
Outcomes	FEV1   Morning PEFR   Evening PEFR   Daily beta2 agonist use
Notes	No reply from author to clarify details of randomisation procedure
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: Finland, hospital outpatient clinic  Length of intervention: 2 years  Design: parallel group, dose down titration  Randomisation: yes, computer randomisation algorithm  Allocation concealment: unclear  Masking: none  Excluded: not stated  Withdrawals: stated (none)   Baseline characteristics: comparable  Jadad score: 3
Participants	102 adults: 38M 74F  Inclusion criteria:  Not stated explicitly but study included adult asthmatics who required moderate to high doses of inhaled BDP  Excluson criteria:   None stated
Interventions	BDP: variable dose via aerosol MDI + Volumatic spacer BUD: variable dose via Turbuhaler DPI
Outcomes	Daily dose inhaled corticosteroid (mg)  FEV1   FEV1 (% predicted)   Daily PEFR   Daily PEFR (% predicted)   Incidence of local oral side‐effects
Notes	Author confirmed method of random order generation.  Dose down titration study design: two year 'run‐in' period during which time all patients had their daily dose of BDP down‐titrated to the minimal dose effective in controlling symptoms. However there was no pre‐defined scheme based on objective measures of control for doing this. During study dose down titration was attempted if patient was a) completely or almost completely symptom free and b) FEV1 and PEFR were no lower than at previous assessment.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: Israel, paediatric outpatient clinic  Length of intervention: 4 weeks  Design: crossover, no washout  Randomisation: yes, method not stated   Allocation concealment: unclear  Masking: double blind  Excluded: not stated  Withdrawals: stated  Baseline characteristics: no tabulated demographic data presented  Jadad score: 3
Participants	10 children  Age range: 9‐15  Inclusion criteria:  Asthma dependant on treatment with inhaled steroids.  Exclusion criteria:  Use of oral steroids in the previous month.
Interventions	BDP: 50 mcg 4 puffs 4xdaily (400 mcg/d) BUD: 50 mcg 4 puffs 4xdaily (400 mcg/d) Delivery device: MDI
Outcomes	FEV1 (% predicted)   PEFR (% predicted)   Daily symptom score  24 hour urinary tetrahydrocortisone glucosiduronate   24 hour urinary tetrahydrocortisol glucosiduronate
Notes	Reply from authors but unable to clarify details of randomisation procedure  Not stated if carryover effects were tested for.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Setting: The Netherlands, hospital outpatient clinic  Length of intervention: 8 weeks  Design: crossover, 4 week washout  Randomisation: yes, by computerised randomisation algorithm  Allocation concealment: unclear  Masking: none  Excluded: not stated  Withdrawals: stated   Baseline characteristics: comparable   Jadad score: 3
Participants	16 adults: 14M 2F  Inclusion criteria:  18 years of age or older  Asthma for more than 2 years  %predicted FEV1 40‐85  15% or greater improvement in FEV1 after inhaled beta2 agonist  Bronchial hyper‐responsiveness to histamine (PC20 FEV1 less than or equal to 1.0mg/ml)  Currently receiving inhaled steroid 150‐800 mcg/daily  Exclusion criteria:  Pregnancy or significant co‐existent disease  Asthma exacerbation or respiratory tract infection in previous 2 months
Interventions	BDP: 200 mcg 1 actuation 2xdaily (400 mcg daily) via Rotahaler DPI BUD: 200 mcg 1 actuation 2xdaily (400 mcg daily) via Turbuhaler DPI
Outcomes	FEV1  FVC  Morning PEFR   Evening PEFR   Daytime wheeze score Daytime breathlessness score   Daytime cough score  Night‐time wheeze score  Night‐time breathlessness score  Night‐time cough score  Daytime beta2 agonist use (puffs/day)  Night‐time beta2 agonist use (puffs/day)  Bronchial responsiveness to histamine (PC20 FEV1)
Notes	Author confirmed method of random order generation and provided original data for all outcomes.  Carryover effects were tested for and excluded.  Significant improvement in at least one efficacy measure for both BDP and BUD groups compared to placebo washout
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Study	Reason for exclusion
Birkebaek 1997	Study concerned with the effects of BDP and BUD on markers of bone and collagen turnover only
Bjorkander 1982b	Unequal nominal daily doses of BDP and BUD compared: BDP 400 mcg/d v BUD 200 mcg/d
de Graaff 1996	Not clear if study randomised.
Kiviranta 1993	Described as randomised in paper publication, however following contact with authors it was apparent that patients were not allocated to intervention groups in a randomised manner
Piquet 1996	Unequal nominal daily doses of BDP and BUD compared: BDP 1500‐2000 mcg/d v BUD 800 mcg/d
Rosenhall 1982	Unequal doses of BDP and BUD compared: BDP 400 mcg/d v BUD 200 or 800 mcg/d
Struijs 1997	Patients enrolled with chronic obstructive airways disease, not asthma