Fluticasone versus placebo for chronic asthma in adults and children

Abstract

Background

Inhaled fluticasone propionate (FP) is a relatively new inhaled corticosteroid for the treatment of asthma.

Objectives

To assess efficacy and safety outcomes in studies that compared FP to placebo for treatment of chronic asthma.

Search methods

We searched the Cochrane Airways Group Specialised Register (January 2008), reference lists of articles, contacted trialists and searched abstracts of major respiratory society meetings (1997‐2006).

Selection criteria

Randomised trials in children and adults comparing FP to placebo in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and risk of bias.

Data collection and analysis

Two review authors extracted data. Quantitative analyses were undertaken using Review Manager software.

Main results

Eighty‐six studies met the inclusion criteria, recruiting 16,160 participants. In non‐oral steroid treated asthmatics with mild and moderate disease FP resulted in improvements from baseline compared with placebo across all dose ranges (100 to 1000 mcg/d) in FEV1 (between 0.1 to 0.43 litres); morning PEF (between 23 and 46 L/min); symptom scores (based on a standardised scale, between 0.44 and 0.7); reduction in rescue beta‐2 agonist use (between 1 and 1.4 puffs/day). High dose FP increased the number of patients who could withdraw from prednisolone: FP 1000‐1500 mcg/day Peto Odds Ratio 14.07 (95% CI 7.17 to 27.57). FP at all doses led to a greater likelihood of sore throat, hoarseness and oral Candidiasis.

Authors' conclusions

Doses of FP in the range 100‐1000 mcg/day are effective. In most patients with mild‐moderate asthma improvements with low dose FP are only a little less than those associated with high doses when compared with placebo. High dose FP appears to have worthwhile oral‐corticosteroid reducing properties. FP use is accompanied by an increased likelihood of oropharyngeal side effects.

Plain language summary

Fluticasone versus placebo for chronic asthma in adults and children

Fluticasone is a well‐established inhaled steroid for use a preventative agent in controlling asthma symptoms. This review found that it is highly effective even in low doses. The effect does appear to increase with higher doses, but these improvements are small. This drug is associated with symptoms such a thrush, sore throat and hoarseness and these get worse with higher doses. In people with severe asthma who need oral steroid tablets to control their asthma, it can reduce the dose of oral steroids they need and improve their asthma at the same time. However, high or very high doses are needed for this effect. The drug appears to work in children and adults.

Background

There is now wide recognition that asthma is a chronic inflammatory disease characterised by inflammatory cell infiltration, inflammatory mediator release, and epithelial damage within the airways (Barnes 1998). Current management guidelines reflect this awareness in a recommendation that inhaled corticosteroids are considered in all patients except those with the mildest disease and intermittent symptoms (BTS 1997; GINA 1995; NHBLI 1997). Fluticasone propionate (FP) is a newer synthetic corticosteroid widely used for the treatment chronic asthma in the UK, Europe and United States. Many controlled studies have been undertaken to assess its efficacy and safety and a number of narrative reviews have summarised these studies in qualitative fashion (Barnes 1998; Pedersen 1997).

This systematic review has been carried out to determine how the efficacy of FP varies with dose and explore the potential influence of asthma severity, age, and delivery device and treatment duration on clinically relevant outcomes. This review has been conducted with the aim of trying to provide answers to these questions by assessing those trials that have compared FP to placebo.

Objectives

To assess efficacy and safety outcomes in studies that compared inhaled fluticasone propionate to placebo in the treatment of chronic asthma.

Methods

Criteria for considering studies for this review

Types of studies

Only prospective, randomised controlled trials (RCTs) were considered. Double, single and unblinded studies were eligible for inclusion. Both parallel group design and crossover studies were considered, although only data from parallel studies were combined for analysis.

Types of participants

Studies including children and/or adults with a clinical diagnosis of chronic asthma were reviewed. The patients needed to be at least two years of age or older. A diagnosis of chronic asthma; diagnosis based on the physician opinion alone was acceptable, as well as asthma diagnosed using objective criteria related to asthma symptoms airway reversibility, and all bronchial hyper‐responsiveness. Treatment in the setting of primary care, hospital outpatient clinic, or institutional care was considered.

Types of interventions

Fluticasone propionate versus placebo. Treatment periods had to be for at least one week. Delivery by metered dose inhalers (MDI), with or without a spacer/chamber, or dry powder (DPI) was acceptable. Studies using nebulisers were specifically excluded. The nominal daily dose of fluticasone had to be stated. Any concurrent therapy was acceptable, including the use of oral corticosteroids (OCS).

Types of outcome measures

Primary outcomes

Our primary outcome was forced expiratory volume in one second (FEV1).

Secondary outcomes

We identified a number of key secondary outcomes which were of interest to people with asthma and clinicians:

1. Diary card and clinic PEFR, diurnal PEFR variability.

2. Symptoms.

3. Rescue bronchodilator use

4. Health status/health related quality of life (HRQOL)

5. Rates of asthma exacerbation leading to primary care physician visits, emergency room visits, hospital admission and days loss from work or school

6. Safety assessment: hypothalamo‐pituitary‐adrenal (HPA) function, as assessed by plasma and urinary cortisol measures

7. Oropharyngeal side‐effects and skin bruising

Search methods for identification of studies

Electronic searches

Trials were identified using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts. All records in the Specialised Register coded as 'asthma' were searched using the following terms:

steroid* OR glucocorticoid* OR corticosteroid* OR fluticasone OR Flixotide OR Flovent

The most recent search was conducted in January 2008. See Table 1 for the full search history of this review.

1. Search history detail.

Issue of CLIB	Time frame of search	Search detail
Issue 3, 2001	All years to March 1999	Stage 1 electronic search: 6494 citations retrieved, 2162 unique citations imported to Inhaled Steroid Register; Stage 2 electronic search: Fluticasone Register: 258 citations (180 excluded on basis of abstract: 150 not RCT; 30 not chronic asthma in humans). 78 papers retrieved in full text form ‐ 50 excluded on full paper: 6 not RCT, 38 no randomised placebo arm, 2 treatment period < 1 week; 1 infants; 3 nebuliser delivery device; 28 papers meeting inclusion criteria; 21 unique studies meeting inclusion criteria. Other sources: Two studies (Galant 1999; Li 1999) were identified by GSK. These studies were published after the date of the final electronic search (March 1999). Five studies (Ekroos 1999; Hofstra 2000; Nathan 1999; Busse 2001; Van Schoor 2002) were identified as a result of searching respiratory society meeting abstracts.
Issue 2, 2005	March 1999 to January 2004	From handsearching the updated inhaled steroids search results (1301 additional references), a 'fluticasone' register was created consisting of 197 citations (121 references excluded from abstracts as irrelevant comparisons). Three studies reported data from two different trials each, and so two study identities were created for each study (Berger 2002 BD; Berger 2002 ICS; Sorkness 1999; Sorkness 1999a; Wolfe 2000 BD; Wolfe 2000 ICS). Seventy‐five references, pertaining to 55 studies were retrieved in full. We excluded studies for the following reasons: Wrong comparison (11); no clear diagnosis of asthma (2); acute asthma (1); not randomised (1). One study was a full published version of a previously included abstract (Busse 2001). Forty new studies were included in the January 2004 update: Allen 2000; Arets 2002; Berger 2002 BD; Berger 2002 ICS; Casale 2001; Convery 2000; Corsico 2000; Derom 1999; Derom 2005; Falcoz 2000; Giannini 2003; Hart 2000; Jayaram 2002; Jeffery 2002; Kavuru 2000; Laforce 2000; Langley 2002; Lanz 2001; Li 1999a; Li 1999b; Lindqvist 2003; Micheletto 2000; Nathan 2000; Nielsen 2002; Parameswaren 2000; Pauwels 2002; Pearlman 1999; Pearlman 2002; Rooklin 2001; Shapiro 2000; Sorkness 1999; Sorkness 1999a; Sovijärvi 2003; van Grunsven 2000; van Rensen 1999; Ward 2001; Weinstein 2001 (now Pearlman 2004); Wolfe 2000 BD; Wolfe 2000 ICS; ZuWallack 2000.
Issue 4, 2005	January 2004‐2005	Seven new trials were included, giving a total of 75 studies. The new trials were: Lipworth 2005, Given 2004 (now Levy 2006); SAS30021; SAS30022; SAS30023; SAS30024 (now Chuchalin 2008); Kemp 2004.

Searching other resources

1. Reference lists of all included studies and relevant narrative reviews were searched for additional RCTs.

2. The UK headquarters of GSK (manufacturers of Becotide, Becloforte and Flixotide) and the Swedish headquarters of Astra Zeneca (manufacturers of Pulmicort) were asked if they were aware of further missed trials.

3. We handsearched the GSK trials register for unpublished data

4. Authors of studies were asked if they were aware of further missed trials.

5. The British Journal of Clinical Research and the European Journal of Clinical Research (journals not electronically indexed on MEDLINE or EMBASE) were hand‐searched.

6. Proceedings of the British Thoracic Society (1997 to 2003), European Respiratory Society (1997 to 2003) and the American Thoracic Society (1997 to 2003) were searched for relevant trials.

Data collection and analysis

Selection of studies

The decision to exclude studies prior to full paper retrieval was made independently by two reviewers (NPA and JB). In cases of disagreement, the full text article was retrieved. Papers retrieved in full text were assessed by two reviewers independently (NPA and JB), any disagreement regarding eligibility was resolved by consensus. Two reviewers (NPA and JB) who were blinded to the author's names, institution and funding sources, independently assessed included studies for methodological quality

Data extraction and management

Two authors (NPA and TL) extracted data for each outcome from the published results of included trials. In the case of continuous outcomes (such as FEV1), only data from the last evaluable time point was used. Where data had to be extracted from graphical plots, an attempt was made to verify the data by contacting authors.

Assessment of risk of bias in included studies

We assessed the risk of bias for each included study according to recommendations described in the Cochrane Handbook. We have assessed the risk of bias for the generation and concealment of allocation schedules for the eligible studies. Our previous approach is described in Appendix 1.

Measures of treatment effect

For continuous outcomes, a weighted mean difference (WMD) or standardised mean difference (SMD) was calculated, as appropriate. For binary/dichotomous outcomes odds ratios (OR) were calculated.

Dealing with missing data

Authors were written to (by mail, fax and/or electronic mail) in an attempt to clarify details of methods, and to request missing or incomplete outcome data. Attempts were made to send requests to correct current addresses by searching MEDLINE, EMBASE and hospital web sites for up to date contact details. Glaxo Wellcome (UK) was also approached for data concerning trials in which contact authors did not initially reply, or when authors suggested doing so. Data that were not available for inclusion in the meta‐analysis have been listed in Table 2.

2. Incomplete data not included in meta‐analysis.

Study ID	Data
Allen 1997	Medical Outcomes Study Short Form (SF‐36A) Living with asthma questionnaire No SD values available for above outcomes Sleep scale No numerical data available for above outcome
Chervinsky 1994	Change in urinary free cortisol compared to baseline Change in urinary 17‐hydroxy steroids compared to baseline Change in morning plasma cortisol compared to baseline Change in plasma cortisol 60 min post cosyntropin No SD values available for above outcomes
Ekroos 1998	Histamine bronchial hyperresponsiveness (PD15 FEV1) Log transformed data not available
Faul 1998	FEV1 (after treatment: baseline ratio) FEV1/FVC (after treatment: baseline ratio) FEF 25‐75 (after treatment: baseline ratio) Histamine bronchial responsiveness PC20 FEV1 (after treatment: baseline ratio) Results expressed using medians and ranges for above outcomes
Galant 1999	Morning plasma cortisol No numerical data available
Hart 2000	FEV1(reported as non‐significant) am PEF Both outcomes recorded but no data presented.
Hofstra 2000	PD20 Unable to ascertain distribution around geometric mean
Hoekstra 1997	Night‐time (4am) PEFR Morning serum cortisol Morning urine cortisol (collection time frame not specified) No SD values available for above outcomes
Jayaram 2002	All outcomes reported in study could not be entered as dosage was unclear.
Jeffery 2002	FEV1; am PEF Recorded but not reported.
Katz 1998	Change in FEV1 compared to baseline Change in FVC compared to baseline Change in FEF25‐75 compared to baseline Change in evening PEFR compared to baseline Change in night‐time awakening score compared to baseline No SD values available for above outcomes
Langley 2002	Rescue medication usage Median values reported.
Lindqvist 2003	FEV1 ‐ change from baseline in L/min Symptoms ‐ change from baseline Medication usage ‐ change from baseline No SDs presented
MacKenzie 1993	FEV1 Morning PEFR Evening PEFR Clinic PEFR No SD values available for above outcomes Daily asthma symptom score Morning plasma cortisol No numerical data available for above outcomes
Noonan 1998	Change in log e methacholine bronchial responsiveness PD20 FEV1 Error bars plotted on graphical display of results, but unclear whether these represent SD or SEM values
Olivieri 1997	Methacholine bronchial responsiveness PC20 FEV1 Randomised treatment groups were not compared: results expressed as change compared to baseline for each individual treatment group.
Overbeek 1996	Daily asthma symptom score No numerical data available for above outcome
Pearlman 1997	Change in evening PEFR compared to baseline No SD values available for above outcome Morning serum cortisol Plasma cortisol 30‐60 min post 250 mcg iv cosyntropin No numerical data available for above outcome Physician rated global assessment of efficacy Data not presented in a form suitable for meta‐analysis
Wasserman 1996	Physician‐rated global assessment of effectiveness Data not presented in a form suitable for meta‐analysis
Wolfe 1996	Change FEV1 compared to baseline No SD values available for above outcome Change in morning PEFR compared to baseline Change in evening PEFR compared to baseline Daily wheeze, cough, shortness of breath scores Daily beta2 agonist use Morning plasma cortisol No numerical data available for above outcomes

In previous versions of this review we imputed a number of missing standard deviations for a number of studies.

We have maintained an approach consistent with the recommendations regarding imputation in the Cochrane Handbook, whereby these studies represent a small proportion of the studies included in a given outcome.

Assessment of heterogeneity

Heterogeneity in effect size, across studies pooled was calculated with P < 0.05 used as the cut‐off level for significance.

Data synthesis

A weighted treatment effect across trials was calculated using the Cochrane statistical package RevMan 5.1. Pooled treatment effects are expressed with their 95% confidence intervals (95% CI).

A number of conditions were established a priori regarding the comparisons to be made. Firstly, parallel and crossover trials were not pooled. Secondly, studies were categorised based on the presence or absence of regular oral corticosteroid use (OCS) at enrolment. It was expected that most trials in patients on regular oral steroids would use a 'steroid‐sparing' design in which daily dose of OCS was progressively reduced. In such studies the principal outcome variable is the dose of oral steroid needed to maintain asthma control unchanged. Conversely, studies in which patients were not treated with regular OCS would be more likely to have designs aimed at detecting improvements in asthma control. It would be inappropriate to combine trials with such different designs and aims.

All comparisons concern fluticasone versus placebo. Because many studies assessed more than one dose of fluticasone within the same trial but only had a single placebo group, it was not appropriate to pool different doses of fluticasone in the meta‐analysis. Comparisons are therefore made according to daily dose i.e. 100 mcg/day or less, 200 mcg/day, 500 mcg/day or 1000 mcg/day.

Subgroup analysis and investigation of heterogeneity

For each reported outcome, subgroup analyses have been undertaken. These are based on patient age (children or adults); treatment duration (one to four weeks, one to five months, six months or longer); delivery device (MDI or DPI); asthma severity (mild, mild‐to‐moderate, moderate). These analyses have been used to explore variations in treatment response according to these factors. In particular, for outcomes where heterogeneity exists between studies, subgroup analyses have been used to try to identify factors that may account for heterogeneity. These are discussed as appropriate in the following section.

Results

Description of studies

Results of the search

See Table 1 for a description of the search histories for this review. This update includes an additional 12 trials; a total of 86 studies represented by 196 references, recruiting 16,160 participants are included in the review. See Table 3 for text of archived 'What's New' sections.

3. What's New Archive.

Date of search

Detail

January 2005

7 new trials were included, giving a total of 75 studies. The new trials are: Lipworth 2005, Boonsawat 2004; Given 2004; SAS30021; SAS30024; Dorinksy 2004; Kemp 2004. Impact of the new studies The effects of these studies was to tighten confidence intervals around the significant effects already obtained in the review. Some subgroup analyses based on severity are now starting to show a more pronounced effect in moderately severe patients, than in milder patients. This observation should be tempered with some caution, as other variables could explain these differences.

Included studies

A detailed description of the studies is provided in the included studies table.

Populations The majority of studies were large multicentre trials conducted in the USA. The remaining studies largely recruited patients from Europe (Belgium, Finland, Italy, The Netherlands, UK). Two multicentre studies (Katz 1998; MacKenzie 1993) also recruited patients from Asia and South Africa respectively. All studies were undertaken in a secondary care/hospital outpatient clinic setting. No studies were conducted in primary care. Eight studies (Arets 2002; Allen 1998; Caffey 2005; Hoekstra 1996; Hofstra 2000; Katz 1998; Laforce 2000; MacKenzie 1993; Peden 1998) were conducted in children. All remaining studies were in adults and adolescents.

Study design Seventy‐five studies had a parallel group design. Twelve studies had a crossover design (Agertoft 1997; Caffey 2005; O'Shaughnessy 1993; van Schoor 2002; Derom 2005; Parameswaren 2000; Langley 2002; Lanz 2001; Derom 1999; Jeffery 2002; Pauwels 2002). The majority of parallel group studies had a treatment period of 12 weeks. Twenty‐one studies had treatment periods of between four and eight weeks, six studies had a treatment period of between 16 and 24 weeks. Four studies (Allen 1998; Li 1999b; Ward 2001; Chuchalin 2008) had longer treatment periods of between 12 and 24 months.

Interventions The studies compared a range of nominal daily doses of FP to placebo, and several studies had multiple treatment arms. Twenty‐one studies assessed FP 50‐100 mcg/day; 42 studies assessed FP 200 mcg/day; 26 studies assessed FP 500 mcg/day; 18 studies assessed FP 1000 mcg/day. In one study the dosage was unclear (Jayaram 2005). Seven studies (Faul 1998; Nelson 1999; Noonan 1995; Convery 2000; Corsico 2000; van Rensen 1999; Ward 2001) assessed FP 1500‐2000 mcg/day versus placebo. Thirteen studies (SAS30023; Caffey 2005; Kavuru 2000; Lipworth 2005; SAS30021; Chuchalin 2008; SAS30022; Condemi 1997; Busse 2001; Shapiro 2000; Sorkness 1999a; Sorkness 1999b) incorporated treatment arms with agents other than fluticasone or placebo including triamcinolone, salmeterol and zafirlukast. These interventions were not considered in this review. 
 
 Delivery device Thirty‐seven studies used a dry powder delivery device. Twenty‐four studies used a metered dose inhaler; six studies used a MDI/spacer combination. In one crossover study, both devices were assessed (Langley 2002). In the case of ten studies, the delivery device used was not stated.

Prior treatment with corticosteroids Three studies (Allen 2000; Noonan 1995; Nelson 1999) recruited oral corticosteroid dependent asthmatics. This was a specific inclusion criterion for these studies. In the remaining trials, oral corticosteroid use was either a specific exclusion criterion, or it was clear from a description of the baseline characteristics of patients enrolled than none were receiving oral corticosteroids at the time of randomisation. In 27 studies patients were not receiving inhaled corticosteroid at the time of enrolment. In 17 studies prior treatment with an inhaled corticosteroid was an inclusion criterion. In five studies (Allen 1998; Galant 1999; Nelson 1999; Noonan 1995; Peden 1998) a proportion of patients were receiving inhaled corticosteroids at the time of enrolment but this was not an inclusion criterion for the study. Laforce 2000 recruited participants if they required unspecified pharmacotherapy for three months previously. In 15 studies it was unclear if patients had received regular steroid therapy prior to enrolment.

Asthma severity Patients with a range of asthma severity were studied. Table 4 provides a breakdown of included studies according to baseline FEV 1 (% predicted), symptom frequency reported at baseline, and the stated opinion of investigators as to degree of asthma severity. To obtain an index of the severity of asthma at baseline and in the absence of any other standardised approach to the classification of asthma severity, we applied NHBLI 1997/GINA 1995 criteria to each study, recognising these criteria were developed for the assessment of untreated patients. Twenty‐four studies recruited patients with mild asthma, 19 studies mild to moderate asthma, 23 studies moderate asthma and three studies (Allen 2000; Noonan 1995; Nelson 1999) severe asthma. In the case of eight studies asthma severity could not be estimated (Derom 2005; Faul 1998; Hofstra 2000; Jayaram 2005; Micheletto 2000; Nielsen 2002; Pauwels 2002).

4. Asthma severity: characteristics of included patients at baseline.

Study ID	FEV1: incl. criteria	FEV1: mean baseline	Symptom frequency	OCS treatment	ICS treatment	Author opinion	Overall estimation
Agertoft 1997	Not stated	Not stated	No	No	Not stated	Mild	Mild
Allen 1998	>60	88‐89	Not stated	No	Approx. 50% patients ICS naive at baseline, 50% previous regular ICS use	Mild to moderate	Mild to moderate
Allen 2000	Not stated	61%	Not stated	Yes	Not stated	Not stated	Severe
Arets 2002	Not stated	99‐104	SABA >1600mcg/d during >30% days of last year excluded	No	Only ICS <100mcg/d	Mild	Mild
Berger 2002 BD	60‐85%	72‐71.9%	>/=2 puffs BD on 2 of last 7 days of run‐in; symptom scores >/=2 of last 7 days	No	Not within 1 month of study	Not stated	Mild to moderate
Berger 2002 ICS	60‐90%	75.9‐75.8%	</=30 puffs over past 7 days	No	For three months prior to randomisation	Not stated	Moderate
Boonsawat 2004	Not stated	Not stated	Requirement for SABAs alone	No	No	Mild	Mild
Busse 2001	50‐80	68‐69	Symptomatic despite treatment with short acting beta2 agonist	No	No	Not stated	Moderate
Busse 2005	40‐65	Not stated	Not stated	Not stated	Not stated	Severe	Unclear
Caffey 2005	Not stated	88%	Not stated	No	Not clear ‐ one 'preventer' medication allowed per participant	Mild to moderate	Mild to moderate
Casale 2001	>/=65%	3 Litres	Not stated	No	No	Mild to moderate	Mild to moderate
Chervinsky 1994	60‐90	71‐73	Not stated	No	Yes: at least 1 month regular treatment with BDP prior to study	Mild to moderate	Mild to moderate
Condemi 1997	50‐80	66‐68	"< 3 days needing > 12 puffs beta2 agonist in 7 days< 4 days with diurnal PEFR variability of > 20% in 7 days"	No	Yes: ICS for at least 1 month prior to study	Not stated	Moderate
Convery 2000	Not stated	100‐103	Not stated	Not stated	Not stated	Not stated	Mild
Corsico 2000	>80%	98‐102	Stable asthma for previous 2 months	Not stated	Not stated	Mild	Mild
Derom 1999	>/=40%	80%	Exacerbation free for 1 month	No	No	Not stated	Mild
Derom 2005	Not stated	Not stated	Not stated	Not stated	Not stated	Not stated	Unclear
Dorinsky 2004	50‐85%	Not stated	4 days of week preceding randomisation; pre‐treatment with SABA only	No	No	Not stated	Mild‐moderate
Ekroos 1999	Not stated	Not stated	Not stated	No	No	Mild	Mild
Falcoz 2000	50‐80%	Not stated	Not stated	Not stated	Not stated	Mild‐moderate	Mild‐moderate
Falcoz 2000a	50‐80%	Not stated	Not stated	Not stated	Not stated	Mild‐moderate	Mild‐moderate
Faul 1998	>40	73	Not stated	No	No	Not stated	Unclear
FLIC15	>/=60% predicted	Not stated	Not stated	No	No	Mild to moderate	Mild
FLTA2007	50‐85%	74%	Not stated	No	Yes	Not stated	Moderate
FLTA3014	50‐85%	2.47‐2.5L	Not stated	No	Yes	Not stated	Moderate
FLTA3020	60‐90% predicted	Not stated	Not stated	No	No	Not stated	Mild to moderate
FLTA4030	50‐80%	Not stated	Stable during 7 day run‐in, controlled with SABA alone	No	No	Not stated	Mild to moderate
Galant 1999	50‐80	65‐67	"Mean beta2 agonist use 3.5 puffs/dMean night awakenings/week 0.05 to 0.08"	No	24‐30% of patients ICS treated	Mild to moderate	Mild to moderate
Galant 1996	45‐75	60‐62	> 8 puffs/d beta2 agonist or 2‐4 night‐time awakenings in week run‐in	No	No	Mild to moderate	Moderate
Giannini 2003	Not stated	3.23 L 96 % predicted	Use of ß‐agonist during run‐in (unspecified)	Not stated	Not stated	Mild‐moderate	Mild
Given 2004	Not stated	85%	Not stated	No	Yes ‐ 49%	Not stated	Mild to moderate
Gross 1998	50‐80%	67	<4 days usage of > 12 puffs/d	No	100%	Not stated	Moderate
Hart 2000	Not stated	98.5%	Not stated	Not stated	Not stated	Mild	Mild
Hoekstra 1996	>75	88‐92	Not stated	No	No	Moderate	Moderate
Hofstra 2000	Not stated	96.6‐93.2%	Not stated	No	No	Not stated	Unclear
Jayaram 2002	Not stated	Not stated	Not stated	Not stated	Not stated	Not stated	Unclear
Jeffery 2002	Not stated	75.6%	Not stated	No	No ‐ SABA treatment only	Not stated	Mild
Katz 1998	Not stated	PEFR 75 (% predicted) or less	Asthma symptoms on at least 4 out of 10 days of run in period or at least one night‐time awakening in 10 days or 4 or puffs beta2 agonist on at least 4 days	No	No	Not stated	Moderate
Kavuru 2000	40‐85% predicted	64% predicted	Participants excluded if excessive use of SABA during run‐in, and frequent nocturnal awakenings	No	Yes	Not stated	Moderate
Kemp 2004	50‐100% predicted	82‐85% predicted	Mild stable asthma	No	No	Mild	Mild
LaForce 2000	50‐85% predicted	70‐73% predicted	Participants had to have stable asthma during run‐in	No	Pharmacotherapy required for at least 3 months prior to the study (irrespective of whether ICS or not)	Not stated	Mild‐moderate
Langley 2002	>/=60%	93.5%	Not stated	No	No	Not stated	Mild
Lanz 2001	50‐85%	75%	Not stated	No	No	Moderate	Mild‐moderate
Lawrence 1997	50‐80%	65‐68	"Mean beta2 agonist use 3.2 ‐ 4.2 puffs/d "	No	Yes: 3 months treatment or longer prior to study	Not stated	Moderate
Li 1999	>60	91	Not stated	No	No	Mild	Mild
Li 1999a	>60%	80‐83%	Use of SABA on 50% days in run‐in	No	Yes ‐ 12 months with BDP up to 500mcg/d	Not stated	Moderate
Li 1999b	>/=50%	82‐89%	Not stated	Prednisolone </=140mg in past year or equivalent	No	Not stated	Mild‐moderate
Lindqvist 2003	60‐100%	79‐83%	Participants were to have been 'symptomatic'	No	No	Not stated	Mild
Lipworth 2005	>/=70%	82%	Use of SABA 2 x per week for 6 months	No	No	Mild to moderate	Mild
Lumry 2006	45‐80%	65%	Not stated	No	ICS for >/=3 months	Not stated	Moderate
MacKenzie 1993	Not stated	Not stated	"Patients had experienced a worsening of asthma with deterioration in lung function leading to change in medication or hospitalisation in last month; symptoms on at least 4 out of 7 days "	No	No	Moderate	Moderate
Michelletto 2000	Not stated	73‐74%	Not stated	Not stated	Not stated	Mild‐moderate	Unclear
Nathan 2000	45‐75% predicted	63.3‐64.3	Not stated	No	Yes	Moderate	Moderate
Nelson 1999	40‐80	60‐62	Not stated	Yes	Almost 100% of patients receiving ICS	Severe	Severe
Nielsen 2002	Not stated	Not stated	Not stated	No	Yes	Not stated	Unclear
Noonan 1998	60‐85	73‐76	"No more than 12 puffs/d beta2 agonist and no more than 3 nights with awakening due to asthma"	No	No	Mild to moderate	Moderate
Noonan 1995	40‐80	56‐57.4	Requirement for rescue beta2 agonist for 2 weeks prior to study due to symptoms	Yes	87% of patients receiving ICS	Severe	Severe
Olivieri 1997	> 80	98	< 2 puffs/d beta2 agonist	No	No	Mild	Mild
O'Shaughnessy 1993	> 60	Not stated	No	No	Not stated	Mild	Mild
Overbeek 1996	Not stated	84‐86	Not stated	No	Not stated	Not stated	Mild
Parameswaren 2000	Not stated	90.2	Few or no symptoms	No	No	Mild	Mild
Pauwels 2002	Not stated	Not stated	Not stated	Not stated	Not stated	Not stated	Unclear
Pearlman 1997	50‐80	66‐67	"Mean beta2 agonist use 3.4‐4.1 puffs/dNo more than 12 puffs/d beta2 agonist and no more than 2 nights with awakening due to asthma symptoms in last 7 days"	No	Yes: at least 3 months	Moderate	Moderate
Pearlman 1999	50‐80% predicted	65‐69	No more than 12 puffs of SABA on more than 2 days during run‐in	No	Not in previous month	Not stated	Mild‐moderate
Pearlman 2002	45‐80% predicted	65.3‐65.6	Not stated	Not stated	Yes	Not stated	Moderate
Pearlman 2004	40‐85%	Not reported	Described as symptomatic	Not stated	Requirement for pharmacotherapy	Not stated	Mild to moderate
Peden 1998	50‐85	72‐73	"No more than 12 puffs/d beta2 agonist and no more than 3 nights with awakening due to asthmaMean awakenings per night due to asthma 0.05 to 0.09Mean beta2 agonist use 1.4 to 2.0 puffs/d"	No	Some patients: amount and type of ICS not stated	Not stated	Moderate
Pinnas 2005	45‐80%	67	Not specified	No	No	Moderate to severe	Mild to moderate
Qaquandah 2006	Not stated	Not stated	Requirement for rescue beta2 agonist for 2 weeks prior to study due to symptoms	No	Yes	Not stated	Unclear
Rooklin 2001	40‐85%	68%	Not stated	Not stated	Yes	Not stated	Moderate
SAS30021	Not stated (am PEF 50‐85% predicted)	Not stated (am PEF 75.2‐76.7% predicted)	Symptoms on >/=4 days of week prior to randomisation	No	No	Not stated	Mild
SAS30024	Not stated (pre‐BD PEF had to be >80% predicted)	3.1 Litres	0.57 puffs rescue medication per day	No	Not stated	Mild	Mild
Shapiro 2000	40‐85%	66‐68%	Not stated	No	Yes	Not stated	Moderate
Sheffer 1996	45‐75	62‐64	"During 7 day run‐in:> 2 night‐time awakenings due to asthma in last 7 days20% or greater PEFR diurnal variability at least one day in which 8 puffs beta2 agonist used "	No	No	Mild to moderate	Moderate
Sorkness 1999	>/=50%	83‐88%	Not stated	No	No	Mild to moderate	Mild to moderate
Sorkness 1999a	>/=50%	83‐88%	Not stated	No	No	Mild to moderate	Mild to moderate
Sovijärvi 2003	>/=65%	79‐84	Stable asthma	No	No	Mild	MIld
Subbarao 2005	>70%	Not stated	Stable asthma	No	No	Mild	Mild
van Grunsven 2000	Not stated	93%	Not stated	Not stated	Not stated	Not stated	Mild to moderate
van Rensen 1999	>75%	95.6‐96.2%	Stable asthma	No	No	Not stated	Mild
Van Schoor 2002	Not stated	Not stated	Not stated	No	Not stated	Mild	Mild
Ward 2001	Not stated	91.3%	Mild to moderate symptomatic asthma	No	No	Mild to moderate	Mild to moderate
Wasserman 1996	50‐80	Not stated	"Mean beta2 agonist use 3.1 to 3.3 puffs/dDuring last 7 days run‐in no more than 12 puffs/d beta2 agonist and no more than 2 nights with awakening due to asthma"	No	No	Not stated	Moderate
Weinstein 2002	45‐80	67	Not stated ‐ no run‐in period described	No	No	Not stated	Mild‐moderate
Wolfe 1996	50‐80	64‐66	During 2 week run‐in period no more than 12 puffs/d beta2 agonist and no more than 2 nights with awakening due to asthma	No	Yes	Moderate	Moderate
Wolfe 2000 BD	50‐80	69	During 2 week run‐in: 0 days with >/= 12 puffs of SABA prn	No	No	Not stated	Mild‐moderate
Wolfe 2000 ICS	50‐80	70	During 2 week run‐in: 0 days with >/= 12 puffs of SABA prn	No	Yes ‐ for 3 months prior to study entry	Not stated	Moderate
ZuWallack 2000	50‐80%	66‐68%	Not stated	No	Yes	Not stated	Moderate

Outcomes assessed An extensive range of outcomes was reported, and almost all have been considered in this review. Those measures that have not been considered include height assessment in children, bone densitometry, and biochemical markers of bone turnover. These were excluded because of the complexity of the issues lay outside the scope of this review. Markers of inflammation were also not reviewed, because this review was concerned with clinical efficacy, rather than basic mechanisms. Studies of FP on such markers include: bronchial biopsy inflammatory cell counts and/or broncho‐alveolar lavage fluid cell counts (Faul 1998; Olivieri 1997), exhaled nitric oxide levels (Ekroos 1999), serum and urine eosinophil derived neurotoxin levels (Hoekstra 1996), detailed characteristics of the methacholine dose response curve (Overbeek 1996), spirometry and histamine BHR following inhaled allergen challenge (O'Shaughnessy 1993), neurokinin‐A BHR (van Schoor 2002) and urinary leukotriene levels (O'Shaughnessy 1993).

Risk of bias in included studies

The overall risk of bias as determined by the processes of allocation and blinding in the studies we included was low. In only nine cases was there insufficient information available to us to make any judgment regarding trial design (Caffey 2005; Casale 2001; Convery 2000; Corsico 2000; Ekroos 1999; Hofstra 2000; Jayaram 2005; Sovijärvi 2003; van Rensen 1999). These studies were generally small and constitute a small amount of the available evidence. Our judgments for the two domains of bias we have assessed for this review are represented in Figure 1. All studies were described as randomised, and all were double blind. Following correspondence with GSK from a related review of inhaled therapy we were able to ascertain the process by which GSK‐sponsored studies are randomised (Appendix 2). On this basis we have assigned a low risk of bias to the studies we have identified as GSK‐sponsored. Identical inhaler devices were used for the majority of the trials we have included.

1.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Effects of interventions

Primary outcome: FEV1

Change in FEV1 compared to baseline

Children

In children at daily doses of between 100 and 200mcg, FP led to improvements in FEV1 of between 0.1 and 0.18 L compared with placebo. We could not find any placebo‐controlled studies that assessed the effects of FP above a daily dose of 200mcg on FEV1 in children:

Daily dose of FP	Point estimate (L)	95% confidence intervals	Number of studies	Number of participants	Figure
100mcg	0.1	0.36 to 0.15	4	719	Analysis 1.2
200mcg	0.18	0.13 to 0.23	4	670	Analysis 3.2*
500mcg	NA	NA	0	0	NA
1000‐1500mcg	NA	NA	0	0	NA

Adults

In adults at daily doses of between 100 and 1500 mcg, FP led to improvements in FEV1 of between 0.26 to 0.43 L

Daily dose of FP	Point estimate (L)	95% confidence intervals	Number of studies	Number of participants	Figure
100mcg	0.26	0.21 to 0.31	8	1352	Analysis 1.2
200mcg	0.25	0.23 to 0.27	25	5414	Analysis 3.2*
500mcg	0.39	0.34 to 0.43	11	1724	Analysis 5.1*
1000‐1500mcg	0.43	0.37 to 0.5	5	816	Analysis 7.3*

*Significant heterogeneity apparent when studies were pooled for the lower three FP doses (100 mcg/day, 200 mcg/day, 500 mcg/day). The I square tests all exceeded 60% for these outcomes, but random‐effects modelling did not alter the significance of the findings in all three cases.

The subgroup analyses based on delivery device, length of treatment and severity did not adequately explain heterogeneity to non‐significant levels. Statistically significant differences between subgroup estimates disappeared with a random effects model, and the degree of variation within subgroups suggested that our definitions may be confounded. It should be noted that in the majority of individual studies FP led to significant improvements in FEV1 compared to baseline, when compared with placebo.

FEV1: other measurements

Change and absolute data in litres and percent predicted FEV1 were also recorded in several studies. There were significant differences in favour of FP for both measurements in the 200 mcg/day dose range: Change in FEV1: WMD 13% (95%CI 8 to 18%; two studies, 280 participants); change in predicted FEV1: WMD 10% (95% CI 8 to 12%; five studies, 674 participants).

The findings were also significant when data were presented as absolute scores for FEV1 % predicted:

FP 200 mcg/day WMD 4% (95% CI 1 to 8%; four trials, 157 participants) 
 FP 500 mcg/day WMD 25% (95% CI 16 to 33%; two trials, 50 participants)

When data were presented as litres for two studies in the 200 mcg/d dose range, this was only marginally significant: WMD 0.06 litres (95% CI 0 to 0.13 litres; two trials, 86 participants). This may reflect the relatively low statistical power of the studies in this outcome.

Absolute FEV1 was also recorded in three studies in the 1000 mcg/day dose range. There was no significant difference between FP and placebo: WMD 0.13 litres (95% CI ‐0.2 to 0.5 litres; 3 studies, 73 participants). As with the FEV1 outcome presented above, low statistical power in this analysis may explain the discrepancy between these findings and the change from baseline data.

Change in FVC and FEF 25‐75 compared to baseline

One study (Chervinsky 1994) in adult patients conducted over an eight week treatment period assessed the effects of FP 100 mcg/day, 200 mcg/day and 1000 mcg/day versus placebo. A second study (Chuchalin 2008) measured change in FEF 25‐75 for FP given at 200mcg/day. Compared to placebo, there was a significantly greater improvement in FVC compared to baseline at each dose of FP: FP 100 mcg/day WMD 0.29 litres (95% CI 0.09 to 0.49 litres); FP 200 mcg/day WMD 0.39 litres (95% CI 0.2 to 0.58 litres); FP 1000 mcg/day WMD 0.52 (95% CI 0.35 to 0.69 litres). 
 
 Chervinsky 1994 also reported change in FEF 25‐75 compared to baseline at doses of 100, and 1000mcg/day. Again, for each daily doses FP there were significant improvements in the active treatment group when compared to placebo: FP 100 mcg/day WMD 0.38 litres per second (95% CI 0.15 to 0.61 litres per second) and FP 1000 mcg/day WMD 0.56 litres per second (95% CI 0.34 to 0.78 litres per second). At a dose of 200mcg/day, there was a significant change from baseline in favour of FP when data from the studies were polled (WMD: 0.25 litres per second (95% CI 0.16 to 0.34 litres per second). Although there was a high level of heterogeneity, the pooled effect remained significant with random‐effects modelling.

Peak flow

The majority of studies that reported diary card peak flow measures expressed the outcome as a change compared to baseline. For all daily doses of FP, there were significantly greater improvements in both morning and evening PEFR compared to baseline, when compared with placebo:

Change in morning PEFR compared to baseline

Children

FP significantly improved the change in am PEF in children by 26 L/min (100mcg, Analysis 1.5) and 21 L/min (200mcg, Analysis 3.7). One study assessed the effect of 500mcg of FP in children and reported a significant change in am PEF favouring FP of 16L/min.

1.5. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 5 Change in morning PEFR compared to baseline (L/min).

3.7. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 7 Change in morning PEFR compared with baseline (L/min ‐ generic inverse variance)).

Adults

FP significantly improved the change in am PEF in adults by 22 L/min (100mcg, Analysis 1.5*), 28 L/min (200mcg, Analysis 3.7*), 40 L/min (Analysis 5.6*) and 46L/min (1000‐1500 mcg, Analysis 7.7*).

5.6. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 6 Change in morning PEF (L/min).

*In spite of high levels of heterogeneity observed in these outcomes, random‐effects modelling did not alter the significance or the direction of the effects which remained in favour of FP. This suggests that whilst there may be some variation between the response to therapy exhibited by the study populations, there does remain a significant underlying effect in favour of FP.

Change in evening peak flow compared to baseline

Children

FP significantly improved the change in pm PEF in children by 7L/min (100mcg, Analysis 1.8) and 21 L/min (200mcg, Analysis 3.11). We could not identify studies which assessed the effects of FP on evening PEF.

1.8. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 8 Change in evening PEFR compared to baseline.

3.11. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 11 Change in evening PEFR compared to baseline.

Adults

FP significantly improved the change in pm PEF in adults by 17L/min (100mcg, Analysis 1.8*), 23 L/min (200mcg, Analysis 3.11*), 31 L/min (500mcg, Analysis 5.9*), 41 L/min (1000‐1500mcg, Analysis 7.6*).

5.9. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 9 Change in evening PEF compared with baseline.

7.6. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 6 Change in evening PEFR compared to baseline (L/min).

*There were moderate to high levels of statistical heterogeneity observed in all of the above outcomes. Random‐effects modelling did not alter the significance or the direction of the effect, which remained in favour of FP.

Change in clinic PEFR compared to baseline

A single study (Peden 1998) reported change in clinic recorded PEFR compared to baseline. The effects of FP 100 mcg/day, 200 mcg/day or placebo were assessed in 437 children with moderately severe asthma over a 12 week treatment period. Both daily doses of FP led to significantly greater improvements compared to placebo.

Absolute clinic PEFR

Two small trials assessed FP given at 200 mcg/day (Giannini 2003; Li 1999a). There was a significant difference in favour of FP of WMD 69 L/min (95% CI 8 to 128 L/min; two trials, 50 participants). There was a high level of statistical heterogeneity observed. When a random‐effects model was applied, this resulted in a non‐significant difference. Both trials contributed small sample sizes undermining the statistical power of the pooled effect estimate for this outcome.

Diary card PEFR: other measures

Only two trials reported diary card peak flow as an absolute measure (L/min). In the 100 mcg/d dose range MacKenzie 1993 assessed FP in 258 children with moderately severe asthma over a four week treatment period. Active treatment resulted in a significantly greater morning PEFR (19 L/min, 95% CI 10 to 27 L/min) and evening PEFR (18 L/min, 95% CI 10 to 26 L/min) compared to placebo. Hoekstra 1996 assessed FP 200 mcg/day versus placebo in 34 children with moderately severe asthma over a 12 week treatment period. This study was also of fair methodological quality (Jadad score 3). Active treatment led to significant improvements in morning peak PEFR (41 L/min, 95% CI 19 to 62 L/min) and evening PEFR are (33 L/min, 95% CI 13 to 52 L/min).

Asthma symptoms

Change in daily asthma symptom score compared to baseline

FP at all daily doses led to significantly greater improvement in daily asthma symptom score from baseline when compared to placebo:

FP 100 mcg/day or less: SMD ‐0.57 (95% CI ‐0.69 to ‐0.46; eight trials, 1238 participants, Analysis 1.14)* 
 FP 200 mcg/day: SMD ‐0.44 (95% CI ‐0.50 to ‐0.38; 26 trials, 5093 participants, Analysis 3.17)* 
 FP 500 mcg/day: SMD ‐0.69 (95% CI ‐0.8. to ‐0.58; eight trials, 1371 participants, Analysis 5.11)* 
 FP 1000 mcg/day: SMD ‐0.67 (95% CI ‐0.84 to ‐0.51; four trials, 611 participants, Analysis 7.7)

1.14. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 14 Change in daily asthma symptom score compared to baseline.

3.17. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 17 Change in daily asthma symptom score compared to baseline.

5.11. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 11 Change in daily asthma symptom score compared to baseline.

7.7. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 7 Change in daily asthma symptom score compared to baseline.

*Although we observed a significant degree of variation between the trials in the lower dose ranges, Random‐effects modelling did not alter the significance of the summary estimates.

Change in number of night‐time awakenings per week

FP at all daily doses led to significant reductions in the number of night‐time awakenings per week compared to placebo:

FP 100 mcg/day or less: WMD ‐0.11 awakenings/wk (95% CI ‐0.17 to ‐0.05 awakening/wk) 
 FP 200 mcg/day: WMD ‐0.17 awakenings/wk (95% CI ‐0.23 to‐0.12 awakening/wk) * 
 FP 1000 mcg/day: WMD ‐0.18 awakenings/wk (95% CI ‐0.11 to ‐0.25 awakenings/wk) 
 
 * Significant heterogeneity

Change in number of night‐time awakenings per night

Treatment with FP significantly reduced the number of awakenings per night:

FP 200: WMD ‐0.12 awakenings/nt (95% CI ‐0.17 to ‐0.08; five trials, 1359 participants)

One study in the 500 mcg/day range reported data on the change in the number of night time awakenings per night (ZuWallack 2000). FP significantly reduced the frequency of nocturnal awakenings.

Change in nighttime awakenings (unspecified timeframe)

There was a significant reduction in nocturnal awakenings in the 200 mcg/day dose range: WMD ‐0.07 awakenings (95% CI ‐0.11 to ‐0.02; two trials, 280 participants).

One study in the 500 mcg/day reported a significant difference in favour of FP in terms of the percentage change of nocturnal awakenings compared with baseline (Shapiro 2000).

Change in night‐time awakenings score compared to baseline

Two trials (Condemi 1997; Peden 1998) reported night‐time awakenings but did not specify the time scale over which awakenings were calculated (i.e. per night or per week). The scores from these trials have been combined with those from trials that reported the number of night‐time awakenings per week. The pooled treatment effect for each dose has been expressed as a standardised mean difference (SMD). Incorporating the results of the trials led to the following results for change in night‐time awakenings score compared to baseline. Again, FP resulted in significantly greater reductions in night‐time awakening compared to baseline when compared to placebo:

FP 100 mcg/day or less: SMD 0.25 (95% CI 0.1 to 0.38) 
 FP 200 mcg/day: SMD 0.45 (95% CI 0.3 to 0.59) * 
 FP 500 mcg/day: SMD 0.74 (95% CI 0.5 to 0.96)

* Significant heterogeneity

Asthma symptoms: other measures

Change in symptom free days

There was a significant difference in favour of FP: 
 
 200 mcg/day: WMD 7.03 (95% CI 3.3 to 11%; three trials, 971 participants)* 
 500 mcg/day: WMD 21.32 (95% CI 13.54 to 29.09%; two trials, 361 participants)

*Significant heterogeneity

Although there was a modest level of statistical heterogeneity between the trials in the 200 mcg/day dose range (I square 35.7%), Random‐effects modelling did not alter the significance of the summary estimate.

Rescue Beta‐2 agonist use

Change in daily use of beta 2 agonist compared with baseline

When beta‐2 agonist use was reported, this was usually as a change in daily use compared to baseline. FP resulted in significantly greater reductions in beta‐2 agonist use from baseline, when compared with placebo:

FP 100 mcg/day or less: WMD ‐0.94 puffs/day (95% CI ‐1.14 to ‐0.74 puffs/d; 10 trials, 2000 participants, Analysis 1.19)* 
 FP 200 mcg/day: WMD ‐1.13 puffs/day (95% CI ‐1.25 to ‐1.01 puffs/d; 28 trials, 6373 participants, Analysis 3.26)* 
 FP 500 mcg/day: WMD ‐1.73 puffs/day (95% CI ‐1.98 to ‐1.49 puffs/d; eight trials, 1367 participants, Analysis 5.16)* 
 FP 1000 mcg/day: WMD ‐1.36 puffs/day (95% CI ‐1.64 to ‐1.08 puffs/d; five trials, 810 participants, Analysis 7.9)*

1.19. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 19 Change in daily use of beta2 agonist compared to baseline (puffs/d).

3.26. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 26 Change in daily use of beta2 agonist compared to baseline (puffs/d).

5.16. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 16 Change in daily use of beta2 agonist compared to baseline (puffs/d).

7.9. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 9 Change in daily use of beta2 agonist compared to baseline (puffs/d).

* Significant heterogeneity. It should be noted however that all individual trials found significant reductions in rescue beta‐2 agonist use favouring FP over placebo, and that in all instances, random‐effects modelling yielded statistically significant summary estimates.

Rescue beta‐2 agonist use: other measures

Change in percentage of rescue beta‐2 agonist free days compared with baseline.

There was a significant difference in favour of FP 200 mcg/day (WMD 10.49% (95% CI 5.48 to 15.51; two trials, 809 participants). A single study in the 500 mcg/day dose range reported a significantly greater improvement in the percentage of rescue beta‐2 agonist free days (Condemi 1997; WMD 25% (95% CI 14 to 36%).

Subjective assessment of treatment efficacy

Physician rated efficacy

A number of trials reported the investigator assessment of global treatment efficacy when patients attended clinic during the trial. All doses of FP led to significantly greater numbers of patients deemed to have effective or very effective treatment compared to placebo: 
 
 FP 100 mcg/day or less: Peto OR 5.12 (95% CI 3.76 to 6.98; four trials, 664 participants)* 
 FP 200 mcg/day: Peto OR 5.83 (95% CI 4.16 to 8.16; three trials, 568 participants)* 
 FP 500 mcg/day: Peto OR 5.86 (95% CI 4.09 to 8.39; three trials, 480 participants)* 
 FP 1000 mcg/day: Peto OR 9.62 (95% CI 6.18 to 14.99; two trials, 311 participants)*

* Significant heterogeneity

There were significant levels of heterogeneity when we pooled data across the dose ranges for this outcome. In all the trials assembled for this outcome, significant differences were reported individually by each study.

Health Status

Allen 1998 studied 344 children with mild to moderate asthma who received treatment over 12 months with either FP 100 mcg/day, FP 200 mcg/day or placebo. The heath status of children was assessed using two instruments completed by parents: the Functional Status IIR (FSII) and the Sleep Scale‐Children Questionnaire (SLP‐C). Significantly better FSII and SLP‐C scores were apparent for both FP groups when compared to placebo. The health status of parents was also evaluated using the Quality of Life of Parents of Asthmatic Children Questionnaire (QOL‐PAC). Significantly better (i.e. lower) scores were found for parents of children receiving either daily dose of FP when compared to placebo for the Burden dimension of this instrument. FP 200 mcg/day also led to significantly better scores compared to placebo for the Social dimension of the QOL‐PAC questionnaire, however no difference between FP 100 mcg/day and placebo was demonstrated. No difference between FP and placebo was apparent for the Subjective Norms dimension of the QOL‐PAC for either daily dose of FP.

Data for the AQLQ in adults were available, indicating that in the 200mcg dose range, FP led to statistically significant differences in quality of life compared with placebo (Analysis 3.29)

3.29. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 29 HRQOL: AQLQ (absolute scores).

A single study in adult asthmatics (Pearlman 1997) assessed health status. This 12 week study in 342 subjects with moderately severe asthma assessed FP 100 mcg/day, 200 mcg/day, 500 mcg/day and placebo. All doses of FP led to significantly better (i.e. higher) scores for a number of dimensions of the Medical Outcomes Study Short Form 36 (SF‐36), a general health status questionnaire. Similarly, all doses of FP led to significantly better (i.e. lower) scores compared to placebo for the Living With Asthma Questionnaire (LWA‐20), an asthma‐specific health status instrument.

Bronchial hyper‐responsiveness (BHR)

Bronchial hyper responsiveness to methacholine and histamine was reported in a number of trials, however data was rarely reported in a form suitable for inclusion in the meta‐analysis. In one study (Olivieri 1997) methacholine BHR was assessed, however randomised treatment groups were not compared directly (results expressed as a change compared to baseline for each group only). Only two other trials (Noonan 1998; Overbeek 1996) reported methacholine BHR. Both were conducted in adult patients, and had treatment periods of between 8 and 12 weeks . A range of daily doses of FP were compared to placebo. Methacholine BHR was expressed as either the provocative dose (PD) or the provocative concentration (PC) required producing a 20% fall in FEV1. In both trials, data were log transformed prior to analysis. FP at doses of 100 mcg/day and 200 mcg/day led to significantly greater improvements in methacholine BHR compared to baseline (Noonan 1998), the reader is referred to the original paper for further details as change scores are reported in graphical format only. FP 1000 mcg/day (Overbeek 1996) resulted in a significantly greater absolute methacholine BHR when compared to placebo: WMD 3.51 log base 2 PC20 FEV1 (95% CI 1.84 to 5.18 log base 2 PC20 FEV1). Histamine BHR was assessed in two trials. One study (Ekroos 1999) was only available in abstract form and provided no comparative results for FP and placebo treated groups. Hoekstra 1996 was a small study (34 subjects) of fair quality (Jadad score 3) conducted in children. FP 200 mcg/day led to a significantly higher histamine BHR compared to placebo after 12 weeks of treatment: WMD 1.23 log base 2 PC20 FEV1 (95% CI 0.30 to 1.23 log base 2 PC20 FEV1).

Withdrawal due to worsening asthma

Withdrawal due to lack of treatment efficacy

A number of trials used criteria for patient withdrawal due to lack of efficacy that were defined a priori. Patients were withdrawn if they experienced reductions in clinic measured FEV1 (15‐20%), PEFR in the week prior to clinic visit (> 20% on 3 to 4 or more days), night time awakening due to symptoms (on two to three or more nights in seven days prior to visit) or a need for excessive rescue beta‐2 agonist use (12 or more puffs or two to three or more days in seven days prior to clinic visit). The precise criteria for withdrawal due to lack of treatment efficacy is provided in Table 5; these were all very similar. FP at all daily doses resulted in a significantly lower likelihood of withdrawal due to lack of treatment efficacy compared to placebo:

5. Criteria for trial withdrawal due to lack of efficacy.

Study ID	FEV1	PEFR	Beta2 agonist use	Night‐time awakening	Exacerbations
Chervinsky 1994	20% or greater decrease compared to baseline	20% decrease in morning or evening PEFR on 4 or more days out of 7 in week prior to clinic visit	12 or more puffs on 3 or more days out of 7 in week prior to clinic visit	2 or more nights with 2 awakening out of 7 in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
Galant 1996	15% or greater decrease compared to baseline	20% or greater decrease in morning PEFR on 3 or more days out of 7 in week prior to clinic visit	12 or more puffs on 3 or more days out of 7 in week prior to clinic visit	3 or more awakening in week prior to clinic visit
Katz 1997	15% or greater decrease compared to baseline	15% or greater decrease in morning PEFR on 3 or more days out of 7 in week prior to clinic visit	8 or more puffs on 2 or more days out of 7 in week prior to clinic visit	2 or more nights with awakening out of 7 in week prior to clinic visit
Kavuru 2000	20% or greater decrease compared to baseline	20% or greater decrease from mean am PEF compared to baseline on 3 or more days out of 7 in week prior to clinic visit	12 or more puffs on 2 or more days out of 7 in week prior to clinic visit	2 or more awakening in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
Nathan 2000	20% or greater decrease compared to baseline	20% or greater decrease compared to baseline	12 or more puffs on 2 or more days out of 7 in week prior to clinic visit	2 or more awakening in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
Pearlman 1997	20% or greater decrease compared to baseline	20% or greater decrease in morning PEFR on 3 or more days out of 7 in week prior to clinic visit	12 or more puffs on 2 or more days out of 7 in week prior to clinic visit	2 or more awakening in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
Peden 1997	15% or greater decrease compared to baseline	20% or greater decrease in morning PEFR on 3 or more days out of 7 in week prior to clinic visit	12 or more puffs on 3 or more days out of 7 in week prior to clinic visit	3 or more awakening in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
Shapiro 2000	20% or greater decrease compared to baseline	20% or greater decrease compared to baseline on 3+ days out of preceding 7 prior to clinic visit	12 or more puffs on 2 or more days out of 7 in week prior to clinic visit	2 or more awakening in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
Sheffer 1996	15% or greater decrease compared to baseline	20% or greater decrease in morning PEFR on 3 or more days out of 7 in week prior to clinic visit	12 or more puffs on 3 or more days out of 7 in week prior to clinic visit	3 or more nights with awakening out of 7 in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
Wolfe 2000 (BD and ICS studies)	20% or greater decrease compared to baseline	20% or greater decrease compared to baseline	12 or more puffs on 2 or more days out of 7 in week prior to clinic visit	2 or more awakening in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist
ZuWallack 2000	20% or greater decrease compared to baseline	20% or greater decrease compared to baseline on 3+ days out of preceding 7 prior to clinic visit	12 or more puffs on 2 or more days out of 7 in week prior to clinic visit	2 or more awakening in week prior to clinic visit	Any clinical exacerbation requiring emergency treatment, hospital admission or additional asthma medication other than rescue beta 2 agonist

FP 100 mcg/day: Peto OR 0.27 (95% CI 0.22 to 0.34; 10 trials, 1908 participants, Analysis 1.29)* 
 FP 200 mcg/day: Peto OR 0.22 (95% CI 0.19 to 0.25; 23 trials, 5204 participants, Analysis 3.38)* 
 FP 500 mcg/day: Peto OR 0.15 (95% CI 0.12 to 0.17; nine trials, 1538 participants, Analysis 5.22) 
 FP 1000 mcg/day: Peto OR 0.11 (95% CI 0.07 to 0.15; seven trials, 1077 participants, Analysis 7.17)

1.29. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 29 Withdrawal due to lack of treatment efficacy (No. of patients).

3.38. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 38 Withdrawal due to lack of treatment efficacy (No. of patients).

5.22. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 22 Withdrawal due to lack of treatment efficacy (No. of patients).

7.17. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 17 Withdrawal due to lack of treatment efficacy (No. of patients).

* Significant heterogeneity. All individual trials demonstrated a lower likelihood of withdrawal due to lack of treatment efficacy for FP treated patients compared to placebo. Heterogeneity was present when trials were pooled for the lower three doses. It is possible that the variations in response are a consequence of the minor differences in the criteria used to define lack of treatment efficacy, although this conclusion can only be speculative.

Withdrawal due to clinical asthma exacerbation

Withdrawal due to clinical asthma exacerbation was reported in only a few trials. Allen 1998 reported a significant difference in favour of FP 100 mcg/day in reducing the likelihood of study withdrawal due to an asthma exacerbation.

We pooled data for the following dose ranges: 
 FP 200 mcg/day: Peto OR 0.22 (95% CI 0.12 to 0.39; four trials, 702 participants, Analysis 3.37) 
 FP 500 mcg/day: Peto OR 0.4 (95% CI 0.23 to 0.72; three studies, 394 participants, Analysis 5.21)

3.37. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 37 Withdrawal due to clinical asthma exacerbation (No. of patients).

5.21. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 21 Withdrawal due to clinical asthma exacerbation (No. of patients).

Where definitions of withdrawal criteria were reported in the trials, these were similar (Table 6), and featured deteriorating lung function, frequent nocturnal symptoms and increased beta‐agonist usage beyond threshold values.

6. Definitions of exacerbation leading to study withdrawal.

Study ID	Definition
Allen 1998	Requirement for more than two 7‐day courses of oral corticosteroid for asthma exacerbation
Berger 2002	Requirement for treatment with oral or parenteral steroids
Hoekstra 1996	Treatment with oral steroids
Oliveri 1997	Not given
Overbeek 1996	Not given
Pearlman 1999	Not given
Shapiro 2000	Requirement for emergency treatment, hospitalisation or usage of medication not allowed by study protocol

A single study (Overbeek 1996) conducted in 33 adults with mild asthma assessed the effects of FP 1000 mcg/day versus placebo over a 12 week treatment period and did not demonstrate any difference between treatment groups in terms of the number of patients experiencing a 'pulmonary exacerbation', but no definition of an exacerbation was given.

Safety and tolerability

Withdrawal due to adverse events

FP 100mcg/day or less: Peto OR 0.89 (95% CI 0.37 to 2.12; five trials, 1378 participants, Analysis 1.30)

1.30. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 30 Withdrawals due to adverse events.

FP 200mcg/day: Peto OR 1.23 (95% CI 0.81 to 1.86; 22 trials, 5284 participants, Analysis 3.40)

3.40. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 40 Withdrawals due to adverse events.

Oropharyngeal side‐effects

Sore throat/pharyngitis was more likely with FP than with placebo across the 200 to 1000mcg/day dose ranges: 
 
 FP 100 mcg/day or less: Peto OR 1.34 (95% CI 0.78 to 2.29; nine trials, 1928 participants, Analysis 1.33) 
 FP 200 mcg/day: Peto OR 1.78 (95% CI 1.34 to 2.35; 23 trials, 4778 participants, Analysis 3.43) 
 FP 500 mcg/day: Peto OR 2.2 (95% CI 1.17 to 4.13; seven trials, 1158 participants, Analysis 5.25) 
 FP 1000 mcg/day: Peto OR 4.95 (95% CI 1.83 to 13.43; four trials, 524 participants, Analysis 7.18) 
 
 No heterogeneity was apparent when trials were pooled for any daily dose of FP.

1.33. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 33 Sore throat or pharyngitis (No. of patients).

3.43. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 43 Sore throat or pharyngitis (No. of patients).

5.25. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 25 Sore throat or pharyngitis (No. of patients).

7.18. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 18 Sore throat or pharyngitis (No. of patients).

At all daily doses FP, there was a significantly greater likelihood of patient reporting hoarseness/dysphonia compared to placebo:

FP 100 mcg/day or less: Peto OR 5.00 (95% CI 1.53 to 16.37; seven trials, 1215 participants, Analysis 1.34) 
 FP 200 mcg/day: Peto OR 4.13 (95% CI 2.21 to 7.72; 14 trials, 2321 participants, Analysis 3.45) 
 FP 500 mcg/day: Peto OR 5.56 (95% CI 2.6 to 11.9; eight trials, 1361 participants, Analysis 5.26) 
 FP 1000 mcg/day: Peto OR 6.42 (95% CI 3.37 to 12.26; eight trials, 1175 participants, Analysis 7.19)

1.34. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 34 Hoarseness or dysphonia (No. of patients).

3.45. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 45 Hoarseness or dysphonia (No. of patients).

5.26. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 26 Hoarseness or dysphonia (No. of patients).

7.19. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 19 Hoarseness or dysphonia (No. of patients).

There was no significant heterogeneity in effect size at any dose of FP. The trials using the higher two daily doses of FP were 6 to 24 weeks in duration.

Oral candidiasis

All daily doses of FP led to a significantly greater likelihood of oral candidiasis compared to placebo:

FP 100 mcg/day or less: Peto OR 3.45 (95% CI 1.29 to 9.26; 12 trials, 1298 participants, Analysis 1.35) 
 FP 200 mcg/day: Peto OR 2.9 (95% CI 1.78 to 4.72; 17 trials, 2841 participants, Analysis 3.42) 
 FP 500 mcg/day: Peto OR 5.17 (95% CI 2.5 to 10.67; seven trials, 1254 participants, Analysis 5.27) 
 FP 1000 mcg/day: Peto OR 4.57 (95% CI 2.48 to 8.43; eight trials, 1175 participants, Analysis 7.20)

1.35. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 35 Oral Candidiasis (No. of patients).

3.42. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 42 Oral Candidiasis (No. of patients).

5.27. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 27 Oral Candidiasis (No. of patients).

7.20. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 20 Oral Candidiasis (No. of patients).

It is important to note that diagnosis of oral Candidiasis was made, based upon a variety of assessments. Mouth swab cultures were used to confirm the diagnosis in only one study (Katz 1998). Diagnosis based on clinical examination alone was used in three trials (Allen 1998; Sheffer 1996; Wolfe 1996). In nine trials (Chervinsky 1994; Condemi 1997; MacKenzie 1993; Kavuru 2000; Laforce 2000; Pearlman 1997; Shapiro 2000; Sorkness 1999b; Wasserman 1996) it was not clearly stated how the diagnosis was made, although it seems likely to have been by clinical examination alone. No significant heterogeneity in effect size was apparent when trials were pooled for any daily dose of FP versus placebo.

Hypothalamo‐pituitary‐adrenal (HPA) function

Basal adrenocortical activity: plasma cortisol

Absolute morning plasma cortisol levels were assessed in a number of trials, but complete numerical data (mean and standard deviation values) were rarely available in the study reports. Only a limited amount of data could be pooled in a formal meta‐analysis. Three trials in children (Hoekstra 1996; MacKenzie 1993; Peden 1998) assessed FP 100 mcg/day and 200 mcg/day. No significant differences between FP and placebo were apparent. Three trials in adults (Pearlman 1997; Wolfe 1996; Li 1999b) assessed FP 100‐200 mcg/day, 500 mcg/day and 1000 mcg/day, whilst Galant 1999 assessed FP 1000 mcg/day. Significant differences were not apparent between any daily dose of FP and placebo. A pooled analysis was possible for trials in the 100 mcg/day dose range; no significant difference was observed (WMD 0.27 mcg/dL (95% CI ‐1.05 to 1.59 mcg/dL; two trials, 197 participants).

Two trials reported change in plasma cortisol levels compared to baseline. Lawrence 1997 assessed FP 100 mcg/day, 1000 mcg/day and placebo. This was a large study (261 adults). No significant difference between FP 100 mcg/day and placebo was apparent. However FP 1000 mcg/day led to a small but significantly greater fall in plasma cortisol level from baseline value when compared to placebo over the six week treatment period of the trial: mean difference 3.1 mcg/dL (95% CI 0.37 to 5.83 mcg/dL). Chervinsky 1994 assessed FP 50 mcg/day, 100 mcg/day, 1000 mcg/day and placebo over an eight week treatment period in 331 adults. This study found no significant difference between any FP group and placebo for this measure.

Basal adrenocortical activity: urinary cortisol

Two trials reported urinary cortisol measures. Peden 1998 assessed 24 hour urinary free cortisol excretion rates in children with moderately severe asthma receiving FP 100 mcg/day, 200 mcg/day or placebo over a 12 week treatment period. 24 hour urinary free cortisol was measured in a subgroup of patients (153 subjects). These data were pooled with that of Li 1999b in the 100 mcg/day dose range: WMD 0 mcg/dL (95% CI ‐1.33 to 1.33 mcg/dL; two trials, 194 participants). No difference between any daily dose of FP and placebo was demonstrated. Chervinsky 1994 reported change in 24 hour urinary free cortisol compared to baseline for adults with mild to moderate asthma randomised to receive FP 100 mcg/day, 200 mcg/day, 1000 mcg/day or placebo over an eight week treatment period. No difference between any FP dose and placebo was apparent.

Dynamic tests of adrenocortical reserve

Two trials in adults conducted over eight weeks (Chervinsky 1994) and 12 weeks (Pearlman 1997) reported results of the standard short ACTH stimulation test, i.e. plasma cortisol measured 30‐60 min post 250 mcg iv injection of cosyntropin. No difference in post ACTH cortisol levels between FP and placebo were demonstrated over a daily dose range of 50 to 1000 mcg/day. A single study (Li 1999b) reported the effects of treatment on sensitive measures of adrenocortical reserve. In this study adults with mild asthma received either FP 1000 mcg/day or placebo over a two year treatment period. During a six hour infusion of synthetic ACTH (cosyntropin), stimulated plasma cortisol measurements were made. 8 hour area under curve (AUC) plasma cortisol levels were significantly higher in placebo treated patients compared to FP: WMD 35.5 mcg hour/dL (95% CI 2.0 to 69.0 mcg hour/dL); as were peak plasma cortisol levels during infusion: WMD 5.7 mcg/dL (95% CI 0.3 to 11.1 mcg/dL).

Oral steroid‐treated asthma

Two parallel group trials were conducted in oral steroid‐treated patients (Noonan 1995; Nelson 1999). Results from these trials were pooled. Both trials were large, Multicentre trials conducted in the USA in adult asthmatics. Both were conducted over 16 weeks. Patient treatment with, and dependence on, oral prednisolone for asthma control at the time of enrolment was an inclusion criterion for both trials. Two nominal daily doses of FP were compared to placebo in each trial; either FP 1000 mcg/day or 2000 mcg/day (Nelson 1999) delivered via the Accuhaler DPI, and FP 1500 mcg/d or 2000 mcg/d delivered via MDI (Noonan 1995). The mean daily baseline dose of oral prednisolone was 13.0‐13.6 mg/d and 9.5‐10.2 mg/day for the two trials, respectively. In both, a high proportion of patients (>80%) were also receiving treatment with a regular ICS (beclomethasone, triamcinolone or flunisolide) at enrolment but this was not an inclusion criterion in either case. Reduction in daily dose of oral prednisolone was the primary outcome measure in both trials. A priori defined criteria for prednisolone dose reduction were established in both trials, and were based around maintenance of stable asthma control in relation to baseline. This was assessed using changes in FEV1, PEFR, rescue beta‐2 agonist use and frequency of symptoms at clinic visits. Over a 16 week treatment period, significantly more patients treated were able to discontinue prednisolone completely when treated with FP compared to placebo.

Patients able to discontinue prednisolone completely:

FP 1000‐1500 mcg/day: Peto OR 0.07 (95% CI 0.04 to 0.14) 
 FP 2000 mcg/day: Peto OR 0.04 (95% CI 0.02 to 0.08)

Significantly greater reductions in the mean daily dose of prednisolone were achieved in FP treated patients compared to placebo:

FP 1000‐1500 mcg/day: WMD 7.5 mg/day (95% CI 5.3 to 9.9 mg/day) 
 FP 2000 mcg/day: WMD 9.7 mg/day (95% CI 7.4 to 12.1 mg/day)

In these trials, treatment with FP led to significant improvements in FEV1 and PEFR, significant reductions in asthma symptom scores and rescue beta‐2 agonist use and (or despite) a significantly greater reduction in oral corticosteroid dose compared to placebo.

In addition to these measures, health status was also assessed. An asthma specific instrument, the Asthma Quality of Life Questionnaire (AQLQ) was used by Nelson 1999. Both daily doses of FP (1000 mcg/day, 2000 mcg/day) led to significant improvements in all domains of this questionnaire compared to placebo. A general health status questionnaire, i.e. the Medical Outcomes Study Short Form‐36 (SF‐36) was used by Noonan 1995. FP 2000 mcg/day led to significant improvements in most dimensions of this instrument, FP 1500 mcg/day led to significant improvements in fewer dimensions

These benefits of FP were accompanied by an increased risk of oropharyngeal side effects:

Hoarseness or dysphonia

FP 1000‐1500 mcg/day: Peto OR 0.08 (95% CI 0.01 to 0.16) 
 FP 2000 mcg/day: Peto OR 0.17 (95% CI 0.07 to 0.27)

Oral Candidiasis

FP 1000‐1500 mcg/day: Peto OR 0.09 (95% CI 0.01 to 0.17) 
 FP 2000 mcg/day: Peto OR 0.18 (95% CI 0.06 to 0.29)

Non‐OCS‐treated asthma: Crossover trials

Although most trials reported non‐significant differences across clinical parameters, the difficulties associated with conducting crossover trials with pharmacological interventions such as inadequate washout and more general issues such as the exclusion of data from first arm withdrawals in paired analyses preclude firm answers being drawn from these trials. Data from these trials can be accessed in comparisons 18‐21 of the data screen.

Discussion

This review has compared the efficacy and safety of fluticasone compared to placebo in both non‐oral steroid treated and oral steroid dependent asthma. Only randomised, prospective trials were assessed. Eighty‐seven trials (14,208 participants) met the inclusion criteria. The risk of bias based on our assessment of the studies was low.

NON‐ORAL CORTICOSTEROID TREATED ASTHMA

Efficacy: overall effectiveness

There is clear evidence that FP offers worthwhile treatment benefits compared with placebo in the treatment of non‐oral steroid dependent asthma. This was evident for a number of outcomes. Withdrawal criteria based around clinically significant thresholds for deterioration in asthma control were defined in a number of trials (Table 4). Over a wide daily dose range (100‐1000 mcg/day), FP led to a significantly lower likelihood of trial withdrawal compared to placebo. The numbers needed to treat (NNT) to prevent one withdrawal over a 6‐24 week treatment period ranged between 2.9 (with FP 100 mcg/day or less) to 2.1 (with FP 1000 mcg/day). Such advantages are clearly worthwhile from a clinical perspective.

FP also led to improvements in FEV1. Trials reporting this outcome usually did so in the form of change compared to baseline. The observed changes in FP treated subjects when compared to placebo are clinically significant. A clinically significant change in spirometric values has not been established, but a change in FEV1 of 0.20 litre from baseline is commonly accepted as constituting the size of bronchodilator response needed for the purposes of asthma diagnosis (NHBLI 1997). The improvement in FEV1 across the dose ranges studied was either close to or in excess of this threshold value. FP treatment led to statistically significant reductions in rescue beta‐2 agonist use compared to placebo. Mean baseline beta‐2 agonist use in trials contributing to the analysis ranged between one and a half and five puffs per day. When set against the level of baseline use, the observed reductions compared with placebo of between one and two puffs per day, these differences also appear clinically worthwhile.

More frequent use of health status measurements in clinical trials has also confirmed the beneficial effect of fluticasone on quality of life of people with moderate asthma. A major research priority for future trials will be to ascertain the effects of this drug in terms of quality of life with validated instruments in children and in people of all ages with more severe disease. 
 
 The greater improvements in diary card morning PEFR and evening PEFR observed for FP are harder to assess in terms of their clinical significance. Over the dose range of 100 mcg/day to 1000 mcg/day changes favouring FP of between 23 L/min and 46 L/min for morning PEFR and between 12 L/min and 41 L/min for evening PEFR were seen.

The greater reductions in frequency of night‐time awakening from 0.11/wk (FP 100 mcg/day) to 0.18 (FP 1000 mcg/day) compared to placebo seem small. However the magnitude of this effect should be set against the baseline frequency of awakenings. Only one study reported baseline levels of sleep disturbance, with a mean of 0.05 awakenings per week (Pearlman 1997). If this low level, equating to one awakening per 20 weeks, was representative of other trials in the pooled analysis then perhaps the change scores attain greater clinical significance.

Efficacy: dose response effects

The primary aim of this review is to test efficacy and not dose response, as all the comparisons we have analysed are between FP and placebo. Therefore any apparent response to increasing doses of FP are based upon indirect comparisons between summary estimates from across the dose ranges, and should be interpreted with caution. Many of the trials contributing data had a multiple arm design, in which comparisons of between two and four‐fold increases, in addition to a placebo arm, were made. Whilst this lends a certain degree of authority to apparent dose response effects for the likelihood of trial withdrawal due to lack of efficacy, change in FEV1, morning PEFR, evening PEFR, night‐time awakening score and physician rated efficacy, it does not supplant randomised comparisons between FP at different doses. For example, it is important to appreciate that a 'dose response' was only evident when improvements over placebo were compared for highest dose FP (1000 mcg/day) and lowest dose FP (100 mcg/day). The 95% confidence intervals for treatment effects overlapped heavily for these outcomes when any other doses were compared (e.g. FP 200 versus 100 mcg/day, FP 500 versus 200 mcg/day, FP 1000 versus 500 mcg/day).

Steroid dose may be a proxy for asthma severity, with more severe patients being recruited to trials assessing higher doses of FP. In such a scenario any differences in effect sizes between differing doses of FP and placebo would be unrepresentative of a dose response relationship in a homogenous patient population.

Efficacy: influence of patient age, delivery device, treatment duration and asthma severity

The trials that could be included in this review encompassed: children and adults; mild to moderate‐severe asthma and treatment periods ranging from less than a month to one year. Both MDI and DPI delivery devices were used. The studies were conducted in similar patient populations and settings, characterised by largely adult and adolescent participants with moderately severe asthma, receiving therapy for around three months. In this update, we have observed some significant subgroup differences on measurements of lung function, which would indicate that patients with lower baseline FEV1s show larger increases than those with higher FEV1 at outset. This conclusion should be tempered with the observation that the majority of trials were in moderately severe asthma, and the lesser effect in mild and mild to moderate subgroups were drawn from a relatively small number of trials. Furthermore the number of subgroup analyses in this review make this exercise one more of hypothesis generation rather than hypothesis testing. Nevertheless baseline severity is a clinically plausible explanation for these differences, in spite of high levels of heterogeneity within these subgroups.

Without access to individual patient data, the degree of methodological similarity between the trials did not allow us to explore adequately whether diverse characteristics of baseline populations or study duration affect treatment outcome. Although subgroups identified some potentially meaningful differences in patients more likely to respond, they did not help to explain heterogeneity between trials within subgroups. It could be that the combination of study duration, baseline FEV1, and whether patients were steroid naive at outset determines response to treatment. Further trials in children may only serve to tighten confidence intervals around an already clinically important effect. trials in distinctly mild and severe asthma would also assist in better exploring variability in response to therapy.

Safety

Improvements in asthma control with FP compared to placebo are accompanied by an increased likelihood of a number of oropharyngeal side effects. The incidence of hoarseness and oral Candidiasis were significantly greater in FP treated subjects at all daily doses and appeared higher with larger doses. Individual trials assessed absolute basal plasma cortisol levels, absolute urinary free cortisol levels and stimulated plasma cortisol levels following the short ACTH stimulation test over a range of daily doses in adults and children. Significant differences between FP and placebo treated subjects were not found. Only two trials found statistically significant differences between FP and placebo for measures of adrenal function; both assessed FP 1000 mcg/day in adults. These effects included a change in morning plasma cortisol following six weeks of treatment (Lawrence 1997), and post ACTH infusion plasma cortisol levels following two years of treatment (Li 1999b).

The short term randomised controlled design of most of the studies in our review is not a reliable way of confirming serious systemic effects of prolonged inhaled steroid exposure. Adrenal suppression has been documented as a serious side‐effect of fluticasone (Tattersfield 2004). The clinical implications of small perturbations observed in Li 1999b are hard to interpret. The long‐term predictive value that changes in such measures have on the risk of developing an acute adrenal crisis are unknown (Sorkness 1998), although there is some evidence that fluticasone may have a greater effect on the adrenal glands than budesonide (Harrison 2001). Information on these harms are more likely to emerge from case‐controlled or cohort studies.

ORAL CORTICOSTEROID DEPENDENT ASTHMA

A clear oral steroid sparing effect of FP was evident. The numbers needed to treat to allow one patient to stop oral prednisolone completely compared to placebo over a 16 week treatment period are extremely low: 1.6 for FP 1000‐1500 mcg/day and 1.2 for FP 2000 mcg/day. There was a significantly greater risk of hoarseness and oral Candidiasis associated with active treatment.

Methodological Limitations

1. A large volume of literature was searched for trials meeting the inclusion criteria. There is a possibility that further relevant trials were missed, however this possibility is offset by the fact that Glaxo Wellcome, world‐wide manufacturers of FP were only able to identify two additional trials that were published following the date of the electronic search. This provides reassurance that the search strategy was comprehensive and effective. A number of unpublished trials, and documents containing unpublished data from full‐text articles were identified from the online GSK trials registry; their inclusion in our analyses will have to some degree limited the influence of publication bias.

2. A proportion of incompletely reported outcome data from individual trials could not be included in the meta‐analysis (Table 2). Authors were approached for this data but were unable or unwilling to provide it. This missing data will have diminished the power of the meta‐analysis. We have attempted to overcome this with imputing or calculating estimates of variance. This will have gone some way to redressing the potential bias of under‐reporting outcome data, but it does not replace raw data from the trials, and may itself be subject to unmet assumptions regarding the distribution of data within each study. Our methods are described in Table 1. Outcomes including both unimputed (i.e. completely available) and imputed standard deviations are presented in the review.

3. There was a notable absence of studies conducted in a primary care setting. Although it seems reasonable to extrapolate the conclusions regarding efficacy and safety to patients treated in primary care there is a possibility that such patients may differ in terms of their overall asthma severity (e.g. relatively milder disease/less impaired control at baseline). Although subjects with mild asthma were included in the studies reviewed there remains the possibility that inclusion of a greater proportion of such patients may have made a quantitative (if not qualitative) difference to the pooled treatment effects found. The direction of any such change cannot be predicted, however. Milder patients may show greater responsiveness to corticosteroids, but may have less capacity to show improvement.

4. The results for non‐oral steroid treated chronic asthmatics apply to children and adults, treated for up 12 months with FP delivered via MDI , MDI+spacer/chamber or DPI. The results should not be extrapolated to infants under the age of two years, or for adults over the age of 65, nor for FP delivered via nebuliser.

5. We have combined data from trials where once and twice daily administrations of fluticasone were studied. Masoli 2005 has undertaken a meta‐analysis which suggests that where head‐to‐head comparisons have been made between once and twice daily dosing schedules of the same dose of FP, the twice daily dosing schedule led to greater benefit in FEV1, peak flow and withdrawals due to poor asthma control. However, it is possible that evening administration may produce a more significant impact on airway calibre than morning administration. The placebo‐controlled trials in this review have assessed once daily dosing schedules tended to be conducted in mild/mild to moderate asthma, and so apparent differences in response to therapy could also be explained by baseline asthma severity.

Authors' conclusions

Implications for practice.

This review strongly supports the use of fluticasone in the treatment of patients with non‐oral steroid treated chronic asthma. This applies to children aged over two years, adolescents and adults. Current guidelines recommend a dose titration approach for the use of inhaled corticosteroids in asthma (BTS 2003). The findings of this review are consistent with the rationale for this approach, since they indicate that most patients achieve improved asthma control on lower doses of FP. Based upon indirect comparisons with the effects of higher doses of FP, it would appear that FP in the lower dose ranges confers similar benefit when compared with placebo. This factor should reinforce the recommendation that, in clinical practice, patients receiving FP for asthma prophylaxis should have their daily dose requirements regularly assessed and down titrated as necessary.

All oral steroid treated asthmatics should be considered for a trial of fluticasone. Clinically worthwhile reductions in oral prednisolone use can be achieved when patients are treated with high dose FP 1000‐2000 mcg/day.

Implications for research.

An important outstanding area of research is the need to compare differences in time course of response and ultimate outcome with different dosing regimes e.g.:

• Low dose through out

• High then low dose.

• trials in children and in more severe asthma across all age ranges would add to the evidence base for FP.

Such studies should be carried out over time periods that are realistic for routine asthma care and should not be less than six months in duration and preferably longer. All serious adverse events should also be fully documented.

What's new

Date	Event	Description
12 November 2008	Amended	Reference added to Derom 2001 (now Derom 2005); minor amendments to data from Pinnas 2005.

History

Protocol first published: Issue 1, 1999
 Review first published: Issue 3, 2001

Date	Event	Description
4 July 2008	New citation required and conclusions have changed	Substantive amendment. New studies (12): Caffey 2005; Pinnas 2005; FLIC15; FLTA4030; FLTA3014; FLTA2007; FLTA3020; FLTA3022; Philips 2004; Bernstein 2004; Subbarao 2005; Oaquandah 2006 Unpublished data for previously published studies: Allen 1998; Pearlman 2002; Pearlman 2004; Kemp 2004; Wolfe 2000 BD; Wolfe 2000 ICS; Rooklin 2001; Peden 1998; Chervinsky 1994; Busse 2001; Katz 1998; MacKenzie 1993 The data from these studies do not alter the conclusions of the review.
4 July 2008	Amended	Converted to new review format.
2 January 2008	New search has been performed	Search re‐run in January 2008

Appendices

Appendix 1. Archive of methodological approach to assessing study quality

All trials were scored using the Cochrane approach:

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

Studies were also assessed using a five point scoring instrument (Jadad 1996):

1. Was the study described as randomised? (Yes = 1 no = 0) 
 2. Was the study described as double blind? (Yes = 1 no = 0) 
 3. Was of a description of withdrawals and dropouts? (Yes = 1 no = 0) 
 4. Was the method of randomisation well described and appropriate? (Yes = 1 no = 0) 
 5. Was the method of double blinding well described and appropriate? (Yes = 1 no = 0) 
 6. Deduct one point if method of randomisation or blinding inappropriate

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

Appendix 2. GSK randomisation procedures

The procedures for randomising GSK sponsored studies has been detailed in correspondence between Richard Follows and TL, the details of which are given below:

The randomisation software is a computer‐generated, centralised programme (RandAll). After verification that the randomisation sequence is suitable for the study design (crossover, block or stratification), Clinical Supplies then package the treatments according to the randomisation list generated. Concealment of allocation is maintained by a third party, since the sites phone in and are allocated treatments on that basis. Alternatively a third party may dispense the drug at the sites. Unblinding of data for interim analyses can only be done through RandAll, and are restricted so that only those reviewing the data are unblinded to treatment group allocation.

Data and analyses

Comparison 1. FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in FEV1 compared to baseline (litres)	11		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 Children	4	719	Mean Difference (IV, Fixed, 95% CI)	0.10 [0.04, 0.17]
1.2 Adults	7	1043	Mean Difference (IV, Fixed, 95% CI)	0.38 [0.32, 0.43]
2 Change in FEV1 compared to baseline (litres)	12		Litres (Fixed, 95% CI)	Subtotals only
2.1 Children	4	719	Litres (Fixed, 95% CI)	0.10 [0.06, 0.15]
2.2 Adults	8	1352	Litres (Fixed, 95% CI)	0.26 [0.21, 0.31]
3 FEV1 ‐ Litres (absolute values)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Change in FEV1 (% predicted)	1		% (Fixed, 95% CI)	Totals not selected
4.1 Children	0		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Adults	1		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Change in morning PEFR compared to baseline (L/min)	10		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
5.1 Children	2	353	Mean Difference (IV, Fixed, 95% CI)	26.41 [18.03, 34.79]
5.2 Adults	8	1352	Mean Difference (IV, Fixed, 95% CI)	21.91 [17.76, 26.06]
6 Change in am PEF (predicted)	1		% (Fixed, 95% CI)	Totals not selected
6.1 Children	1		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Adults	0		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Change in evening PEFR compared to baseline (L/min)	8		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
7.1 Children	2	780	Mean Difference (IV, Fixed, 95% CI)	6.98 [2.26, 11.71]
7.2 Adults	6	1014	Mean Difference (IV, Fixed, 95% CI)	15.60 [11.06, 20.15]
8 Change in evening PEFR compared to baseline	9		Litres/min (Fixed, 95% CI)	Subtotals only
8.1 Children	2	780	Litres/min (Fixed, 95% CI)	6.98 [2.26, 11.70]
8.2 Adults	7	1174	Litres/min (Fixed, 95% CI)	16.51 [12.12, 20.91]
9 Change in evening PEF (predicted)	1		% (Fixed, 95% CI)	Totals not selected
9.1 Children	1		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Adults	0		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Peak flow ‐ L/min (absolute values)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Change in clinic PEFR compared to baseline (L/min)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
11.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Change in FVC compared to baseline (litres)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Change in FEF25‐75 compared to baseline (L/second)	2	467	Mean Difference (IV, Fixed, 95% CI)	0.20 [0.05, 0.34]
13.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Adults	2	467	Mean Difference (IV, Fixed, 95% CI)	0.20 [0.05, 0.34]
14 Change in daily asthma symptom score compared to baseline	8	1238	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.57 [‐0.69, ‐0.46]
14.1 Children	2	353	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.52 [‐0.73, ‐0.31]
14.2 Adults	6	885	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐0.73, ‐0.46]
15 Symptoms ‐ absolute scores	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
15.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Change in night‐time wakening score	6	895	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.25 [‐0.38, ‐0.12]
16.1 Children	1	176	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.29 [‐0.59, 0.01]
16.2 Adults	5	719	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.24 [‐0.39, ‐0.09]
17 Nighttime awakenings/night	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
17.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Change in number night‐time wakenings per week	5	809	Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.17, ‐0.05]
18.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Adults	5	809	Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.17, ‐0.05]
19 Change in daily use of beta2 agonist compared to baseline (puffs/d)	10	2000	Mean Difference (IV, Fixed, 95% CI)	‐0.94 [‐1.14, ‐0.74]
19.1 Children	3	957	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐0.87, ‐0.33]
19.2 Adults	7	1043	Mean Difference (IV, Fixed, 95% CI)	‐1.36 [‐1.66, ‐1.06]
20 Rescue medication usage ‐ puffs/d (absolute scores)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
20.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
21 HRQOL: AQLQ	0		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
21.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
21.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22 HRQOL: Functional Status IIR questionnaire (short version)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
22.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, burden dimension	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
23.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, subjective norms dimension	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
24.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
25 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, social dimension	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
25.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
25.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
26 HRQOL: Sleep Scale Children questionnaire	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
26.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
26.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
27 Physician‐rated efficacy: effective or very effective	4	664	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.12 [3.76, 6.98]
27.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.2 Adults	4	664	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.12 [3.76, 6.98]
28 Withdrawal due to clinical asthma exacerbation (No. of patients)	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected
28.1 Children	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
28.2 Adults	0		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
29 Withdrawal due to lack of treatment efficacy (No. of patients)	10	1908	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.27 [0.22, 0.34]
29.1 Children	4	782	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.36 [0.25, 0.52]
29.2 Adults	6	1126	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.23 [0.17, 0.31]
30 Withdrawals due to adverse events	5	1378	Odds Ratio (M‐H, Fixed, 95% CI)	0.89 [0.37, 2.12]
30.1 Children	2	862	Odds Ratio (M‐H, Fixed, 95% CI)	0.73 [0.24, 2.20]
30.2 Adults	3	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.30, 5.13]
31 Morning plasma cortisol (mcg/dL)	2	197	Mean Difference (IV, Fixed, 95% CI)	0.27 [‐1.05, 1.59]
31.1 Children	1	159	Mean Difference (IV, Fixed, 95% CI)	0.70 [‐0.84, 2.24]
31.2 Adults	1	38	Mean Difference (IV, Fixed, 95% CI)	‐0.90 [‐3.46, 1.66]
32 Total urinary free cortisol excretion (mcg/24 hours)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
32.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
32.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
33 Sore throat or pharyngitis (No. of patients)	9	1928	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.34 [0.78, 2.29]
33.1 Children	4	1250	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.39 [0.67, 2.91]
33.2 Adults	5	678	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.28 [0.58, 2.81]
34 Hoarseness or dysphonia (No. of patients)	7	1215	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.00 [1.53, 16.37]
34.1 Children	2	395	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.19 [0.74, 69.93]
34.2 Adults	5	820	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.36 [1.09, 17.52]
35 Oral Candidiasis (No. of patients)	7	1298	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.45 [1.29, 9.26]
35.1 Children	3	653	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.98 [0.40, 9.85]
35.2 Adults	4	645	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.84 [1.39, 16.88]
36 Headaches	5	1291	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.61, 1.16]
36.1 Children	2	775	Odds Ratio (M‐H, Fixed, 95% CI)	0.75 [0.52, 1.09]
36.2 Adults	3	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.63, 2.17]

1.1. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 1 Change in FEV1 compared to baseline (litres).

1.2. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 2 Change in FEV1 compared to baseline (litres).

1.3. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 3 FEV1 ‐ Litres (absolute values).

1.4. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 4 Change in FEV1 (% predicted).

1.6. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 6 Change in am PEF (predicted).

1.7. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 7 Change in evening PEFR compared to baseline (L/min).

1.9. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 9 Change in evening PEF (predicted).

1.10. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 10 Peak flow ‐ L/min (absolute values).

1.11. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 11 Change in clinic PEFR compared to baseline (L/min).

1.12. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 12 Change in FVC compared to baseline (litres).

1.13. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 13 Change in FEF25‐75 compared to baseline (L/second).

1.15. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 15 Symptoms ‐ absolute scores.

1.16. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 16 Change in night‐time wakening score.

1.17. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 17 Nighttime awakenings/night.

1.18. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 18 Change in number night‐time wakenings per week.

1.20. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 20 Rescue medication usage ‐ puffs/d (absolute scores).

1.22. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 22 HRQOL: Functional Status IIR questionnaire (short version).

1.23. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 23 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, burden dimension.

1.24. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 24 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, subjective norms dimension.

1.25. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 25 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, social dimension.

1.26. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 26 HRQOL: Sleep Scale Children questionnaire.

1.27. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 27 Physician‐rated efficacy: effective or very effective.

1.28. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 28 Withdrawal due to clinical asthma exacerbation (No. of patients).

1.31. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 31 Morning plasma cortisol (mcg/dL).

1.32. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 32 Total urinary free cortisol excretion (mcg/24 hours).

1.36. Analysis.

Comparison 1 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (all ages), Outcome 36 Headaches.

Comparison 2. FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (subgroups).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Paediatric studies: change in FEV1 compared to baseline; duration	4		Litres (Fixed, 95% CI)	Subtotals only
1.1 1‐4 weeks	1	258	Litres (Fixed, 95% CI)	0.1 [0.02, 0.18]
1.2 1‐5 months	3	461	Litres (Fixed, 95% CI)	0.10 [0.05, 0.16]
1.3 6 months or longer	0	0	Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Adult studies: change in FEV1; duration	8		Mean Difference (Fixed, 95% CI)	Subtotals only
2.1 1‐4 weeks	0		Mean Difference (Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 1‐5 months	8		Mean Difference (Fixed, 95% CI)	0.26 [0.21, 0.31]
3 Paediatric studies: change in FEV1 compared to baseline; inhaler device	4		Litres (Fixed, 95% CI)	Subtotals only
3.1 MDI	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 DPI	4		Litres (Fixed, 95% CI)	0.10 [0.06, 0.15]
4 Adult studies: change in FEV1 compared to baseline; inhaler device	8		Odds Ratio (Fixed, 95% CI)	Subtotals only
4.1 MDI	4		Odds Ratio (Fixed, 95% CI)	1.49 [1.37, 1.62]
4.2 DPI	4		Odds Ratio (Fixed, 95% CI)	1.22 [1.15, 1.29]
5 Paediatric studies: change in FEV1 compared to baseline (litres); severity	4		Litres (Fixed, 95% CI)	Subtotals only
5.1 Mild	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Mild to moderate	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Moderate	4		Litres (Fixed, 95% CI)	0.10 [0.06, 0.15]
6 Adult studies: change in FEV1 compared to baseline (litres); severity	8		Litres (Fixed, 95% CI)	Subtotals only
6.1 Mild	1		Litres (Fixed, 95% CI)	0.02 [‐0.06, 0.10]
6.2 Mild to moderate	1		Litres (Fixed, 95% CI)	0.35 [0.19, 0.51]
6.3 Moderate	6		Litres (Fixed, 95% CI)	0.38 [0.32, 0.44]

2.1. Analysis.

Comparison 2 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (subgroups), Outcome 1 Paediatric studies: change in FEV1 compared to baseline; duration.

2.2. Analysis.

Comparison 2 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (subgroups), Outcome 2 Adult studies: change in FEV1; duration.

2.3. Analysis.

Comparison 2 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (subgroups), Outcome 3 Paediatric studies: change in FEV1 compared to baseline; inhaler device.

2.4. Analysis.

Comparison 2 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (subgroups), Outcome 4 Adult studies: change in FEV1 compared to baseline; inhaler device.

2.5. Analysis.

Comparison 2 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (subgroups), Outcome 5 Paediatric studies: change in FEV1 compared to baseline (litres); severity.

2.6. Analysis.

Comparison 2 FP versus placebo: Parallel group studies, no oral steroids: 100 mcg/d or less (subgroups), Outcome 6 Adult studies: change in FEV1 compared to baseline (litres); severity.

Comparison 3. FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in FEV1 compared to baseline (litres)	28		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 Children	3	524	Mean Difference (IV, Fixed, 95% CI)	0.18 [0.12, 0.23]
1.2 Adults	25	5416	Mean Difference (IV, Fixed, 95% CI)	0.25 [0.22, 0.27]
2 Change in FEV1 compared to baseline (litres)	29		Litres (Fixed, 95% CI)	Subtotals only
2.1 Children	4	670	Litres (Fixed, 95% CI)	0.18 [0.13, 0.22]
2.2 Adults	25	5421	Litres (Fixed, 95% CI)	0.25 [0.23, 0.28]
3 Change in FEV1 (% predicted)	9	1322	% (Fixed, 95% CI)	6.94 [5.59, 8.29]
3.1 Children	3	399	% (Fixed, 95% CI)	6.57 [4.21, 8.94]
3.2 Adults	6	923	% (Fixed, 95% CI)	7.12 [5.48, 8.76]
4 Change in FEV1 (%)	6	938	Mean Difference (IV, Fixed, 95% CI)	6.90 [4.92, 8.89]
4.1 Children	1	207	Mean Difference (IV, Fixed, 95% CI)	3.2 [0.10, 6.30]
4.2 Adults	5	731	Mean Difference (IV, Fixed, 95% CI)	9.48 [6.90, 12.07]
5 FEV1 (% predicted ‐ absolute values)	4	157	% (Fixed, 95% CI)	4.22 [0.94, 7.50]
5.1 Children	3	125	% (Fixed, 95% CI)	5.92 [2.22, 9.62]
5.2 Adults	1	32	% (Fixed, 95% CI)	‐2.0 [‐9.08, 5.08]
6 FEV1 (absolute values)	1		Litres (Fixed, 95% CI)	Totals not selected
6.1 Children	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Adults	1		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Change in morning PEFR compared with baseline (L/min ‐ generic inverse variance))	29		Litres/min (Fixed, 95% CI)	Subtotals only
7.1 Children	5	775	Litres/min (Fixed, 95% CI)	20.79 [16.01, 25.57]
7.2 Adults	24	5345	Litres/min (Fixed, 95% CI)	27.83 [25.31, 30.36]
8 Change in morning PEFR compared to baseline (L/min)	27	4823	Mean Difference (IV, Fixed, 95% CI)	27.15 [24.63, 29.67]
8.1 Children	4	741	Mean Difference (IV, Fixed, 95% CI)	19.74 [14.83, 24.65]
8.2 Adults	23	4082	Mean Difference (IV, Fixed, 95% CI)	29.79 [26.86, 32.73]
9 Change in am PEF (% predicted)	2	665	% (Fixed, 95% CI)	4.49 [2.92, 6.05]
9.1 Children	1	241	% (Fixed, 95% CI)	6.0 [2.08, 9.92]
9.2 Adults	1	424	% (Fixed, 95% CI)	4.2 [2.49, 5.91]
10 Change in evening PEFR compared to baseline (L/min)	20		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
10.1 Children	2	331	Mean Difference (IV, Fixed, 95% CI)	20.77 [13.06, 28.47]
10.2 Adults	18	3676	Mean Difference (IV, Fixed, 95% CI)	22.39 [19.42, 25.36]
11 Change in evening PEFR compared to baseline	21	4172	Litres/min (Fixed, 95% CI)	22.43 [19.69, 25.16]
11.1 Children	2	331	Litres/min (Fixed, 95% CI)	20.77 [13.07, 28.46]
11.2 Adults	19	3841	Litres/min (Fixed, 95% CI)	22.67 [19.74, 25.59]
12 Change in clinic PEFR compared to baseline (L/min)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Peak flow L/min (absolute values)	2	50	Mean Difference (IV, Fixed, 95% CI)	68.07 [7.89, 128.25]
13.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Adults	2	50	Mean Difference (IV, Fixed, 95% CI)	68.07 [7.89, 128.25]
14 Change in FVC compared to baseline (litres)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
14.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Change in FEF25‐75 compared to baseline (L/second)	2	1423	Mean Difference (IV, Fixed, 95% CI)	0.25 [0.16, 0.34]
15.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 Adults	2	1423	Mean Difference (IV, Fixed, 95% CI)	0.25 [0.16, 0.34]
16 Histamine BHR (log base 2 PC20 FEV1 mg/ml)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
16.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Change in daily asthma symptom score compared to baseline	26	5093	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.44 [‐0.50, ‐0.38]
17.1 Children	5	1083	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.34 [‐0.46, ‐0.22]
17.2 Adults	21	4010	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.47 [‐0.53, ‐0.40]
18 Change in night‐time wakening score	6	884	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.45 [‐0.59, ‐0.32]
18.1 Children	1	173	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.41 [‐0.71, ‐0.11]
18.2 Adults	5	711	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.47 [‐0.62, ‐0.32]
19 Change in symptom free days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
19.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
20 Change from baseline in symptom free days (%)	4	1178	Mean Difference (IV, Fixed, 95% CI)	8.45 [4.94, 11.95]
20.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.2 Adults	4	1178	Mean Difference (IV, Fixed, 95% CI)	8.45 [4.94, 11.95]
21 Percentage nights without awakening ‐ change from baseline	2	208	Mean Difference (IV, Fixed, 95% CI)	10.65 [4.84, 16.46]
21.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
21.2 Adults	2	208	Mean Difference (IV, Fixed, 95% CI)	10.65 [4.84, 16.46]
22 Change in number night‐time awakenings per week	5	802	Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.23, ‐0.12]
22.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.2 Adults	5	802	Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.23, ‐0.12]
23 Change from baseline in nighttime awakenings/night	8	1860	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.16, ‐0.08]
23.1 Children	1	158	Mean Difference (IV, Fixed, 95% CI)	‐0.1 [‐0.16, ‐0.04]
23.2 Adults	7	1702	Mean Difference (IV, Fixed, 95% CI)	‐0.13 [‐0.18, ‐0.08]
24 Change in nocturnal awakenings (unspecified time)	2	280	Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐0.11, ‐0.02]
24.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.2 Adults	2	280	Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐0.11, ‐0.02]
25 Symptoms (absolute values)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
25.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
25.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
26 Change in daily use of beta2 agonist compared to baseline (puffs/d)	30	6730	Mean Difference (IV, Fixed, 95% CI)	‐1.13 [‐1.25, ‐1.01]
26.1 Children	5	1089	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐1.07, ‐0.53]
26.2 Adults	25	5641	Mean Difference (IV, Fixed, 95% CI)	‐1.21 [‐1.35, ‐1.07]
27 Change from baseline in rescue medication free days (%)	4	1232	Mean Difference (IV, Fixed, 95% CI)	12.08 [7.84, 16.32]
27.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.2 Adults	4	1232	Mean Difference (IV, Fixed, 95% CI)	12.08 [7.84, 16.32]
28 Rescue medication (absolute scores)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
28.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
28.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
29 HRQOL: AQLQ (absolute scores)	2	343	Mean Difference (IV, Fixed, 95% CI)	0.65 [0.41, 0.88]
29.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
29.2 Adults	2	343	Mean Difference (IV, Fixed, 95% CI)	0.65 [0.41, 0.88]
30 HRQOL: Functional Status IIR questionaire (short version)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
30.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
30.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
31 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, burden dimension	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
31.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
32 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, subjective norms dimension	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
32.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
32.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
33 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, social dimension	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
33.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
33.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
34 HRQOL: Sleep Scale Children questionnaire	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
34.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
34.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
35 Physician‐rated efficacy: effective or very effective (No. of patients)	4	784	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.17 [3.14, 5.55]
35.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
35.2 Adults	4	784	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.17 [3.14, 5.55]
36 Exacerbations requiring OCS treatment	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected
36.1 Children	0		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
36.2 Adults	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
37 Withdrawal due to clinical asthma exacerbation (No. of patients)	4	702	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.22 [0.12, 0.39]
37.1 Children	2	248	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.18 [0.09, 0.38]
37.2 Adults	2	454	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.29 [0.11, 0.79]
38 Withdrawal due to lack of treatment efficacy (No. of patients)	23	5204	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.22 [0.19, 0.25]
38.1 Children	3	592	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.24 [0.16, 0.35]
38.2 Adults	20	4612	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.21 [0.18, 0.25]
39 Withdrawals (any reason)	16	3423	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.43 [0.36, 0.50]
39.1 Children	2	399	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.41 [0.27, 0.65]
39.2 Adults	14	3024	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.43 [0.35, 0.51]
40 Withdrawals due to adverse events	22	5284	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.23 [0.81, 1.86]
40.1 Children	2	610	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.12 [0.61, 7.41]
40.2 Adults	20	4674	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.15 [0.74, 1.78]
41 Adverse events (any)	12	2291	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [1.02, 1.47]
41.1 Children	1	241	Odds Ratio (M‐H, Fixed, 95% CI)	1.15 [0.66, 2.00]
41.2 Adults	11	2050	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [1.02, 1.50]
42 Oral Candidiasis (No. of patients)	17	2841	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.90 [1.78, 4.72]
42.1 Children	4	754	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.32 [0.55, 3.20]
42.2 Adults	13	2087	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.09 [2.28, 7.35]
43 Sore throat or pharyngitis (No. of patients)	24	4778	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.78 [1.34, 2.35]
43.1 Children	3	613	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.66 [0.75, 3.69]
43.2 Adults	21	4165	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.79 [1.33, 2.42]
44 Headaches	18	4009	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.17 [0.95, 1.44]
44.1 Children	2	399	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.30 [0.64, 2.64]
44.2 Adults	16	3610	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.16 [0.93, 1.44]
45 Hoarseness or dysphonia (No. of patients)	14	2321	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.13 [2.21, 7.72]
45.1 Children	2	394	Peto Odds Ratio (Peto, Fixed, 95% CI)	8.10 [0.83, 79.01]
45.2 Adults	12	1927	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.91 [2.04, 7.49]
46 Upper respiratory tract infection	12	3389	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.88, 1.31]
46.1 Children	3	758	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.61, 1.41]
46.2 Adults	9	2631	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.89, 1.40]
47 Sinusitis	12	3238	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.30 [0.94, 1.80]
47.1 Children	2	399	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.96 [0.84, 4.56]
47.2 Adults	10	2839	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.22 [0.86, 1.73]
48 Total urinary free cortisol excretion (mcg/24 hours)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
48.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
48.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
49 AUC serum cortisol (ng*h/mL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
49.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
49.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
50 Morning plasma cortisol (mcg/dL)	2	194	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐1.33, 1.33]
50.1 Children	1	154	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐1.23, 1.83]
50.2 Adults	1	40	Mean Difference (IV, Fixed, 95% CI)	‐0.90 [‐3.57, 1.77]
51 Change in morning plasma cortisol compared to baseline (mcg/dL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
51.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
51.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
52 Change in peak plasma cortisol expression (mcg/dL)	2	117	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐2.56, 1.36]
52.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
52.2 Adults	2	117	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐2.56, 1.36]

3.1. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 1 Change in FEV1 compared to baseline (litres).

3.2. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 2 Change in FEV1 compared to baseline (litres).

3.3. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 3 Change in FEV1 (% predicted).

3.4. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 4 Change in FEV1 (%).

3.5. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 5 FEV1 (% predicted ‐ absolute values).

3.6. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 6 FEV1 (absolute values).

3.8. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 8 Change in morning PEFR compared to baseline (L/min).

3.9. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 9 Change in am PEF (% predicted).

3.10. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 10 Change in evening PEFR compared to baseline (L/min).

3.12. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 12 Change in clinic PEFR compared to baseline (L/min).

3.13. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 13 Peak flow L/min (absolute values).

3.14. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 14 Change in FVC compared to baseline (litres).

3.15. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 15 Change in FEF25‐75 compared to baseline (L/second).

3.16. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 16 Histamine BHR (log base 2 PC20 FEV1 mg/ml).

3.18. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 18 Change in night‐time wakening score.

3.19. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 19 Change in symptom free days.

3.20. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 20 Change from baseline in symptom free days (%).

3.21. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 21 Percentage nights without awakening ‐ change from baseline.

3.22. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 22 Change in number night‐time awakenings per week.

3.23. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 23 Change from baseline in nighttime awakenings/night.

3.24. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 24 Change in nocturnal awakenings (unspecified time).

3.25. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 25 Symptoms (absolute values).

3.27. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 27 Change from baseline in rescue medication free days (%).

3.28. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 28 Rescue medication (absolute scores).

3.30. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 30 HRQOL: Functional Status IIR questionaire (short version).

3.31. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 31 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, burden dimension.

3.32. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 32 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, subjective norms dimension.

3.33. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 33 HRQOL: Quality of Life of Parents of Asthmatic Children questionnaire, social dimension.

3.34. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 34 HRQOL: Sleep Scale Children questionnaire.

3.35. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 35 Physician‐rated efficacy: effective or very effective (No. of patients).

3.36. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 36 Exacerbations requiring OCS treatment.

3.39. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 39 Withdrawals (any reason).

3.41. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 41 Adverse events (any).

3.44. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 44 Headaches.

3.46. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 46 Upper respiratory tract infection.

3.47. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 47 Sinusitis.

3.48. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 48 Total urinary free cortisol excretion (mcg/24 hours).

3.49. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 49 AUC serum cortisol (ng*h/mL).

3.50. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 50 Morning plasma cortisol (mcg/dL).

3.51. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 51 Change in morning plasma cortisol compared to baseline (mcg/dL).

3.52. Analysis.

Comparison 3 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (all ages), Outcome 52 Change in peak plasma cortisol expression (mcg/dL).

Comparison 4. FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (subgroups).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Paediatric studies: change in FEV1 compared to baseline (litres); study duration	4		Litres (Fixed, 95% CI)	Subtotals only
1.1 1‐4 weeks	0	0	Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 1‐5 months	3	477	Litres (Fixed, 95% CI)	0.18 [0.13, 0.24]
1.3 6 months or longer	1	193	Litres (Fixed, 95% CI)	0.16 [0.08, 0.24]
2 Adult studies: change in FEV1 compared to baseline (litres); study duration	25		Litres (Fixed, 95% CI)	Subtotals only
2.1 1‐4 weeks	1		Litres (Fixed, 95% CI)	0.27 [0.05, 0.49]
2.2 1‐5 months	21		Litres (Fixed, 95% CI)	0.28 [0.25, 0.30]
2.3 6 months or longer	3		Litres (Fixed, 95% CI)	0.16 [0.10, 0.21]
3 Paediatric studies: change in FEV1 compared to baseline (litres); inhaler device	4		Litres (Fixed, 95% CI)	0.18 [0.13, 0.22]
3.1 MDI	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 DPI	4		Litres (Fixed, 95% CI)	0.18 [0.13, 0.22]
4 Adult studies: change in FEV1 compared to baseline (litres); inhaler device	25		Litres (Random, 95% CI)	Subtotals only
4.1 MDI	15		Litres (Random, 95% CI)	0.33 [0.25, 0.40]
4.2 DPI	10		Litres (Random, 95% CI)	0.27 [0.18, 0.36]
5 Paediatric studies: change in FEV1 compared to baseline (litres); severity	4		Litres (Fixed, 95% CI)	0.18 [0.13, 0.22]
5.1 Mild	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Mild to moderate	2		Litres (Fixed, 95% CI)	0.20 [0.13, 0.26]
5.3 Moderate	2		Litres (Fixed, 95% CI)	0.15 [0.08, 0.22]
6 Adult studies: change in FEV1 compared to baseline (litres); severity	25		Litres (Fixed, 95% CI)	Subtotals only
6.1 Mild	2	1334	Litres (Fixed, 95% CI)	0.10 [0.05, 0.16]
6.2 Mild to moderate	10	1650	Litres (Fixed, 95% CI)	0.23 [0.18, 0.27]
6.3 Moderate	13	2430	Litres (Fixed, 95% CI)	0.32 [0.28, 0.35]

4.1. Analysis.

Comparison 4 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (subgroups), Outcome 1 Paediatric studies: change in FEV1 compared to baseline (litres); study duration.

4.2. Analysis.

Comparison 4 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (subgroups), Outcome 2 Adult studies: change in FEV1 compared to baseline (litres); study duration.

4.3. Analysis.

Comparison 4 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (subgroups), Outcome 3 Paediatric studies: change in FEV1 compared to baseline (litres); inhaler device.

4.4. Analysis.

Comparison 4 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (subgroups), Outcome 4 Adult studies: change in FEV1 compared to baseline (litres); inhaler device.

4.5. Analysis.

Comparison 4 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (subgroups), Outcome 5 Paediatric studies: change in FEV1 compared to baseline (litres); severity.

4.6. Analysis.

Comparison 4 FP versus placebo: Parallel group studies, no oral steroids: 200 mcg/d (subgroups), Outcome 6 Adult studies: change in FEV1 compared to baseline (litres); severity.

Comparison 5. FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in FEV1 compared to baseline (Litres)	11	1730	Mean Difference (IV, Fixed, 95% CI)	0.39 [0.34, 0.43]
1.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Adults	11	1730	Mean Difference (IV, Fixed, 95% CI)	0.39 [0.34, 0.43]
2 FEV1 (absolute values)	1	68	Litres (Fixed, 95% CI)	0.06 [‐0.00, 0.12]
2.1 Children	1	68	Litres (Fixed, 95% CI)	0.06 [‐0.00, 0.12]
2.2 Adults	0	0	Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Change in FEV1 (%)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Change in FEV1 (% predicted)	2	402	% (Random, 95% CI)	9.91 [4.05, 15.78]
4.1 Children	0	0	% (Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Adults	2	402	% (Random, 95% CI)	9.91 [4.05, 15.78]
5 FEV1 (% predicted ‐ absolute scores)	2	50	Mean Difference (IV, Fixed, 95% CI)	24.43 [15.90, 32.95]
5.1 Children	1	26	Mean Difference (IV, Fixed, 95% CI)	4.30 [‐25.66, 34.26]
5.2 Adults	1	24	Mean Difference (IV, Fixed, 95% CI)	26.20 [17.31, 35.09]
6 Change in morning PEF (L/min)	12		Litres/min (Fixed, 95% CI)	Subtotals only
6.1 Children	1	68	Litres/min (Fixed, 95% CI)	16.0 [4.55, 27.45]
6.2 Adults	11	1595	Litres/min (Fixed, 95% CI)	39.59 [35.43, 43.75]
7 Change in morning PEFR compared to baseline (L/min)	10	1557	Mean Difference (IV, Fixed, 95% CI)	40.01 [35.68, 44.34]
7.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Adults	10	1557	Mean Difference (IV, Fixed, 95% CI)	40.01 [35.68, 44.34]
8 Change in am PEF (% predicted)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Change in evening PEF compared with baseline	6	791	Litres/min (Fixed, 95% CI)	30.11 [23.62, 36.59]
9.1 Children	0	0	Litres/min (Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Adults	6	791	Litres/min (Fixed, 95% CI)	30.11 [23.62, 36.59]
10 Change in evening PEF compared with baseline (L/min)	5	629	Mean Difference (IV, Fixed, 95% CI)	29.24 [22.51, 35.98]
10.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Adults	5	629	Mean Difference (IV, Fixed, 95% CI)	29.24 [22.51, 35.98]
11 Change in daily asthma symptom score compared to baseline	8	1371	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.69 [‐0.80, ‐0.58]
11.1 Children	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Adults	8	1371	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.69 [‐0.80, ‐0.58]
12 Change in number night‐time awakenings per week	2	364	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.34, ‐0.20]
12.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Adults	2	364	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.34, ‐0.20]
13 Change in number of night‐time awakenings per night	2	240	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.20, ‐0.04]
13.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Adults	2	240	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.20, ‐0.04]
14 Change in % nights with no awakenings	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
14.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Change in night‐time wakening score	2	351	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.74 [‐0.96, ‐0.52]
15.1 Children	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 Adults	2	351	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.74 [‐0.96, ‐0.52]
16 Change in daily use of beta2 agonist compared to baseline (puffs/d)	8	1369	Mean Difference (IV, Fixed, 95% CI)	‐1.73 [‐1.98, ‐1.49]
16.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.2 Adults	8	1369	Mean Difference (IV, Fixed, 95% CI)	‐1.73 [‐1.98, ‐1.49]
17 Change in percentage of symptom free days compared to baseline	2	361	Mean Difference (IV, Fixed, 95% CI)	21.32 [13.54, 29.09]
17.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 Adults	2	361	Mean Difference (IV, Fixed, 95% CI)	21.32 [13.54, 29.09]
18 Change in percentage of rescue beta2 agonist free days compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
18.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 HRQOL: AQLQ	0		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
19.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
20 Physician rated global efficacy: effective or very effective (No. of patients)	3	480	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.86 [4.09, 8.39]
20.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.2 Adults	3	480	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.86 [4.09, 8.39]
21 Withdrawal due to clinical asthma exacerbation (No. of patients)	3	394	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.40 [0.23, 0.72]
21.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
21.2 Adults	3	394	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.40 [0.23, 0.72]
22 Withdrawal due to lack of treatment efficacy (No. of patients)	9	1538	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.15 [0.12, 0.19]
22.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.2 Adults	9	1538	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.15 [0.12, 0.19]
23 Withdrawals (total)	4	778	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.21 [0.15, 0.28]
23.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
23.2 Adults	4	778	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.21 [0.15, 0.28]
24 Withdrawals due to adverse events	4	691	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.42, 1.88]
24.1 Children	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.2 Adults	4	691	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.42, 1.88]
25 Sore throat or pharyngitis (No. of patients)	7	1158	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.20 [1.17, 4.13]
25.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
25.2 Adults	7	1158	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.20 [1.17, 4.13]
26 Hoarseness or dysphonia (No. of patients)	8	1361	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.56 [2.60, 11.90]
26.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
26.2 Adults	8	1361	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.56 [2.60, 11.90]
27 Oral Candidiasis (No. of patients)	7	1254	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.17 [2.50, 10.67]
27.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.2 Adults	7	1254	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.17 [2.50, 10.67]
28 Upper respiratory tract infection	4	658	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.79, 1.73]
28.1 Children	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
28.2 Adults	4	658	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.79, 1.73]
29 Headache	4	691	Odds Ratio (M‐H, Fixed, 95% CI)	1.56 [0.82, 2.97]
29.1 Children	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
29.2 Adults	4	691	Odds Ratio (M‐H, Fixed, 95% CI)	1.56 [0.82, 2.97]
30 Sinusitis	2	291	Odds Ratio (M‐H, Fixed, 95% CI)	2.49 [0.36, 17.36]
30.1 Children	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
30.2 Adults	2	291	Odds Ratio (M‐H, Fixed, 95% CI)	2.49 [0.36, 17.36]
31 No. patients with </=18 mcg/dL post‐stimulation cortisol	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected
31.1 Children	0		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.2 Adults	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
32 Plasma cortisol (AUC)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
32.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
32.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

5.1. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 1 Change in FEV1 compared to baseline (Litres).

5.2. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 2 FEV1 (absolute values).

5.3. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 3 Change in FEV1 (%).

5.4. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 4 Change in FEV1 (% predicted).

5.5. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 5 FEV1 (% predicted ‐ absolute scores).

5.7. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 7 Change in morning PEFR compared to baseline (L/min).

5.8. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 8 Change in am PEF (% predicted).

5.10. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 10 Change in evening PEF compared with baseline (L/min).

5.12. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 12 Change in number night‐time awakenings per week.

5.13. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 13 Change in number of night‐time awakenings per night.

5.14. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 14 Change in % nights with no awakenings.

5.15. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 15 Change in night‐time wakening score.

5.17. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 17 Change in percentage of symptom free days compared to baseline.

5.18. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 18 Change in percentage of rescue beta2 agonist free days compared to baseline.

5.20. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 20 Physician rated global efficacy: effective or very effective (No. of patients).

5.23. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 23 Withdrawals (total).

5.24. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 24 Withdrawals due to adverse events.

5.28. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 28 Upper respiratory tract infection.

5.29. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 29 Headache.

5.30. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 30 Sinusitis.

5.31. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 31 No. patients with </=18 mcg/dL post‐stimulation cortisol.

5.32. Analysis.

Comparison 5 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (all ages), Outcome 32 Plasma cortisol (AUC).

Comparison 6. FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (subgroups).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adults studies: change in FEV1 compared to baseline (litres); study duration	10		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 1‐5 months	9	1357	Mean Difference (IV, Fixed, 95% CI)	0.39 [0.35, 0.44]
1.3 6 months or longer	1	203	Mean Difference (IV, Fixed, 95% CI)	0.5 [0.35, 0.65]
2 Adult studies: change in FEV1 compared to baseline (litres); inhaler device	10		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 MDI	5	714	Mean Difference (IV, Fixed, 95% CI)	0.35 [0.29, 0.41]
2.2 DPI	5	846	Mean Difference (IV, Fixed, 95% CI)	0.44 [0.38, 0.50]
3 Adult studies: change in FEV1 compared to baseline (litres); severity	10		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1 Mild	1	26	Mean Difference (IV, Fixed, 95% CI)	0.46 [0.29, 0.63]
3.2 Mild to moderate	2	278	Mean Difference (IV, Fixed, 95% CI)	0.20 [0.10, 0.31]
3.3 Moderate	7	1256	Mean Difference (IV, Fixed, 95% CI)	0.44 [0.39, 0.49]

6.1. Analysis.

Comparison 6 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (subgroups), Outcome 1 Adults studies: change in FEV1 compared to baseline (litres); study duration.

6.2. Analysis.

Comparison 6 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (subgroups), Outcome 2 Adult studies: change in FEV1 compared to baseline (litres); inhaler device.

6.3. Analysis.

Comparison 6 FP versus placebo: Parallel group studies, no oral steroids: 500 mcg/d (subgroups), Outcome 3 Adult studies: change in FEV1 compared to baseline (litres); severity.

Comparison 7. FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV1 (litres)	3	73	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.22, 0.48]
1.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Adults	3	73	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.22, 0.48]
2 Change in FEV1 compared to baseline (litres)	5	820	Mean Difference (IV, Fixed, 95% CI)	0.42 [0.36, 0.48]
2.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Adults	5	820	Mean Difference (IV, Fixed, 95% CI)	0.42 [0.36, 0.48]
3 Change in FVC compared to baseline (litres)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Change in FEF25‐75 compared to baseline (L/second)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Change in morning PEFR compared to baseline (L/min)	5	823	Mean Difference (IV, Fixed, 95% CI)	46.19 [39.58, 52.79]
5.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Adults	5	823	Mean Difference (IV, Fixed, 95% CI)	46.19 [39.58, 52.79]
6 Change in evening PEFR compared to baseline (L/min)	3	477	Mean Difference (IV, Fixed, 95% CI)	36.87 [28.68, 45.07]
6.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Adults	3	477	Mean Difference (IV, Fixed, 95% CI)	36.87 [28.68, 45.07]
7 Change in daily asthma symptom score compared to baseline	4	611	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.67 [‐0.84, ‐0.51]
7.1 Children	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Adults	4	611	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.67 [‐0.84, ‐0.51]
8 Change in number of night‐time awakenings per week compared to baseline	2	277	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.25, ‐0.11]
8.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Adults	2	277	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.25, ‐0.11]
9 Change in daily use of beta2 agonist compared to baseline (puffs/d)	5	812	Mean Difference (IV, Fixed, 95% CI)	‐1.36 [‐1.64, ‐1.08]
9.1 Children	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Adults	5	812	Mean Difference (IV, Fixed, 95% CI)	‐1.36 [‐1.64, ‐1.08]
10 Methacholine BHR (log base 2 PC20 FEV1 mg/ml)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Physician‐rated efficacy: effective or very effective (No. of patients)	2	311	Peto Odds Ratio (Peto, Fixed, 95% CI)	9.62 [6.18, 14.99]
11.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Adults	2	311	Peto Odds Ratio (Peto, Fixed, 95% CI)	9.62 [6.18, 14.99]
12 Morning plasma cortisol (mcg/dL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Change in morning plasma cortisol compared to baseline (mcg/dL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
13.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 8 hour area under curve (AUC) plasma cortisol during 6 hour 250 mcg co‐syntropin infusion (mcg hour/dL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
14.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Peak plasma cortisol during during 6 hour 250 mcg co‐syntropin infusion (mcg/dL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
15.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Withdrawal due to clinical asthma exacerbation (No. of patients)	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected
16.1 Children	0		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.2 Adults	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Withdrawal due to lack of treatment efficacy (No. of patients)	7	1077	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.11 [0.09, 0.15]
17.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 Adults	7	1077	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.11 [0.09, 0.15]
18 Sore throat or pharyngitis (No. of patients)	6	929	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.64 [1.46, 4.77]
18.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Adults	6	929	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.64 [1.46, 4.77]
19 Hoarseness or dysphonia (No. of patients)	8	1175	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.42 [3.37, 12.26]
19.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.2 Adults	8	1175	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.42 [3.37, 12.26]
20 Oral Candidiasis (No. of patients)	8	1175	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.57 [2.48, 8.43]
20.1 Children	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.2 Adults	8	1175	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.57 [2.48, 8.43]
21 HRQOL: AQLQ	0		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
21.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
21.2 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22 Log PD20 mg	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
22.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23 FVC (absolute values ‐ Litres)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
23.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24 Withdrawals (any reason)	5	557	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.35, 0.73]
24.1 Children	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.2 Adults	5	557	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.35, 0.73]
25 Withdrawal due to adverse events	4	509	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.54, 3.50]
25.1 Children	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
25.2 Adults	4	509	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.54, 3.50]
26 Any adverse event	2	405	Odds Ratio (M‐H, Fixed, 95% CI)	1.43 [0.96, 2.12]
26.1 Children	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
26.2 Adults	2	405	Odds Ratio (M‐H, Fixed, 95% CI)	1.43 [0.96, 2.12]

7.1. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 1 FEV1 (litres).

7.2. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 2 Change in FEV1 compared to baseline (litres).

7.3. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 3 Change in FVC compared to baseline (litres).

7.4. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 4 Change in FEF25‐75 compared to baseline (L/second).

7.5. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 5 Change in morning PEFR compared to baseline (L/min).

7.8. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 8 Change in number of night‐time awakenings per week compared to baseline.

7.10. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 10 Methacholine BHR (log base 2 PC20 FEV1 mg/ml).

7.11. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 11 Physician‐rated efficacy: effective or very effective (No. of patients).

7.12. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 12 Morning plasma cortisol (mcg/dL).

7.13. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 13 Change in morning plasma cortisol compared to baseline (mcg/dL).

7.14. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 14 8 hour area under curve (AUC) plasma cortisol during 6 hour 250 mcg co‐syntropin infusion (mcg hour/dL).

7.15. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 15 Peak plasma cortisol during during 6 hour 250 mcg co‐syntropin infusion (mcg/dL).

7.16. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 16 Withdrawal due to clinical asthma exacerbation (No. of patients).

7.22. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 22 Log PD20 mg.

7.23. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 23 FVC (absolute values ‐ Litres).

7.24. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 24 Withdrawals (any reason).

7.25. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 25 Withdrawal due to adverse events.

7.26. Analysis.

Comparison 7 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (all ages), Outcome 26 Any adverse event.

Comparison 8. FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (subgroups).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adult studies: change in FEV1 compared to baseline (litres); study duration	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 1‐4 weeks	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 1‐5 months	5	820	Mean Difference (IV, Fixed, 95% CI)	0.42 [0.36, 0.48]
1.3 6 months or longer	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Adult studies: change in FEV1 compared to baseline (litres); inhaler devices	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 MDI	3	565	Mean Difference (IV, Fixed, 95% CI)	0.39 [0.32, 0.46]
2.2 DPI	2	255	Mean Difference (IV, Fixed, 95% CI)	0.53 [0.40, 0.67]
3 Adult studies: change in FEV1 compared to baseline (litres); severity	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1 Mild	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Mild to moderate	3	480	Mean Difference (IV, Fixed, 95% CI)	0.38 [0.30, 0.46]
3.3 Moderate	2	340	Mean Difference (IV, Fixed, 95% CI)	0.48 [0.38, 0.58]

8.1. Analysis.

Comparison 8 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (subgroups), Outcome 1 Adult studies: change in FEV1 compared to baseline (litres); study duration.

8.2. Analysis.

Comparison 8 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (subgroups), Outcome 2 Adult studies: change in FEV1 compared to baseline (litres); inhaler devices.

8.3. Analysis.

Comparison 8 FP versus placebo: Parallel group studies, no oral steroids: 1000‐1500 mcg/d (subgroups), Outcome 3 Adult studies: change in FEV1 compared to baseline (litres); severity.

Comparison 9. FP versus placebo: Parallel group studies, no oral steroids: 2000 mcg/d (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 PD20 ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1 Children	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

9.1. Analysis.

Comparison 9 FP versus placebo: Parallel group studies, no oral steroids: 2000 mcg/d (all ages), Outcome 1 PD20 ‐ change from baseline.

Comparison 10. FP versus placebo: Crossover studies, no oral steroids: 100mcg/d or less (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV1 (% predicted ‐ absolute values)	2	88	% (Fixed, 95% CI)	4.30 [‐1.93, 10.53]
1.1 Children	1	52	% (Fixed, 95% CI)	4.0 [‐3.43, 11.43]
1.2 Adults	1	36	% (Fixed, 95% CI)	5.0 [‐6.43, 16.43]
2 PEF (% predicted ‐ absolute values)	1		% (Fixed, 95% CI)	Totals not selected
2.1 Children	0		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Adults	1		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Quality of life (absolute scores ‐ AQLQ)	1		QoL (Fixed, 95% CI)	Totals not selected
3.1 Children	0		QoL (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Adults	1		QoL (Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Symptoms	2	88	SD units (Fixed, 95% CI)	‐0.29 [‐0.58, 0.01]
4.1 Children	1	52	SD units (Fixed, 95% CI)	‐0.21 [‐0.59, 0.18]
4.2 Adults	1	36	SD units (Fixed, 95% CI)	‐0.4 [‐0.85, 0.05]
5 Rescue medication usage (unclear time frame ‐ absolute values)	1		Puffs (Fixed, 95% CI)	Totals not selected
5.1 Children	0		Puffs (Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Adults	1		Puffs (Fixed, 95% CI)	0.0 [0.0, 0.0]

10.1. Analysis.

Comparison 10 FP versus placebo: Crossover studies, no oral steroids: 100mcg/d or less (all ages), Outcome 1 FEV1 (% predicted ‐ absolute values).

10.2. Analysis.

Comparison 10 FP versus placebo: Crossover studies, no oral steroids: 100mcg/d or less (all ages), Outcome 2 PEF (% predicted ‐ absolute values).

10.3. Analysis.

Comparison 10 FP versus placebo: Crossover studies, no oral steroids: 100mcg/d or less (all ages), Outcome 3 Quality of life (absolute scores ‐ AQLQ).

10.4. Analysis.

Comparison 10 FP versus placebo: Crossover studies, no oral steroids: 100mcg/d or less (all ages), Outcome 4 Symptoms.

10.5. Analysis.

Comparison 10 FP versus placebo: Crossover studies, no oral steroids: 100mcg/d or less (all ages), Outcome 5 Rescue medication usage (unclear time frame ‐ absolute values).

Comparison 11. FP versus placebo: Crossover studies, no oral steroids: 200mcg/d (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV1	1		Litres (Fixed, 95% CI)	Totals not selected
1.1 Children	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Adults	1		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Throat irritation	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.1 Children	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Adults	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Upper respiratory tract infections	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.1 Children	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Adults	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Lower respiratory tract infection	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.1 Children	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Adults	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

11.1. Analysis.

Comparison 11 FP versus placebo: Crossover studies, no oral steroids: 200mcg/d (all ages), Outcome 1 FEV1.

11.2. Analysis.

Comparison 11 FP versus placebo: Crossover studies, no oral steroids: 200mcg/d (all ages), Outcome 2 Throat irritation.

11.3. Analysis.

Comparison 11 FP versus placebo: Crossover studies, no oral steroids: 200mcg/d (all ages), Outcome 3 Upper respiratory tract infections.

11.4. Analysis.

Comparison 11 FP versus placebo: Crossover studies, no oral steroids: 200mcg/d (all ages), Outcome 4 Lower respiratory tract infection.

Comparison 12. FP versus placebo: Crossover studies, no oral steroids: 500mcg/d (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV1 (absolute values)	1		Litres (Fixed, 95% CI)	Totals not selected
1.1 Children	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Adults	1		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
2 PC 20	2	70	Doses (n) (Fixed, 95% CI)	2.45 [1.63, 3.27]
2.1 Children	0	0	Doses (n) (Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Adults	2	70	Doses (n) (Fixed, 95% CI)	2.45 [1.63, 3.27]
3 Cortisol suppression	1		% (Fixed, 95% CI)	Totals not selected
3.1 Children	0		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Adults	1		% (Fixed, 95% CI)	0.0 [0.0, 0.0]

12.1. Analysis.

Comparison 12 FP versus placebo: Crossover studies, no oral steroids: 500mcg/d (all ages), Outcome 1 FEV1 (absolute values).

12.2. Analysis.

Comparison 12 FP versus placebo: Crossover studies, no oral steroids: 500mcg/d (all ages), Outcome 2 PC 20.

12.3. Analysis.

Comparison 12 FP versus placebo: Crossover studies, no oral steroids: 500mcg/d (all ages), Outcome 3 Cortisol suppression.

Comparison 13. FP versus placebo: Crossover studies, no oral steroids: 1000mcg/d (all ages).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cortisol suppression	1		% (Fixed, 95% CI)	Totals not selected
1.1 Children	0		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Adults	1		% (Fixed, 95% CI)	0.0 [0.0, 0.0]
2 PC 20	2	100	Doses (n) (Fixed, 95% CI)	2.82 [2.13, 3.51]
2.1 Children	0	0	Doses (n) (Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Adults	2	100	Doses (n) (Fixed, 95% CI)	2.82 [2.13, 3.51]

13.1. Analysis.

Comparison 13 FP versus placebo: Crossover studies, no oral steroids: 1000mcg/d (all ages), Outcome 1 Cortisol suppression.

13.2. Analysis.

Comparison 13 FP versus placebo: Crossover studies, no oral steroids: 1000mcg/d (all ages), Outcome 2 PC 20.

Comparison 14. FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of patients able to discontinue OCS completely	2	139	Peto Odds Ratio (Peto, Fixed, 95% CI)	14.07 [7.17, 27.57]
2 Change in daily dose of oral prednisolone compared to baseline (mg)	2	139	Mean Difference (IV, Fixed, 95% CI)	‐7.59 [‐9.92, ‐5.25]
3 Change in FEV1 compared to baseline (litres)	2	139	Mean Difference (IV, Fixed, 95% CI)	0.26 [0.09, 0.43]
4 Change in morning PEFR compared to baseline (L/min)	2	139	Mean Difference (IV, Fixed, 95% CI)	50.85 [30.96, 70.73]
5 Change in evening PEFR compared to baseline (L/min)	2	139	Mean Difference (IV, Fixed, 95% CI)	26.52 [6.40, 46.65]
6 Change in daily asthma symptom score compared to baseline	2	139	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.76 [‐1.10, ‐0.41]
7 Change in daily use of rescue beta2 agonist compared to baseline (puffs/d)	2	139	Mean Difference (IV, Fixed, 95% CI)	‐3.60 [‐5.04, ‐2.16]
8 Asthma Quality of Life Questionnaire: change in overall score compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9 Asthma Quality of Life Questionnaire: change in activity limitation domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10 Asthma Quality of Life Questionnaire: change in asthma symptoms domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
11 Asthma Quality of Life Questionnaire: change in emotional function domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12 Asthma Quality of Life Questionnaire: change in enviromental exposure domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
13 Sore throat (No. of patients)	2	139	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.42 [0.33, 17.64]
14 Hoarseness or dysphonia (No. of patients)	2	139	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.19 [1.41, 36.63]
15 Oral Candidiasis (No. of patients)	2	139	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.71 [1.98, 16.47]

14.1. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 1 Number of patients able to discontinue OCS completely.

14.2. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 2 Change in daily dose of oral prednisolone compared to baseline (mg).

14.3. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 3 Change in FEV1 compared to baseline (litres).

14.4. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 4 Change in morning PEFR compared to baseline (L/min).

14.5. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 5 Change in evening PEFR compared to baseline (L/min).

14.6. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 6 Change in daily asthma symptom score compared to baseline.

14.7. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 7 Change in daily use of rescue beta2 agonist compared to baseline (puffs/d).

14.8. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 8 Asthma Quality of Life Questionnaire: change in overall score compared to baseline.

14.9. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 9 Asthma Quality of Life Questionnaire: change in activity limitation domain compared to baseline.

14.10. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 10 Asthma Quality of Life Questionnaire: change in asthma symptoms domain compared to baseline.

14.11. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 11 Asthma Quality of Life Questionnaire: change in emotional function domain compared to baseline.

14.12. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 12 Asthma Quality of Life Questionnaire: change in enviromental exposure domain compared to baseline.

14.13. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 13 Sore throat (No. of patients).

14.14. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 14 Hoarseness or dysphonia (No. of patients).

14.15. Analysis.

Comparison 14 FP versus placebo: Parallel group studies, oral steroid dependent: 1000‐1500 mcg/d, Outcome 15 Oral Candidiasis (No. of patients).

Comparison 15. FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of patients able to discontinue OCS completely	2	134	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.04 [0.02, 0.08]
2 Change in daily dose of oral prednisolone compared to baseline (mg)	2	134	Mean Difference (IV, Fixed, 95% CI)	‐9.72 [‐12.10, ‐7.35]
3 Change in FEV1 compared to baseline (litres)	2	134	Mean Difference (IV, Fixed, 95% CI)	0.58 [0.40, 0.76]
4 Change in morning PEFR compared to baseline (L/min)	2	134	Mean Difference (IV, Fixed, 95% CI)	94.35 [72.51, 116.19]
5 Change in evening PEFR compared to baseline (L/min)	2	134	Mean Difference (IV, Fixed, 95% CI)	66.14 [43.04, 89.24]
6 Change in daily asthma symptom score compared to baseline	2	134	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.03 [‐1.39, ‐0.67]
7 Change in daily use of rescue beta2 agonist compared to baseline (puffs/d)	2	134	Mean Difference (IV, Fixed, 95% CI)	‐4.63 [‐6.10, ‐3.15]
8 Asthma Quality of Life Questionnaire: change in overall score compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9 Asthma Quality of Life Questionnaire: change in activity limitation domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10 Asthma Quality of Life Questionnaire: change in asthma symptoms domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
11 Asthma Quality of Life Questionnaire: change in emotional function domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12 Asthma Quality of Life Questionnaire: change in environmental exposure domain compared to baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
13 Sore throat (No. of patients)	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected
14 Hoarseness or dysphonia (No. of patients)	2	134	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.63 [1.50, 38.92]
15 Oral Candidiasis (No. of patients)	2	134	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.62 [1.70, 12.51]

15.1. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 1 Number of patients able to discontinue OCS completely.

15.2. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 2 Change in daily dose of oral prednisolone compared to baseline (mg).

15.3. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 3 Change in FEV1 compared to baseline (litres).

15.4. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 4 Change in morning PEFR compared to baseline (L/min).

15.5. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 5 Change in evening PEFR compared to baseline (L/min).

15.6. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 6 Change in daily asthma symptom score compared to baseline.

15.7. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 7 Change in daily use of rescue beta2 agonist compared to baseline (puffs/d).

15.8. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 8 Asthma Quality of Life Questionnaire: change in overall score compared to baseline.

15.9. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 9 Asthma Quality of Life Questionnaire: change in activity limitation domain compared to baseline.

15.10. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 10 Asthma Quality of Life Questionnaire: change in asthma symptoms domain compared to baseline.

15.11. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 11 Asthma Quality of Life Questionnaire: change in emotional function domain compared to baseline.

15.12. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 12 Asthma Quality of Life Questionnaire: change in environmental exposure domain compared to baseline.

15.13. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 13 Sore throat (No. of patients).

15.14. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 14 Hoarseness or dysphonia (No. of patients).

15.15. Analysis.

Comparison 15 FP versus placebo: Parallel group studies, oral steroid dependent: 2000 mcg/d, Outcome 15 Oral Candidiasis (No. of patients).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Agertoft 1997.

Methods	Setting: Denmark, paediatric outpatient clinic Design: crossover, 2 week washout Length of intervention period: 2 weeks Excluded: stated (none) Withdrawals: stated (one child from low dose group due to sore throat) Baseline characteristics: comparable between groups
Participants	48 children: 27M 21F Age range: 6‐12 years Inclusion criteria: Pre‐pubertal children Mild asthma requiring treatment with as needed beta2 agonists only Exclusion criteria: Inhaled or oral steroid use in last 2 months
Interventions	Group 1 randomised to: 1. FP: 200mcg/d via Accuhaler DPI 2. BUD: 200 mcg/d via Turbuhaler DPI 3. Placebo Group 2 randomised to: 1. FP: 400mcg/d via Accuhaler DPI 2. BUD: 400 mcg/d via Turbuhaler DPI 3. Placebo
Outcomes	24 hour urinary cortisol excretion Growth by lower leg knemometry FEV1 Morning PEFR Evening PEFR Daily asthma symptom score
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer generated random sequence with balanced blocks
Allocation concealment?	Unclear risk	See Appendix 2
Blinding? All outcomes	Unclear risk	Double‐blind

Allen 1998.

Methods	Setting: Multicentre study USA, paediatric outpatient clinic Length of intervention period: 12 months Design: parallel group Excluded: stated Withdrawals: stated Baseline characteristics: comparable
Participants	344 children enrolled, 325 randomised: 81M 244F Age range: M 4‐11 years, F 4‐9 years ) Inclusion criteria: Pre‐pubescent children with mild to moderate asthma (ATS criteria 1987) for at least 3 months FEV1 60 (% predicted) or greater Exclusion criteria: Systemic, intra‐nasal or ophthalmic corticosteroids in last month More than 60 days of systemic corticosteroid use in last 2 years
Interventions	FP: 1. 50 mcg 2xdaily (100 mcg/d) 2. 100 mcg 2xdaily (200 mcg/d) Placebo: 2xdaily via Delivery device: Diskhaler DPI
Outcomes	Height assessment Oral corticosteroids for asthma exacerbation (No. of courses or prednisolone) Withdrawal due to asthma exacerbation HRQOL: Functional Status IIR (FSII) questionnaire, Sleep Scale Children (SLP‐C) questionnaire, Quality of Life of Parents of Asthmatic Children Questionnaire (QOL‐PAC) Oro‐pharyngeal side effects
Notes	Authors confirmed use of allocation concealment Criteria for withdrawal due to lack of efficacy: requirement for more than two seven day courses of oral corticosteroid Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	Randomisation code generated off site and concealed using sealed envelopes
Blinding? All outcomes	Low risk	Double blind; identical inhaler devices

Allen 2000.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 months Design: parallel group Excluded: not stated Withdrawals: stated
Participants	111 adults randomised enrolled. Distribution between groups not clear. Mean FEV1: 61%
Interventions	i) FP 1000mcg BiD (2000); ii) FP500mcg BiD (1000); iii) Placebo. Inhaler device: Diskus.
Outcomes	Steroid consumption; lung function; adverse events Steroid consumption; lung function; adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; method not reported
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Double‐blind; identical inhaler devices

Arets 2002.

Methods	Setting: Multicentre study, paediatric asthma hospital clinic, Europe Length of intervention period: 12 weeks Design: parallel group Excluded: stated Withdrawals: stated
Participants	88 children enrolled, 68 randomised. Mean age: FP: 6.86 (SD 1.5); PLA: 6.97 (SD 1.48); FEV1 (L): FP: 1.54 (SD 0.37); PLA: 1.53 (SD 0.39); FEV1 %: FP: 104.1 (SD 10.8); PLA: 99.8 (SD 17); Rescue medication free days: FP: 49.4 (SD 36.3); PLA: 45.8 (SD 38.3); am PEF L/min: FP: 213.4 (SD 63.9); PLA: 210.6 (SD 58.6); pm PEF: FP: 219.1 (SD 62.3); PLA: 219.8 (SD 58). Inclusion criteria: Age 5‐10; Physician diagnosed asthma Exclusion criteria: Use of systemic steroids in last 2 months; ICS >100mcg/d; Salbutamol >1600mcg/d during >30% days of last year; hospitalisation with asthma in last 2 weeks
Interventions	FP500mcg/d versus Placebo. Inhaler device: MDI + spacer.
Outcomes	FEV1; PEF; Symptom‐free days; wheeze score; parent global evaluation
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Double‐blind; identical inhalers

Berger 2002 ICS.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Masking: double‐blind Excluded: not stated Withdrawals: stated (ITT analysis)
Participants	401 adults randomised. Age range 12‐84; FEV1 (L): FP: 2.47 (SEM 0.04); PLA: 2.47 (SEM 0.04); FEV1 (%): FP: 75.9 (SEM 8.6); PLA: 75.8 (SEM 8.3); am PEF (L/min): FP: 384.5 (SEM 7.5); PLA: 372.9 (SEM 6.1); pm PEF (L/min): FP: 401.2 (SEM 7.9); PLA: 391.1 (SEM 6.43); Composite asthma scores: FP: 1.45 (SEM 0.07); PLA: 1.36 (SEM 0.07); Symptom free days: FP: 25.7 (SEM 2.6); PLA: 28.1 (SEM 2.6); Rescue medication usage (puffs/day): FP: 1.87 (0.12); PLA: 1.82 (SEM 0.11); Rescue medication free days: FP: 41 (SEM 2.7); PLA: 39.3 (SEM 2.8); Night awakenings (in baseline week): FP: 0.68 (SEM 0.06); PLA: 0.54 (sem 0.06) Inclusion criteria: >12 years of age; asthma confirmed by ATS criteria; use of ICS for 3 months prior to study entry; stable low dose of ICS for 1 month prior to study entry (BDP: 168‐504mcg/d; FP: 88‐264mcg/d; Flunisolide: 500‐1000mcg/d; TAA: 400‐1000; BUD: 200‐400mcg/d); FEV1: 60‐90% predicted; >12% reversibility <30mins after inhalation of 180mcg SABA. Exclusion criteria: Life‐threatening/unstable asthma; other clinically significant uncontrolled disease; chicken‐pox within 3 weeks; hypersensitivity to ß‐agonists, sympathomimetics, or corticosteroids; respiratory infection; pregnancy; current tobacco usage or >10 pack‐year history of smoking; use of the investigational drugs; participants not allowed to use LABAs, sodium cromoglycate, nedocromil, anticholinergic agents, leukotriene antagonists
Interventions	FP250 versus placebo. Inhaler device: Diskus.
Outcomes	FEV1; am PEF; pm PEF; Symptoms; Rescue medication usage; Withdrawals; Tolerability; Exacerbations
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer‐generated blocks of four
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double blind; identical inhaler devices

Berger 2002 SABA.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated (ITT analysis)
Participants	408 adults randomised. Age range: 12‐74; FEV1 (L): FP: 2.52 (SEM 0.05); PLA: 2.51 (SEM 0.04); FEV1 (% pred): FP: 72 (SEM 7.3); PLA: 71.9 (SEM 6.9); am PEF (L/min): FP: 363.7 (SEM 7.3); PLA: 356.1 (SEM 6.7); pm PEF (L/min): FP: 394.2 (SEM 7.5); PLA: 380.9 (SEM 7.1); Composite asthma scores: FP: 2.45 (SEM 0.06); PLA: 2.40 (SEM 0.05); Symptom free days (%): FP: 3.1 (SEM 0.7); PLA: 3.5 (SEM 0.9); Rescue medication usage (% days): FP: 13.3 (SEM 1.6); PLA: 13.5 (SEM 1.5); Night awakenings (N during baseline week): FP: 0.94 (SEM 0.09); PLA: 0.82 (SEM 0.08). Inclusion criteria: >12 years of age; asthma confirmed by ATS criteria; requirement for pharmacotherapy for at least 6 mo; previous treatment with SABA; no ICS Rx for 1 mo prior to study entry; FEV1 between 60‐85% predicted; >12% reversibility <30mins after inhalation of 180mcg SABA. Exclusion criteria: Life‐threatening/unstable asthma; other clinically significant uncontrolled disease; chicken‐pox within 3 weeks; hypersensitivity to ß‐agonists, sympathomimetics, or corticosteroids; respiratory infection; pregnancy; current tobacco usage or >10 pack‐year history of smoking; use of the investigational drugs; participants not allowed to use LABAs, sodium cromoglycate, nedocromil, anticholinergic agents, leukotriene antagonists
Interventions	FP250 versus placebo. Inhaler device: Diskus.
Outcomes	FEV1; am PEF; pm PEF; Symptoms; Rescue medication usage; Withdrawals; Tolerability; Exacerbations
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer‐generated blocks of four
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double blind; identical inhaler devices

Bernstein 2004.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	531 adults randomised. Age range: >/=12 years. Inclusion criteria: >12 years; FEV1 40‐65% predicted. Exclusion criteria: not reported
Interventions	FP 440 BID (880mcg/d) Placebo Inhaler device: MDI
Outcomes	Lung function; withdrawal due to lack of efficacy; adverse events
Notes	Unpublished conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	double‐blind, double‐dummy

Busse 2001.

Methods	Setting: Multicentre study Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	338 adults randomised. Age range: 12‐75 years. Baseline pulmonary function 66‐67% predicted across treatment groups; % participants with 70.1‐80% FEV1 predicted: FP 51;Zaf: 55; Pla: 46; Participants with 50 ‐ 70 % predicted FEV1: FP: 60; Zaf: 52; Pla: 65; Participants with asthma diagnosed >/=10 years: 64‐73% across treatment groups. Inclusion criteria: >12 years; asthma diagnosed according to ATS; use of SABA (scheduled or prn) for at least 6 weeks preceding the study FEV1 between 50‐80% predicted; reversibility of FEV1 (12% increase within 30 minutes after inhaling 180mg albuterol). Exclusion criteria: Life‐threatening asthma; significant and uncontrolled disease (COPD/coronary disease); use of tobacco products in preceding year/smoking history of more than 10 pack‐years; systemic steroid within 1 mo of screening; leukotriene modifier within 1 wk of screening.
Interventions	FP 88mcg BID (176mcg/d) + oral placebo Inhaled placebo + oral zafirlukast versus placebo. Inhaler device: MDI
Outcomes	Lung function (Change in FEV1; am/pm PEF); Symptoms (symptom scores; symptom‐free days; awakenings due to asthma); Medication usage (albuterol use (puffs day); albuterol‐free days);
Notes	Study reported in abstract form only Study also included a parallel treatment arm with oral zafirlukast 20 mcg 2xdaily Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double dummy design

Caffey 2005.

Methods	Setting: single centre study (UK) Length of intervention period: 4 weeks Design: crossover group Excluded: not stated Withdrawals: stated
Participants	26 children. Age range 5‐12 years. FEV1 88% predicted Inclusion criteria: Mild to moderate asthma; clinically stable on one long‐term controller drug. Exclusion criteria: systemic steroids within one month of study entry.
Interventions	FP 50mcg BID (100mcg/d) Placebo Inhaler device: DPI
Outcomes	FEV1; Symptoms
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Double‐blind

Casale 2001.

Methods	Setting: Multicentre study, USA Length of intervention period: 3 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	134 adults randomised. Age range: 18‐50. Mean FEV1 (SD): PLA: 3.0 (0.66); FP110: 3.3 (0.86); FP220: 3.2 (0.67); FP330: 3.0 (0.69); FP440: 3.2 (0.77). Inclusion criteria: non‐smokers; 18‐50 years; diagnosis of persistent mild to moderate asthma confirmed within previous 12 months by response to SABA (increase in FEV1 >/= 12%)/methacholine challenge <8mg/mL); FEV1 >/=65% predicted; no OCS/nasal/ICS use in previous 6 months. Exclusion criteria: significant pulmonary disease (e.g. COPD); exacerbation within 6 weeks; URTI within 30 days screening; oestrogen usage; current condition that might confound data interpretation
Interventions	PLA versus FP220 versus FP440 versus FP660 versus FP880. Inhaler device: pMDI Participants also randomised to flunisolide 500 bid, 1000 bid and prednisolone 7.5mg qd
Outcomes	HPA function
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Double‐blind

Chervinsky 1994.

Methods	Setting: Multicentre study USA, hospital outpatient clinic Length of intervention period: 8 weeks Design: parallel group Excluded: stated Withdrawals: stated Baseline characteristics: comparable
Participants	331 adults Mean age: 48‐59 years Inclusion criteria: Mild to moderate asthma (as defined by the Committee on Diagnostic standards for Non‐Tuberculous Respiratory Diseases 1962) Treatment with BDP for at least 1 month prior to study and daily beta2 agonist, or daily theophylline for at least 2 weeks prior to study FEV1 60‐90 (% predicted) Exclusion criteria: Not stated
Interventions	FP: 1. 25 mcg 1 puff 2xdaily (50 mcg/d) 2. 100 mcg 2xdaily (200mcg/d) 3. 500 mcg 2xdaily (1000 mcg/d) Placebo: 2 x daily Delivery device: MDI
Outcomes	Probability of remaining in study All outcomes expressed as change compared to baseline: FEV1; FVC; FEF25‐75; Morning PEFR; Evening PEFR; Daily symptom score; Daily beta2 agonist use; Night awakenings; Morning plasma cortisol; Plasma cortisol 30‐60 min post 250 mcg iv cosyntropin; Urinary free cortisol; Plasma cortisol 60 min post ACTH Physician‐rated global assessment of efficacy Oropharyngeal side‐effects
Notes	No reply from author to clarify details of randomisation method For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices

Chuchalin 2008.

Methods	Setting: Multicentre study (28 countries in North & South America, Asia, Europe, Africa & Australia) Length of intervention period: 52 weeks Design: parallel group Excluded: not stated Withdrawals: stated (ITT)
Participants	1295 adolescents and adults with mild asthma (block randomisation 3:1) Age range: 12‐79 years Inclusion criteria: 12‐79 years; documented history of asthma >/=6 months; SABA prn; pre‐BD PEF >/=80% predicted; symptom score >/=1 on 3‐6 days during last 7 days of run‐in; reversibility of >/=15% PEF
Interventions	FP 100 BID versus Placebo Inhaler device: Diskus/Accuhaler
Outcomes	am PEF; symptoms; FEF25‐75; FEV1; rescue medication use; adverse events; exacerbation rates
Notes	Sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double‐dummy design

Condemi 1997.

Methods	Setting: Multicentre study USA, hospital outpatient clinics Length of intervention period: 24 weeks Design: parallel group Excluded: stated Withdrawals: stated (ITT) Baseline characteristics: comparable
Participants	378 adults enrolled, 291 randomised: 142M 149F Age range: 12‐74 years Inclusion criteria: Diagnosis of asthma (ATS criteria 1987) Requirement or maintenance ICS for 4 weeks or longer FEV1 50‐80 (% predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist One or more urgent or emergency care visit due to asthma in last 12 months During one week run‐in: no more than 3 days of rescue beta2 agonist use 12 puffs/d, no more than 4 days when morning PEFR 20% lower than previous evening PEFR, no more than 3 nights with awakening due to asthma symptoms Adequate compliance Exclusion criteria: Systemic of intranasal steroid in last month Current use of nedocromil or cromolyn Previous treatment with methotrexate or gold salts Immunotherapy requiring change in dose regimen in last 12 weeks Pregnancy or lactation
Interventions	FP: 250 mcg 2xdaily (500 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	Change in FEV1 compared to baseline Change in morning PEFR compared to baseline Change in daily asthma symptom score compared to baseline Change in % symptom free days compared to baseline Change in No. night‐time awakenings compared to baseline Change in daily rescue beta2 agonist use compared to baseline Change in % rescue beta2 agonist free days compared to baseline Withdrawal due to lacy of efficacy Probability of remaining in study Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment Study also included a TA treatment arm: results not considered in this review
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Double‐dummy design

Convery 2000.

Methods	Setting: Multicentre study, Europe and North America Length of intervention period: 6 weeks Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	52 adults randomised. Age range 20‐50. FEV1 % predicted: PLA: 99.5 (SD 13.57); FP: 102.86 (SD 12.41); PD20 mcg: PLA: 5.47 (SD 1.33); FP2000: 5.58 (SD 0.93). Inclusion criteria: PD20 <1600mcg from 2 baseline methacholine tests conducted within 2 weeks but separated by 48 hours; 20‐50 years of age; nonsmokers and smokers who had smoked at least 5 cigarettes daily. Exclusion criteria: Use of ß‐blocking or antimuscarinic drugs; use of aspirin or nonsteroidal anti‐inflammatory; RTI requiring antibiotics in preceding 4 weeks; uncontrolled systemic disease; history of alcohol abuse
Interventions	FP2000 versus PLA. Delivery device: pMDI.
Outcomes	Expired levels of carbon monoxide; FEV1; PD20
Notes	Participants recruited had not knowingly been diagnosed with asthma ‐ Participants with positive PD20 tests were recruited.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Identical inhaler devices used

Corsico 2000.

Methods	Setting: single centre, Italy Length of intervention period: 4 weeks Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	31 adults randomised. Age: FP: 31 (SD 9); PLA: 31 (SD 12); FEV1 %: FP: 98 (SD 15); PLA: 102 (SD 14); FVC % pred: FP: 110 (SD 12); PLA: 112 (SD 12). Participants were described as suffering from mild asthma according to ATS criteria. All participants were on SABAs as needed. Inclusion criteria: Positive response to inhalation challenge with methacholine; clinically stable for previous 2 months; FEV1 >80% predicted; not to have suffered URTI in previous 4 weeks
Interventions	FP: 1500mcg versus PLA. Inhaler device: Unclear.
Outcomes	FEV1; FVC; IVC; Vmax 50; Vp50; log max dose of MCh mcg; log PD20 mg; FVC versus FEV1; Intercept; slope; IVC versus Vp50; Intercept; Slope; Vmax 50 versus Vp 50; Intercept; Slope
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Information not available

Derom 1999.

Methods	Setting: single centre study, Belgium Length of intervention period: 1 week Randomisation: yes (method not stated) Allocation concealment: not stated Design: crossover study Masking: double‐blind Excluded: not stated Withdrawals: stated (non‐ITT)
Participants	23 adults randomised; Age range: 19‐57; FEV1: 2.95 (SD 0.83) (FEV1 % predicted: 80.0 (SD 21.4)); Mean FVC: 4.42 L (SD 0.94). Inclusion criteria: either sex; 18‐60 years of age; ATS defined asthma; >/=40% predicted value; Either post‐BD increase in FEV1 of at least 200ml or >/=12% of baseline, OR diurnal variation of PEF >/=15% on at least 2 days/week during run‐in. Exclusion criteria: Exacerbation 4 weeks before inclusion; use of oral steroids within 4 weeks; use of ICS within 6 months; other systemic steroids within 4 weeks
Interventions	FP 200mcg; FP 1000mcg; BUD: 200mcg; BUD 800mcg; Placebo. Inhaler device: DPI
Outcomes	FEV1; PEFR; Serum cortisol; White blood cell count; Neutrophils; Basophils
Notes	Data reported for effects after 24 hours @ 1 week
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices

Derom 2005.

Methods	Setting: single centre study, Belgium Length of intervention period: unclear Design: crossover study Excluded: not stated Withdrawals: not stated
Participants	25 adults randomised
Interventions	FP500 versus FP1000 versus PLA; washout period: 3 weeks. Study duration: 6 treatment periods unclear duration. Inhaler device: unclear.
Outcomes	Cortisol suppression; PC20
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Double‐dummy design

Ekroos 1999.

Methods	Setting: Finland, hospital outpatient clinic Length of intervention period: 6 weeks Design: parallel group Excluded: no details Withdrawals: no details Baseline characteristics: no demographic data presented
Participants	26 adults: 11M 15F Age range: 21‐59 years Inclusion criteria: Adult non‐smoking asthmatics Histamine BHR (PD15 FEV1) < 0.6mg Exclusion criteria: Oral or inhaled steroid use in last 2 months
Interventions	FP: 250 mcg 2xdaily (500 mcg/d) Placebo: 2xdaily Delivery device: MDI
Outcomes	Exhaled nitric oxide concentration Histamine BHR (PD15 FEV1)
Notes	Study reported in abstract form only
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Identical inhaler devices used

Falcoz 2000.

Methods	Setting: multicentre study Length of intervention period: 6 weeks Design: parallel group Excluded: not stated Withdrawals: stated (non‐ITT)
Participants	232 adults randomised; 230 evaluable. Age range: 18‐72 years. Participants suffered from mild‐to‐moderate asthma Inclusion criteria: Mild‐to‐moderate asthma (defined as FEV1 50‐80%) Exclusion criteria: Not stated
Interventions	FP 100mcg versus FP 500mcg versus placebo. Duration 6 weeks. Inhaler device: DPI.
Outcomes	Plasma concentrations
Notes	Data taken only for study 1. Study 2 assessed equal dose of FP given via different inhalers
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Faul 1998.

Methods	Setting: two centre study UK and Ireland, hospital outpatient clinics Length of intervention period: 8 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	27 adults randomised, 23 completed: 16M 7F Age range: 19‐45 years Inclusion criteria: Diagnosis of asthma (ATS criteria 1987) FEV1 > 40 (% predicted) 12.5% or greater improvement in FEV1 after inhaled beta2 agonist Histamine BHR (PC20 FEV1) 8 mg/ml or less Exclusion criteria: Treatment with corticosteroids in last 3 months Exacerbation of asthma within last 3 months Pregnancy or serious concurrent illness
Interventions	FP: 250 mcg 4 puffs 2xdaily (2000 mcg/d) Placebo: 4 puffs 2xdaily Delivery device: MDI+Volumatic spacer
Outcomes	FEV1 (after:baseline ratio) Change in FEV1 compared to baseline (after:baseline ratio) FEV1/FVC ratio (after:baseline ratio) FEF25‐75 (after:baseline ratio) Histamine bronchial responsiveness (PC20 FEV1) (after:baseline ratio) Bronchial wall immunopathology: Total T cells, primed T cells, CD4:CD8 ratios, CD68+ cells, inductive and suppressive macrophages, eosinophils, activated eosinophils.
Notes	No reply from author to clarify details of randomisation method Non‐parametric analyses for all outcomes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

FLIC15.

Methods	Setting: Multicentre study in Italy Design: parallel group Length of intervention period: 4 weeks Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	33 participants. Mean age 37‐44 years. Inclusion criteria: M/F participants; age 18‐60 years; persistent mild‐moderate asthma (ATS). Exclusion criteria: Preventer medication 4 weeks prior to study entry.
Interventions	i) FP100mcg bid (200mcg/d) ii) FP500mcg bid (1000mcg/d) iii) Placebo Inhaler device: DPI
Outcomes	Withdrawals; FEV1; PEFR; FVC
Notes	Unpublished study downloaded from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

FLTA2007.

Methods	Setting: 21 centres in USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	262 children Mean age: 7.6‐8 Inclusion criteria: Age 4‐11 years; asthma of at least 3 months duration requiring pharmacotherapy; PEF </=85% (ages 4‐5); FEV1 50‐85% predicted (ages 6‐11); 15% variation in FEV1 in last 6 months />/=15% increase in FEV1 within 30mins of 2 puffs albuterol at screening visit. Exclusion criteria: life threatening asthma
Interventions	1. FP50mcg BID (100mcg/d) 2. FP100mcg QD (100mcg/d) 3. Placebo Delivery device: DPI
Outcomes	FEV1; am PEF; pm PEF; clinic PEF; symptoms; day and night use of SABA; withdrawal; adverse events
Notes	Sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

FLTA3014.

Methods	Setting: 21 centres in USA Length of intervention period: 26 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	379 adults and adolescents. Mean age: 37‐39 Inclusion criteria: >/=12 years; 6 month history of asthma requiring pharmacotherapy; FEV1 50‐85%; use of SABA and/or ICS
Interventions	1. FP 100mcg BID (without spacer) 2. FP250mcg BID (with spacer) 3. FP250mcg BID (without spacer) 4. Placebo (with or without spacer) Inhaler device: MDI
Outcomes	FEV1; am PEF; pm PEF; withdrawals; SABA usage; symptoms; adverse events; withdrawals
Notes	Sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

FLTA3020.

Methods	Setting: 25 centres in USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	191 adults and adolescents Mean age: 31‐36 years. Inclusion criteria: >/=12 years; 6 month history of asthma requiring pharmacotherapy; FEV1 50‐85%; use of SABA and/or ICS; pre‐BD FEV1% predicted 60‐90%; SABA prn or regular use only; effective use of MDI. Exclusion criteria: ICS within 30 days of screening; hospitalisation due to asthma on 2+ occasions in 12 months prior to screening; significant other medication within 30 days of screening
Interventions	1. HFA‐FP 110mcg BID 2. HFA‐FP 220mcg BID 3. CFC‐FP 110mcg BID 4. CFC‐FP 220mcg BID 5. Placebo Inhaler device: MDI
Outcomes	FEV1; am PEF; pm PEF; withdrawals; symptoms; rescue medication usage; adverse events
Notes	Sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

FLTA3022.

Methods	Setting: 39 centres in USA Design: parallel group Length of intervention period: 16 weeks (plus 2 week run‐in) Excluded: not stated Withdrawals: stated Baseline characteristics: comparable between groups
Participants	168 adolescents/adults: 78M/90F Age range: >12 (mean age: 50 years) Inclusion criteria: 12 years of age or older FEV1 40‐85 (% predicted); oral steroid dependent asthma Exclusion criteria: History of life‐threatening asthma; 3 or more hospitalisations in past year; therapy with anti leukotrienes, nedocromil and/or ipratropium bromide within 4 weeks of randomisation
Interventions	1. FP440mcg CFC bid 2. FP880mcg CFC bid 3. FP440mcg HFA bid 4. FP880mcg HFA bid 5. Placebo Inhaler device: MDI
Outcomes	Oral steroid reduction FEV1 am PEF pm PEF Symptoms Rescue medication usage AQLQ Withdrawals Adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

FLTA4030.

Methods	Setting: 33 centres in USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	324 adults and adolescents. Mean age: 32‐34 Inclusion criteria: Stable asthma controlled with SABA. Unstable asthma defined as: Fall in FEV1 to below 50% predicted, or greater than 20% decrease compared with pre‐BD FEV1 at baseline; am PEF below stability limit on 3 or more occasions of 7 days immediately preceding clinic visit (defined as 20% decrease from the mean am PEF in run‐in; Nocturnal awakenings due to asthma on >/=3 nights during 7 days immediately preceding clinic visit; Use of >12 puffs of SABA on more than 2 days during 7 days immediately preceding clinic visit.
Interventions	1. FP 88mcg BID 2. Zafirlukast 20mg BID 3. Placebo Inhaler device: MDI
Outcomes	FEV1; am PEF; pm PEF; rescue medication usage; symptoms; asthma exacerbations; adverse events
Notes	Data extracted for total population (including those deemed unstable according to pre‐defined stability criteria) Sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Galant 1996.

Methods	Setting: Multicentre study USA, hospital outpatient clinic Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics:
Participants	353 adolescents/adults: 236M 117F Age range: 12‐75 years Inclusion criteria: 12 years of age or older FEV1 45‐75 (% predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist Significant asthma symptoms during run‐in period: e.g. daily asthma symptoms with > 8 puffs beta2 agonist/day or 2‐ 4 weekly nighttime awakenings due to asthma Exclusion criteria: History of life‐threatening asthma Smokers of 10 pack years or greater Previous use of inhaled, oral, injectable or intra‐nasal corticosteroids Pregnancy
Interventions	FP: 1. 25 mcg 2 puffs 2xdaily (100 mcg/d) 2. 50 mcg 2 puffs 2xdaily (200 mcg/d) Placebo: 2 puffs 2xdaily Delivery device: MDI
Outcomes	Probability of remaining in study All outcomes expressed as change compared to baseline: FEV1 Morning PEFR Daily use of beta2 agonist Daily asthma symptom score Night‐time awakenings per week 'Effective or very effective' Physician rated global assessment of efficacy (No. of patients) Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on diurnal variability in PEFR, night‐time awakenings, rescue beta2 agonist use and FEV1 Study also included an oral theophylline treatment arm: results not considered in this review
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Galant 1999.

Methods	Setting: Multicentre study USA, hospital outpatient clinic Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	229 adults and adolescents: 116M 113F Age range: 13‐76 years Inclusion criteria: 12 years of age or older Diagnosis of asthma (ATS criteria 1987) FEV1 60‐80 (% predicted) 15% or greater reversibility in FEV1 following inhaled beta2 agonist 15% or greater variability in FEV1 in previous 6 months Exclusion criteria: Pregnancy or severe concurrent disease Use of methotrexate, gold salts, oral or injectable corticosteroids in last 4 weeks
Interventions	FP: 1. 500 mcg 2xdaily (1000 mcg/d) via Accuhaler DPI 2. 500 mcg 2xdaily (1000 mcg/d) via Diskhaler DPI Placebo: via 2xdaily
Outcomes	Probability of remaining in study Outcomes expressed as change compared to baseline: FEV1 Morning PEFR Evening PEFR Daily asthma symptom score Daily use of beta2 agonist Night‐time awakenings per week Morning plasma cortisol Oro‐pharyngeal side effects Withdrawal due to lack of efficacy
Notes	No reply from author to clarify details of randomisation method A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings, rescue beta2 agonist use or clinical exacerbation requiring emergency hospital treatment Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double‐dummy design

Giannini 2003.

Methods	Setting: single centre study, Italy Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	27 randomised. Mean age: 38.67 (SD 16.97). M/F: 15/12; history of atopy: 18/6; FEV1: 3.23 (SD 0.91); FEV1 % predicted (median (range)): 96 (76‐122); PD20: 0.220 Inclusion criteria: diurnal/nocturnal symptoms=0, low PEF variability [maximal amplitude(‐MA) <10%). Exclusion criteria: no use of ß‐agonists throughout run‐in
Interventions	FP100 versus FP250 versus PLA. Inhaler device: unclear.
Outcomes	FEV1; PD20; Sputum eosinophils; max amplitude; PEF; Symptoms; Rescue medication use
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Information not available

Gross 1998.

Methods	Setting: 24 centres in USA Length of intervention period: 24 weeks Design: parallel group Excluded: stated Withdrawals: stated
Participants	Diagnosis: chronic asthma (American Thoracic Society criteria). Asthma severity: baseline FEV1 for TAA and placebo groups were 68% (0.8%) versus 67%(0.9%), respectively. N = 304 (204 to relevant treatment). Age: >12 yrs (mean 38). Sex: M167 (116 to relevant treatment), F 137 (88 to relevant treatment). History: patients had FEV1 of 50‐ 80% of predicted normal or required urgent care for their asthma within the past year, and were currently receiving either 400‐600 mcg/day of beclomethasone dipropionate or 800‐1200 mcg/day of TAA. Excluded: pregnancy, lactation or use of methotrexate, gold salts, nedocromil or corticosteroid, having a significant concomitant illness or immunotherapy which requires change in dosage regimen within 12 weeks, taking any medication that might affect the course of asthma.
Interventions	1. Inhaled triamcinolone acetonide 800 µg/d N=101. 2. Placebo N=103. 3. Fluticasone propionate 500 µg/d N=100. Device: MDI
Outcomes	1. Lung function. 2. Albuterol use. 3. Night time awakenings. 4. Adverse events. 5. Rescue salbutamol use. 6. Quality of life based on AQLQ ‐ Activity limitation. ‐ Asthma symptoms. ‐ Emotional function. ‐ Environmental exposure. ‐ Global 7. Quality of life based on (SF‐36): ‐ Physical functioning. ‐ Role ‐ physical. ‐ Role ‐ emotional. ‐ Social functioning. ‐ Mental health. ‐ Pain. ‐ Vitality. ‐ Health perceptions. 8. Leaving the study early. Unable to use‐ Symptom score (not validated scale).
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Hart 2000.

Methods	Setting: single centre study, UK Length of intervention period: 14 weeks Design: crossover study Excluded: not stated Withdrawals: not stated
Participants	15 adults randomised; Age years: 28 (SE 1.4); FEV1 L: 3.7 (SE 0.2); FEV1 (% pred): 98.5 (SE 2.8); log 10 PC20: ‐0.35 (SE 0.15). Participants described as suffering from mild, stable asthma Inclusion criteria: <15% improvement in FEV1 after 200mcg SABA; PC20 <4mg/mL; Atopy (</=2 +ve skin prick test to common allergens; inhaled or oral steroids in preceding 6 months. Exclusion criteria: Current smokers/ex‐smokers of <5 pack years; patients <80% predicted
Interventions	FP1000mcg daily versus placebo. Inhaler device: pMDI.
Outcomes	Cell count; BHR; protein expression; DNA‐binding
Notes	No clinical outcomes reported. Lung function (FEV1 and PEF recorded but not presented)
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Hoekstra 1996.

Methods	Setting: The Netherlands, primary care and hospital outpatient clinic Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	34 children: 26M 8F Inclusion criteria: Diagnosis of asthma (ATS criteria 1975) Serum IgE greater than normal range (corrected for age) At least one specific serum IgE against a major inhaled allergen FEV1 > 75 (%predicted) Histamine BHR (PC20 FEV1) < 8 mg/ml 10% or greater reversibility in spirometric measures after inhaled beta2 agonist Exclusion criteria: Use of inhaled corticosteroids in last 4 weeks Need for systemic corticosteroids > 3 times in last 6 months
Interventions	FP: 100 mcg 2xdaily (200 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	FEV (% predicted) Morning PEFR Evening PEFR Nocturnal (4 am) PEFR Morning wheeze score Histamine BHR (log 2 PC20 FEV1) Change in % reversibility of FEV1 after inhaled beta2 agonist compared to baseline Morning serum cortisol Morning urine cortisol Blood eosinophil count Serum ECP Serum EDN Urinary EDN
Notes	No reply from author to clarify details of randomisation method
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Hofstra 2000.

Methods	Setting: The Netherlands, paediatric outpatient clinic Length of intervention period: 6 weeks Design: parallel group Excluded: no details Withdrawals: no details Baseline characteristics: no details
Participants	37 children Age range: 6‐14 years Inclusion criteria: Diagnosis of asthma 20% or greater fall in FEV1 after exercise test Exclusion criteria: ICS use in last 4 months
Interventions	FP: 1. 100 mcg 2xdaily (200 mcg/d) 2. 250 mcg 2xdaily (500 mcg/d) Placebo: 2xdaily Delivery device: not stated
Outcomes	% fall in FEV1 post exercise test
Notes	Patients were randomised to receive FP or placebo and treated for 6 weeks. After 6 weeks patients receiving placebo were re‐randomised to either dose of FP for a further 18 weeks
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Information not available

Jayaram 2005.

Methods	Setting: unclear Length of intervention period: unclear Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	N = 31 (PLA: N = 13; FP: N = 18)
Interventions	FP versus PLA (dosage unclear)
Outcomes	Sputum eosinophils; symptoms; rescue medication usage; exacerbations; spirometry; am & pm PEF; adverse events
Notes	Conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Information not available

Jeffery 2002.

Methods	Setting: single centre teaching hospital Length of intervention period: 6 weeks Design: crossover study Excluded: not stated Withdrawals: stated
Participants	20 adults randomised; Mean age: 31.3 years; Mean FEV1 (L): 3; Mean FEV1 % pred: 75.6; Mean PC20: 0.29. Inclusion criteria: Diagnosis of asthma; >/=15% reversibility in FEV1; bronchial reactivity had to be <4mg/mL; non‐smoking; receiving SABA treatment only Exclusion criteria: URTI/exacerbation of asthma within 4 weeks of study entry; asthma medication in last 2 weeks (apart from SABA); ICS in last two months; OCS in previous 3 months; females who were pregnant or lactating were excluded; skin prick +ve pts were recruited only if it was outside the season of their allergy
Interventions	FP 500 mcg/day versus SAL 100mcg per day versus PLA. All interventions given via Diskus. Study duration: 3 x 6 week treatment arms (no washout)
Outcomes	Inflammatory cell markers; symptoms; FEV1; PEF; FVC; PC20; erythema
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Katz 1998.

Methods	Setting: multicentre study, Europe, Middle East and Asia, hospital outpatient clinics Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	263 children: 166M 97F Age range: 4‐11 years Inclusion criteria: Diagnosis of asthma (not otherwise defined) Recurrent episodes of bronchoconstriction and cough Able to use delivery device and peak flow meter satisfactorily PEFR 75 (% predicted)or less, or PEFR 75‐90 (% predicted) with asthma symptoms during run‐in period Exclusion criteria: Treatment with inhaled corticosteroids within last 3 months Oral steroids in last month Continuous treatment with oral steroids over 2 months or more in past Hospital admission due to asthma in last 3 months
Interventions	FP: 1. 50 mcg 2xdaily (100 mcg/d) 2. 100 mcg 2xdaily (200 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	Outcomes expressed as change compared to baseline: FEV1 FVC FEF 25‐75 Morning PEFR Evening PEFR Daily asthma symptom score Night‐time wakening score Daily use of beta2 agonists Probability of remaining in study
Notes	Reply from author but unable to clarify details of randomisation method. Detail of randomisation obtained from FDA website (31/08/2005) For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, PEFR, sleep disturbance or rescue beta2 agonist use
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Kavuru 2000.

Methods	Setting: multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: yes Withdrawals: stated
Participants	527 adults and adolescents screened, 356 randomised (four arm study; PLA: N = 82; FP: N = 90), Age range: 12‐67; Mean baseline FEV1 (% predicted): PLA: 64; FP: 64. Reversibility (%): PLA: 32; FP: 30; Therapy @ baseline: PLA: ICS ‐ 55, SAL ‐ 27; FP: ICS ‐ 63, SAL ‐ 27 Inclusion criteria: >/= 12 years of age; medical history of asthma (ATS criteria); at least 6 months duration; FEV1 between 40‐85% predicted; >/= 15% reversibility post SAB; Participants treated with ICS prior to enrolment had to have been treated with BDP 252‐420mcg/d (6‐10 puffs/d), TRA 600‐1000mcg/d (6‐10 puffs/d); FLU: 1000mcg/d (250 QID); FP 176mcg/d (44 QID) for at least 1 month prior to enrolment without change in regimen; If participants using SAL, they had to do so for at least 1 week prior to screening, and demonstrated FEV1 </= 85% predicted post SABA and not received concurrent ICS for 1 month prior to screening; provision of signed consent Exclusion criteria: Female participants had ‐ve pregnancy test, and were sterile, post‐menopausal or using acceptable birth control measures; history of life‐threatening asthma; hypersensitivity to ICSor beta‐agonists; smoking history (>10 pack years); use of oral, inhaled (external to guidelines above) or IM CS therapy, intranasal CS (except for 'Flonase'); use of OCS in previous 6 months; use of over the counter medicines that might affect course of asthma; abnormal chest x‐ray; abnormal ECG; significant concurrent disease. During screening period, participants not eligible if they had >3 awakenings requiring asthma during 7 days immediately preceding randomisation. ICS patients not eligible if using >12 puffs SABA per day for more than 3 days, SAL patients not eligible using >6 puffs SABA per day for more than 3 days
Interventions	FP200 versus PLA. Inhaler device: Diskus. Single‐blind run‐in with a placebo (2 weeks)
Outcomes	FEV1; am PEF; pm PEF; adverse events; symptoms; ECG; rescue medication usage; withdrawals
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Kemp 2004.

Methods	Setting: Multicentre study, USA Length of intervention period: 2 years Design: parallel group Excluded: yes Withdrawals: stated
Participants	190 adults and adolescents screened, 160 randomised (three arm study; PLA: N = 54; FP400: N = 55; FP1000: 51), Age range: 18‐50; Mean baseline FEV1 (% predicted): PLA: 83; FP100: 82; FP500: 85 Inclusion criteria: 18‐50 years (F: 18‐40); mild asthma (6 months); FEV1: 50‐100% predicted Exclusion criteria: Significant co‐morbidity of bone; alterations in body weight; reversal of nocturnal sleeping hours; substance abuse
Interventions	FP200 BID (400) versus FP1000 BID (1000) versus PLA. Inhaler device: MDI
Outcomes	Bome mineral density; withdrawals; adverse events
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Laforce 2000.

Methods	Setting: Multicentre study,USA Length of intervention period: 12 weeks Design: parallel group Excluded: stated Withdrawals: stated
Participants	242 children screened, 192 randomised. Age range: 4‐11; FEV1 (% predicted) (mean (SEM)): FP200: 70 (0.8); FP100: 70 (1.0); Placebo: 73 (0.8); FEV1 (L) (mean (SEM)): FP200: 1.40 (0.04); FP100: 1.36 (0.04); Placebo: 1.51 (0.04); Clinic am PEF (Mean (SEM)): FP200: 208 (7); FP100: 208 (6); Placebo: 219 (7); Diary am PEF L/min (mean (SEM)): FP200: 220 (8); FP100: 222 (7); Placebo: 234 (8); Asthma symptom scores (mean (SEM)): FP200: 0.88 (0.06); FP100: 0.93 (0.07); Placebo: 0.85 (0.06); Albuterol use (puffs/day) (mean (SEM)): FP200: 2.1 (0.3); FP100: 2.0 (0.3); Placebo: 1.7 (0.2); Nighttime awakenings/night (mean (SEM)): FP200: 0.10 (0.02); FP100: 0.10 (0.02); Placebo: 0.08 (0.02) Inclusion criteria: male and premenarchal females; ATS‐diagnosed asthma; Requirement for pharmacotherapy for 3 mo prior to start of the trial; Baseline PEF >/= 85% predicted; Baseline FEV1 50‐85% predicted; >/= 15% reversibility to albuterol or 15% variability in FEV1 within 6 months prior to the study (patients aged 6‐11); Stable asthma (no more than 3 days from preceding 7 where >/‐12 puffs of albuterol per day/6 doses of albuterol power per day; no more than 3 am PEFs more than 20% below previous pm PEF; no more than 3 nights awakening resulting from asthma Exclusion criteria: History of life threatening asthma or other severe chronic disease; any RTI within 2 weeks prior to study; chickenpox 3 weeks prior to study; oral and parenteral steroids within 1 mo prior to study; use of methotrexate/gold salts; use Pf prescription or over the counter medication which may have affected course of asthma; participation in previous Diskus trial.
Interventions	FP200mcg QD (+ placebo for evening) versus FP 100mcg BD versus placebo. Inhaler device: Diskus. Single blind run‐in 7 days (placebo)
Outcomes	Lung function (predose am FEV1; clinic PEF ‐ measurements taken between 7am and 10am; diary PEF (am and pm); Symptoms; Rescue medication use; nighttime awakenings requiring albuterol; Adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Langley 2002.

Methods	Setting: single centre study, UK Length of intervention period: 4 weeks Design: crossover study Excluded: stated Withdrawals: stated
Participants	59 adults randomised. 48 completed; mean age: 32.6 (SD 9.2); M/F: 18/30; FEV1 (L): 3.2 (SD 0.7); Duration of reversible obstruction >15 years: 32; Patients using a spacer: 4; % predicted FEV1: 93.5 (11.8); Never smoked: 28; current smoker: 3. Inclusion criteria: Patients >/=18 years; resting FEV1: >/=60%; PD20 </=3.2MG; no significant asthma medication 4 weeks prior to study (steroids ‐ ICS, OCS, parenteral); LABA, oral beta‐agonists; methylxanthine; leukotriene antagonists); No change to regular medication in this period Exclusion criteria: Inability to perform methacholine test (recent MI/CVA in last 3 months); Females of child‐bearing age except if using appropriate contraception; ‐ve pregnancy test
Interventions	HFA FP100mcg BID (200mcg) via either: 1) pMDI or 2)Diskhaler. Placebo given via two inhalers.
Outcomes	FEV1; rescue medication usage; side effects
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	PACT (computer‐generated package)
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Double dummy design

Lanz 2001.

Methods	Setting: single centre study, USA Length of intervention period: 4 weeks Design: crossover study Excluded: not stated Withdrawals: stated Statistical analysis: paired t test.
Participants	18 adults randomised. Age range: 17‐63; FEV1% pre‐SABA: 75 (50‐85); Reversibility %: 25 (12‐50); M/F: 6/12; Caucasian/Hispanic: 3/15; Medications: SABA: 18; LABAs: 3; IGC in past year: 4; LT/Theo in past year: 4 Inclusion criteria: ATS diagnosed asthma; >/=12% reversibility Exclusion criteria: Use of inhaled/nasal/oral steroids; nasal/inhaled cromolyn; LTRA/theophylline in past 4 weeks
Interventions	FP44 BID versus placebo. arms; Washout period: 4 weeks. Inhaler device: MDI
Outcomes	Exhaled NO; FEV1 %; PEF %; QoL; Symptoms; SABA usage
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Lawrence 1997.

Methods	Setting: Multicentre study USA, hospital outpatient clinics Length of intervention period: 6 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	261 adults Age range: 18‐71 years Inclusion criteria: Diagnosis of asthma (ATS criteria 1987) Treatment with ICS for 3 months or longer Treatment with BDP 336 mcg/d or TA 800 mcg/d at stable dose for 2 weeks FEV1 50‐80 (% predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist Exclusion criteria: Systemic, intra‐nasal or ophthalmic corticosteroids in last 2 months Oral corticosteroids for > 2 months in last 6 months Pregnancy
Interventions	FP: 1.100 mcg 2xdaily (200 mcg/d) 2. 500 mcg 2xdaily (1000 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	Probability of remaining in study Outcomes expressed as change compared to baseline: FEV1 Morning PEFR Daily asthma symptom score Daily use of beta2 agonist Morning plasma cortisol Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method Results for continuous outcomes expressed as change to endpoint (point of withdrawal) A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Levy 2006.

Methods	Setting: Not stated Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	241 children with asthma. Most children had NHLBI moderate‐severe persistent asthma (77‐9%) Inclusion criteria: 4‐11 years of age; >/=6 months diagnosis of asthma requiring treatment; PEF >/=85% predicted Exclusion criteria: systemic steroids >/=10 weeks prior to study entry
Interventions	1. FP 100 2 x daily (200mcg/d) 2. Placebo Inhaler device: HFA‐MDI
Outcomes	Am PEF; symptoms; adverse events
Notes	Unpublished conference abstract Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Li 1999.

Methods	Setting: Multicentre study, USA Length of intervention period: 4 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	128 adults randomised. Age range: 18‐53; Ethnic origin (%) (White/Other): PLA: 94/6; FP88: 95/5; FP220: 88/13; FEV1 % Predicted: PLA: 89.1; FP88: 82.5; FP220: 88.2; Concurrent medication: Salmeterol: PLA: 0; FP88: 0; FP220: 1; Theophylline: PLA: 2; FP88: 0; FP220: 3; Cromolyn: PLA: 0; FP88: 1; FP220: 1; Nedocromil: PLA: 0; FP88: 0; FP220: 1 Inclusion criteria: Non‐smokers; asthma according to ATS criteria; duration of disease >6 months; FEV1 >/=50% predicted. Exclusion criteria: Pregnancy/lactation; use of methotrexate/gold salts; use of inhaled cromolyn/nedocromil; use of oral, intranasal, inhaled or injectable steroids <4 weeks of study commencement; use of >/= 140mg prednisone or equivalent dosage in past year; significant concomitant illness; immunotherapy requiring change in dosage regimen within 12 weeks; reversal of nocturnal sleeping hours; concurrent use of over‐the‐counter medication that might affect course of asthma or interact with sympathomimetic amines or confound cortisol assay.
Interventions	FP88 versus FP220 versus Placebo. Inhaler device: pMDI + spacer.
Outcomes	HPA axis function; plasma concentration; area under the curve; adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Li 1999a.

Methods	Setting: single centre study, Australia Length of intervention period: 12 weeks Design: parallel group Excluded: yes Withdrawals: stated
Participants	71 adults enrolled. 50 randomised (45 completed). Age range: 18‐55; Atopy (+/‐): FP: 11/5; PLA: 12/4; Median PD20: FP: 0.021; PLA: 0.011; Median FEV1 % pred: FP: 80; PLA: 83; Symptom scores: FP: 1.39; PLA: 1.07; SABA (median puffs/day): FP: 1.82; PLA: 1.07; median am PEF (mL): FP: 420; PLA: 404; median pm PEF (mL): FP: 471; PLA: 445 Inclusion criteria: 20‐70 years of age; non‐smoker; diagnosed asthma for previous 12 months with ICS (daily does up to 500mcg BDP/BUD; baseline FEV1 >/=60% predicted; symptomatic post run‐in i.e. symptom score >2 on 7 of last 14 days; SABA more than 7 of last 14 days; variation of >/=15% PEF over 24hrs on at least 7 of last 14 days and some degree of symptoms and SABA use during that time. Exclusion criteria: Acute RTI, change in asthma medication, admission to hospital with airways disease in previous 4 weeks
Interventions	FP200mcg/day versus placebo via diskhaler. Study duration 12 weeks. Inhaler device: unclear.
Outcomes	am PEF; FEV1; symptom; SABA usage; BAL;
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer‐generated randomisation procedure
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Triple dummy (identical inhalers)

Li 1999b.

Methods	Setting: Multicentre study USA, hospital outpatient clinics Length of intervention period: 2 years Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	63 adults: 55M 9F Age range: 18‐50 years Inclusion criteria: Diagnosis of asthma (ATS criteria 1987) FEV1 60 (% predicted) or greater Exclusion criteria: Inhaled steroid use in last month 4 or more weeks of cumulative oral steroid use prior to study More than one year of cumulative corticosteroid use via any route prior to study Life threatening asthma or other serious concurrent disease Glaucoma, posterior subcapsular cataracts, abnormal HPA function, abnormal lumbar spine bone mineral density Postmenopausal or pregnant women
Interventions	FP: 500 mcg 2xdaily (1000 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	Morning plasma cortisol 8 hour area under curve (AUC) plasma cortisol during 6 hour 250 mcg co‐syntropin infusion Peak plasma cortisol during 6 hour 250 mcg co‐syntropin infusion Lumbar spine bone mineral density by dual energy x‐ray absorptiometry Serum osteocalcin Urinary N‐telopeptide/creatinine ratio Incidence of posterior subcapsular cataracts Change in FEV1 compared to baseline
Notes	No reply from author to clarify details of randomisation method ITT analysis undertaken using endpoint data
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Lindqvist 2003.

Methods	Setting: dual centre study, Finland Length of intervention period: 16 weeks Design: parallel group Excluded: stated Withdrawals: stated
Participants	83 adults enrolled, 80 randomised (four treatment arms; SAL, DCSG, FP & PLA); age range: 18‐60; asthma duration: <2 years; FEV1 % predicted: 81 (SEM 1.2). Inclusion criteria: 18‐60 years of age; newly diagnosed symptomatic ATS defined asthma (within previous 2 years); FEV1 60‐100%; moderate‐severe BHR; non‐smoker; Exclusion criteria: Rx with LABA or cromones in previous 4 weeks; ICS/OCS in 2 months prior to study; RTI or exacerbation of asthma; seasonal allergy
Interventions	SAL, FP250 BID (1000mcg/d); DSCG 5mg BID; PLA. Inhaler device: not reported
Outcomes	Eosinophils; lymphocytes; Tenascin; PD15; amPEF; Symptoms; rescue medication usage
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Information not available

Lipworth 2005.

Methods	Seting: multicentre study in USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	82 adults with mild to moderate asthma. Mean age: 36 years; FEV1: 81.7%. Inclusion criteria: >/‐18 years; mild to moderate persistent asthma; acceptable inhaler technique; SABA only for 6 months (at least 2 x daily); FEV1 >/=70% predicted Exclusion criteria: systemic steroid use within 6 months of screening; inhaled steroids within 2 months
Interventions	1. FP880mcg/d 2. Placebo Inhaler device: MDI without a spacer
Outcomes	Hypothalmic pituitary axis function; serum cortisol; safety
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Lumry 2006.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	415 adults and adolescents randomised; Mean FEV1 % predicted: PLA: 65.6; FP172: 65.3; FP440: 65.5; FP880: 66.2; mean am PEF (l/min): PLA: 346; FP172: 334; FP440: 329; FP880: 333.1 Inclusion criteria: >/=12 years; asthma for >6 months requiring Rx with ICS for >/=3 months; FEV1: 45‐80% predicted; >/=12% reversibility Exclusion criteria: not reported
Interventions	HFA FP88 BID (172 mcg/d) versus HFA FP220 BID (440) versus HFA FP440 BID (880). Study duration: 12 weeks. Inhaler device: MDI
Outcomes	am PEF; FEV1 (% predicted)
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

MacKenzie 1993.

Methods	Setting: Multicentre study Europe and South Africa, hospital outpatient clinics Length of intervention period: 4 weeks Design: parallel group Excluded: stated Withdrawals: stated (ITT analysis) Baseline characteristics: comparable
Participants	258 children: 170M 88F Age range: 6‐14 years Inclusion criteria: Asthma judged to require regular therapy with either a bronchodilator or a prophylactic agent Experienced a worsening of asthma i.e.. marked deterioration in lung function leading to a change in medication or hospitalisation in the last month 20% or greater diurnal variation in PEFR or symptoms during 4 out of 7 days of run‐in period Exclusion criteria: Use of inhaled corticosteroids in previous 6 months Course of oral steroids on more than 2 occasions in the previous 3 months Lower respiratory tract infection in the last 2 weeks Unstable concurrent disease
Interventions	FP: 50 mcg 1 actuation 2xdaily (100 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	FEV1 Morning PEFR Evening PEFR Clinic PEFR Daily asthma symptom score Serum cortisol
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Micheletto 2000.

Methods	Setting: Single centre study Length of intervention period: 4 weeks Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	24 adults randomised. Age range: 19‐51; FEV1% predicted: FP: 73.1 (SD 5.3); PLA: 74.2 (SD 13.2) Inclusion criteria: not reported Exclusion criteria: not reported
Interventions	FP250 BID versus PLA BID via Diskhaler.
Outcomes	Exhaled NO; FEV1 % predicted
Notes	Unpublished conference. Pending confirmation from trialists of randomisation.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Nathan 2000.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	330 adults and adolescents randomised. Gender (% M:F): PLA: 56:44; FP100: 65:35; FP200: 56:44; FP500: 55:45; Age range: 12‐75; FEV1 L: PLA: 2.22 (SEM 0.06); FP100: 2.40 (0.07); FP200: 2.21 (SEM 0.07); FP500: 2.26 (SEM 0.05); FEV1 % predicted: PLA: 62.6 (SEM 1.07); FP100: 64.3 (SEM 0.89); FP200: 63.3 (SEM 1.03); FP500: 63.7 (SEM 0.96); am PEF (L/min): PLA: 394 (SEM 10); FP100: 397 (SEM 10); FP200: 395 (SEM 10); FP500: 379 (SEM 10); pm PEF (L/min): PLA: 412 (SEM 10); FP100: 420 (SEM 10); FP200: 414 (SEM 10); FP500: 404 (SEM 10); Asthma symptom scores: PLA: 1.10 (SEM 0.07); FP100: 1.18 (SEM 0.06); FP200: 1.03 (SEM 0.07); FP500: 1.08 (SEM 0.07); Albuterol use (puffs/d): PLA: 3.05 (SEM 0.26); FP100: 3.43 (SEM 0.26); FP200: 2.62 (SEM 0.24); FP500: 3.18 (SEM 0.26); Nighttime awakenings, No. (%): PLA: 0.09 (SEM 0.02); FP100: 0.08 (SEM 0.02); FP200: 0.12 (SEM 0.02); FP500: 0.10 (SEM 0.02)
Interventions	Inhaled FP100mcg QD versus FP200mcg QD versus FP500mcg QD versus placebo. Diskus inhaler.
Outcomes	Lung function (FEV1; am PEF; pm PEF); asthma symptoms; albuterol use; nighttime awakenings; withdrawals; safety; HPA axis function
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Nathan 2006.

Methods	Setting: Multicentre study Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: not stated (ITT)
Participants	365 adults and adolescents randomised. Age range: 12‐82 years. Unclear distribution between the treatment groups. Age range: 12‐82 years. M/F (%): 40/60; Caucasian: 84%; mean FEV1 68%; Reversibility: 28% Inclusion criteria: FP440‐660 mcg/d for at least 3 months prior to study entry; FEV1 40‐85%; reversibility >=15%
Interventions	Combination HFA FP/SAL 110/42 BID (220/84) versus CFC SAL 42 BID (84) versus CFC FP 110 BID (220) versus HFA PLA. Inhaler devices: MDI. Run‐in: 2 weeks
Outcomes	Remaining in study; AUC; withdrawals due to deterioration; FEV1
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Nelson 1999.

Methods	Setting: Multicentre study USA, hospital outpatient clinics Length of intervention period: 16 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	111 adults: 44M 67F Age range: 12‐77 years Inclusion criteria: 12 years of age or older Diagnosis of asthma (ATS criteria 1987) Dependent on oral corticosteroids for asthma control for 6 months or longer Requiring 5‐40 mg/day oral prednisolone FEV1 40‐80 (% predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist Exclusion criteria: Life‐threatening asthma or other severe concurrent disease Use of intra‐nasal, injectable, topical corticosteroids Methotrexate, cyclosporin, azathioprine, troleandomycin within last 3 months
Interventions	FP: 1. 500 mcg 2xdaily (1000 mcg/d) 2. 1000 mcg 2xdaily (2000 mcg/d) Placebo: 2xdaily Delivery device: Accuhaler DPI
Outcomes	100% reduction in daily dose oral prednisolone (% of patients) Outcomes reported as a change compared to baseline: Daily dose oral prednisolone FEV1 Morning PEFR Evening PEFR Daily asthma symptom score Daily beta2 agonist use Night‐time awakenings Health status: Asthma Quality of Life Questionnaire (AQLQ) Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method Usual ICS discontinued at randomisation A priori criteria for prednisolone dose reduction based on FEV1 (% predicted), PEFR (% predicted), number of night‐time awakenings, beta‐2 agonist use compared to run in period values Patients were withdrawn from the study if they experienced asthma exacerbation requiring hospital admission, or 3 bursts of oral prednisolone due to exacerbation
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Noonan 1995.

Methods	Setting: Multicentre study USA, hospital outpatient clinics Length of intervention period: 16 weeks Design: parallel group Excluded: stated Withdrawals: stated Baseline characteristics: comparable
Participants	96 adults: 46M 50F Mean age: 50‐52 years Inclusion criteria: 12 years of age or older Diagnosis of asthma (ATS criteria 1987) Dependent on oral corticosteroids for asthma control for 6 months or longer FEV1 40‐80 (% predicted) Documented evidence of previous attempts to reduce oral steroid dose Exclusion criteria: Use of methotrexate, gold salts or troleandomycin in last 3 months Nasal corticosteroid use 10 pack year history of smoking or greater Pregnancy or lactation
Interventions	FP: 1. 750 mcg 2xdaily (1500 mcg/d) 2. 1000 mcg 2xdaily (2000 mcg/d) Placebo: 2xdaily Delivery device: MDI
Outcomes	100% reduction in daily oral steroid use (% patients) Outcomes expressed as change compared to baseline: Daily oral prednisolone dose FEV1 Morning PEFR Evening PEFR Daily use of beta2 agonists Daily asthma symptom score Health Status: Medical Outcomes Study Short Form (SF‐36) Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method Usual ICS discontinued at randomisation Daily dose oral prednisolone reduced according to pre‐defined criteria An uncontrolled one year open label study was undertaken following the randomised 16 week trial, when all patients received FP 2000 mcg/d. Results not considered in this review
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Noonan 1998.

Methods	Setting: Multicentre study USA, hospital outpatient clinic Length of intervention period: 8 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	138 adults: 84M 54F Age range: 12‐59 years Inclusion criteria: 12 years of age or older Diagnosis of asthma (ATS criteria 1987) 6 months or longer FEV1 60 (% predicted) or greater 15% or greater reversibility in FEV1 after inhaled beta2 agonist Methacholine BHR (PD20 FEV1) < 18 mg Asthma stability during run in period based on a priori defined criteria related to PEFR, medication requirement and symptoms Exclusion criteria: Recent hospitalisation due to asthma exacerbation Treatment with corticosteroids, theophylline, sodium cromoglycate, nedocromil Pregnancy
Interventions	FP: 1. 50 mcg 2xdaily (100 mcg/d) 2. 100 mcg 2xdaily (200 mcg/d) Placebo: 2xdaily Delivery device: MDI
Outcomes	Outcomes expressed as change compared to baseline: FEV1 Morning PEFR Evening PEFR Methacholine BHR (log e PD20 FEV1) Daily asthma symptom score Daily use of beta2 agonist Night‐time awakenings Probability of remaining in study Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment MDI's used for all interventions. Formulations of FP with 1% lecithin and 10% lecithin used. Only data for 1% formulation included in meta‐analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

O'Shaughnessy 1993.

Methods	Setting: UK, hospital outpatient clinic Length of intervention period: 2 weeks Design: crossover, 3 week washout Excluded: not stated Withdrawals: stated Baseline characteristics: no demographic data presented
Participants	11 subjects: 6M 5F Age range: 21 to 39 years Inclusion criteria: Adult patients with mild asthma Non‐smokers FEV1 60 (% predicted) or greater Histamine BHR (PC20 FEV1) 8mg/ml or less Skin prick test positive to either grass pollen or Dermatophagoides Exclusion criteria: Use of inhaled steroids within last 3 months
Interventions	FP: 1000 mcg/d Placebo Delivery device: MDI+spacer
Outcomes	Histamine bronchial responsiveness (change in doubling dose log 2 PC20 FEV1) Histamine bronchial responsiveness (change in doubling dose log 2 PC20 FEV1) following inhaled allergen challenge Maximal % fall in FEV1 within 2 hours compared to test baseline following inhaled allergen challenge: Early asthmatic response Maximal % fall in FEV1 compared to test baseline 2 to 10 hours following inhaled allergen challenge: Late asthmatic response Urinary leukotriene E4 excretion index
Notes	No reply from author to clarify details of randomisation method
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Olivieri 1997.

Methods	Setting: Italy, hospital outpatient clinic Length of intervention period: 6 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	20 adults Age range: 18‐50 years Inclusion criteria: Diagnosis of asthma (ATS criteria 1987) FEV1 > 80 (% predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist Free of asthma attacks for at least 2 months Rescue beta2 agonist < 2 puffs/d and < 10% variability in FEV1 during 2 week run in period Exclusion criteria: ICS in last 6 months Respiratory tract infection in last month Smokers
Interventions	FP: 250 mcg 2xdaily (500 mcg/d) Placebo: 2xdaily Delivery device: not stated
Outcomes	Methacholine BHR (PC20 FEV1) BAL differential cell count, ICAM‐1 and Mac‐1 expression BAL tryptase and ECP levels Bronchial biopsy differential cell count and basement membrane thickness
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Information not available

Overbeek 1996.

Methods	Setting: The Netherlands, hospital outpatient clinic Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	33 subjects: 23 male 10 female Age range: 18‐56 years Inclusion criteria: Adult asthmatic patients At least one positive skin‐prick test to a panel of common aero‐allergens Methacholine BHR (PC20 FEV1) 8 mg/ml or less 9% or greater reversibility in FEV1 after inhaled beta2 agonist Exclusion criteria: Exacerbation of asthma or respiratory tract infection in last month
Interventions	FP: 500 mcg 2xdaily (1000 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	Methacholine BHR (log 2 PC20 FEV1) Change in FEV1 as percentage of initial FEV1, per doubling dose methacholine post methacholine challenge % fall in FEV1 post methacholine challenge compared to test baseline FEV1 Daily asthma symptom score FEV1
Notes	No reply from author to clarify details of randomisation method
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices

Parameswaren 2000.

Methods	Setting: Single centre study, Canada Length of intervention period: 2 weeks Design: crossover study Excluded: not stated Withdrawals: stated
Participants	10 adults randomised (6 male). Mean age: 25 (SD 9.14); mean FEV1 (% predicted): 90.2 (SD 14.33); Mean PC20: 2.56 (SD 1.76). All patients were non‐smokers. Study took place out of allergy season. Beta‐agonist withheld at least 8 hours before each visit. Participants instructed to refrain from rigorous exercise and caffeine in am before visits to laboratory. Inclusion criteria: Mild stable asthma: Few or no symptoms, inhaled SABA prn, FEV1 </= 70% predicted; moderate to borderline methacholine airway hyperresponsiveness
Interventions	Four visit run‐in period: control inhalation test and allergen inhalation test; Randomisation to either: Pretreatment with FP 250mcg 30 mins before allergen challenge followed by 2 weeks of FP 250mcg BID, and allergen inhalation test at end of treatment or Treatment 2: Pretreatment with placebo 30 mins before allergen inhalation test followed by 2 weeks treatment with placebo. Three week washout period before crossover. Inhaler device not described
Outcomes	FEV1; PC20; Sputum inflammatory markers
Notes	Investigator may have noted effects of active treatment on airway responses
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer generated codes
Allocation concealment?	Low risk	Off‐site
Blinding? All outcomes	Unclear risk	Information not available

Pauwels 2002.

Methods	Setting: single centre study, Belgium Length of intervention period: 1 weeks Design: crossover study Excluded: not stated Withdrawals: not stated
Participants	N=26, Other details not reported
Interventions	Ciclesonide (400mcg QID; 800mcg QID; 800mcg QID), FP500 BID & FP1000 BID or PLA.
Outcomes	% Cortisol suppression; PC20
Notes	Unpublished conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Double‐dummy design used

Pearlman 1997.

Methods	Setting: multicentre study USA, hospital outpatient clinic Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	342 subjects randomised Age range: 12‐72 years Inclusion criteria: Diagnosis of asthma (ATS criteria 1987) Required maintenance inhaled corticosteroids for at least 3 months FEV1 50‐80 (%predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist During last 7 days of run‐in period: No more than 12 puffs per day of albuterol No more than 4 morning PEFR 20% less than previous evenings No more than 2 nights wakening due to asthma requiring inhaled albuterol adequate compliance with study medication Exclusion criteria: Previous use of gold or methotrexate for control of asthma Inhaled cromoglycate or oral steroids in the last 4 weeks Significant co‐existent illness Pregnancy or lactation
Interventions	FP: 1. 50 mcg 1 actuation 2xdaily (100 mcg/d) 2. 100mcg 1 actuation 2xdaily (200 mcg/d) 3. 250 mcg 1 actuation 2xdaily (500 mcg/d) Placebo: 2xdaily Delivery device: Diskhaler DPI
Outcomes	Outcomes expressed as change compared to baseline: FEV1 Morning PEFR Evening PEFR Daily asthma symptom score Night‐time awakenings Daily use of beta2 agonist Medical Outcomes Study Short Form‐36, acute version (SF‐36A) Living with Asthma Questionnaire (LWA‐20) Validated sleep scale Probability of remaining in study Physician global assessment of efficacy Plasma cortisol Plasma cortisol 30‐60 min post 250 mcg iv cosyntropin Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; other information not available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Pearlman 1999.

Methods	Setting: multicentre study, USA Length of intervention period: 4 weeks Design: parallel group Excluded: not stated Withdrawals: stated (ITT)
Participants	N = 136 (PLA: 23; FP88: 23; FP220: 23; SAL: 21; SAL/FP88: 25; SAL/FP220: 21).Mean age (range): PLA: 35 (12‐62); SAL: 29 (15‐57); FP88: 27 (13‐50); FP220: 32 (14‐61); SAL/FP88: 33 (14‐60); SAL/FP220: 26 (13‐52); Gender (M:F %): PLA: 43:57; SAL42: 67:33; FP88: 74:26; FP220: 57:43; SAL/FP88: 40:60; SAL/FP220: 67:33; Mean FEV1 (% predicted): PLA: 68; SAL: 70; FP88: 69; FP220: 65; SAL/FP88: 67; SAL/FP220: 69. Inclusion criteria: >/=12 years of age; ATS defined asthma (at least 6 months), requiring medical treatment; FEV1 between 50‐80% predicted; >/=15% increase in FEV1 post‐SABA; treatment with prn SABA; female participants had ‐ve pregnancy tests and either surgically sterile, postmenopausal at 1 year or using acceptable birth control for 1 month prior to participation Exclusion criteria: History of life‐threatening asthma; hypersensitivity reaction to beta‐agonists/corticosteroids; smoking within previous year/history >10 pack years; use of OCS/ICS or parenteral steroids (except for Flonase); use of steroid therapy in previous month; OCS treatment in previous 6 months; use of OTC medication that may affect the course of asthma; abnormal CXR; clinically significant abnormal 12‐lead ECG; history of concurrent disease (glaucoma, diabetes + hypertension)
Interventions	PLA versus FP88mcg versus FP220mcg versus SAL42mcg/FP88mcg versus SAL42mcg/FP220mcg daily. Inhaler device: MDI.
Outcomes	FEV1; Am PEF; Symptoms; % days without asthma; % nights awakening due to asthma; rescue medication use; adverse effects
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Pearlman 2004.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: not stated (ITT)
Participants	N = 360. No details on distribution between the groups provided. Participants described as symptomatic. Baseline medication: prn SABA alone: 142; SAL: 84; ICS: 134) Inclusion criteria: FEV1 40‐85% predicted; Reversibility: >/=15%. No other details provided Exclusion criteria: not listed
Interventions	CFC FP88 BID (176mcg/d) versus HFA PLA. Inhaler device: MDI. 2 week run‐in.
Outcomes	am PEF; probability of remaining in the study; withdrawals due to worsening asthma; FEV1; AUC
Notes	Unpublished conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Peden 1998.

Methods	Setting: Multicentre study USA, paediatric outpatient clinic Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	437 children: 268M 169F Age range: 4‐11 years Inclusion criteria: History of chronic asthma (ATS criteria 1987) Symptoms requiring maintenance therapy for 3 months or more PEFR 85 (% predicted) or greater FEV1 50‐85 (% predicted) 15% or greater improvement in FEV1 after inhaled beta2 agonist Asthma stability during run‐in period, based on a priori beta2 agonist use and morning PEFR Exclusion criteria: Life‐threatening asthma Severe concurrent disease Systemic steroids in last month Previous treatment with methotrexate or gold
Interventions	FP: 1. 50mcg 2xdaily (100 mcg/d) via Accuhaler DPI 2. 100mcg 2xdaily (200mcg/d) via Accuhaler DPI 3. 50 mcg 2xdaily (100 mcg/d) via Diskhaler DPI 4. 100 mcg 2xdaily (200 mcg/d) via Diskhaler DPI Placebo: 2xdaily, Diskhaler and Diskus/Accuhaler
Outcomes	Outcomes expressed as change compared to baseline: FEV1 FEV1 (% predicted) Morning PEFR Morning PEFR (% predicted) Evening PEFR Daily asthma symptom score Daily use of beta2 agonist Night‐time awakening score Morning plasma cortisol Total urinary free cortisol excretion (mcg/24 hours) Probability of remaining in study
Notes	For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported Only data concerning FP v placebo delivered via Accuhaler has been included in the meta‐analysis Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double dummy design used

Phillips 2004.

Methods	Setting: single‐centre study, UK Design: crossover Length of intervention period: 4 weeks Excluded: stated Withdrawals: stated Baseline characteristics: comparable
Participants	18 adults with mild asthma. Age range: 18‐65 years Inclusion criteria: diagnosis and symptoms consistent with asthma Exclusion criteria: inhaled steroids within 4 weeks of study entry; recent exacerbation
Interventions	FP 750mcg BID (1500mcg/d) BUD 800mcg BID (1600mcg/d) Placebo Inhaler device: DPI
Outcomes	PD20; FEV1; am PEF
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Pinnas 2005.

Methods	Setting: Multicentre study USA. Length of intervention period: 12 weeks. Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	397 adults randomised, 312 completed: 212F Age range: >/=12 years Inclusion criteria: treatment with SABA only for 6 months previously; am pre‐SABA FEV1 of 45‐80% predicted; >/=12% reversibility. No run‐in period described.
Interventions	FP: 1. 88mcg 2 x daily 2. 110mcg 2 x daily 2. 220mcg 2 x daily 3. Placebo Inhaler device: MDI
Outcomes	Change in FEV1; am PEF; rescue medication usage; symptoms; quality of life; adverse events
Notes	Conference abstract Sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Qaquandah 2006.

Methods	Setting: Multicentre Length of intervention period: 12 weeks Design: parallel group Excluded: Stated Withdrawals: stated (ITT analysis)
Participants	359 children: 221M 138F Age range: 1‐4 years Inclusion criteria: Children with history of symptomatic asthma; requirement for SABA during run‐in FEV1 not stipulated Exclusion criteria: Recent ICS exposure
Interventions	FP: 200 mcg/d Placebo Delivery device: MDI+spacer
Outcomes	Symptoms; rescue medication use; am PEF (limited number of participants); adverse events;
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	'Randomization was stratified according to age (12 to 23 months and 24 to 47 months) and by pharmacokinetic sampling (1 sample or 3 samples).'
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices

SAS30021.

Methods	Setting: Multicentre study in North & South America. Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated (ITT)
Participants	608 children. Mean age: 7.6‐7 years; am PEF: 75.2‐76.6% predicted. Inclusion criteria: 4‐11 years; diagnosis of asthma for 6 months; treated with SABA or non‐ICS controller only for 1 month prior to screening; am PEF: 50‐85% predicted; >/=15% reversibility post SABA; symptoms on 4 days of previous week/use of SABA on 4 days of previous week
Interventions	1. FP 100 once daily 2. Placebo Inhaler device: DPI
Outcomes	am & pm PEF; symptoms; SABA usage; adverse events
Notes	Sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

SAS30022.

Methods	Setting: Multicentre study in North America Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	FP and PLA groups: 224 adults randomised. Mean age: 32‐33 years; Baseline am PEF: 72‐3% predicted Inclusion criteria: >/=12 years; diagnosis of asthma for at least 3 months; FEV1 50‐85%; >/=15% reversibility to SABA; symptoms on 4 days of week preceding randomisation
Interventions	1. FP250 1 x daily 2. PLA 1 x daily Inhaler device: DPI
Outcomes	am & pm PEF; symptoms; SABA usage; withdrawals; adverse events
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

SAS30023.

Methods	Setting: Multicentre study in Australia, France, UK, Hungary, Ukraine, Italy, Philippines, Thailand, Russia Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated (ITT analysis)
Participants	464 adults with mild asthma randomised to three treatment groups (two groups of relevance to the review: FP100: 155; PLA: 158). Age range: 12‐80 (mean 33‐34 years); Mean baseline FEV1: 3.2‐3.3L Inclusion criteria: 12‐80 years; documented history of asthma >/=6 months; receiving SABA prn alone
Interventions	FP100 OD versus placebo via HFA MDI
Outcomes	mean am & pm PEF; FEV1; adverse events; rescue medication usage; symptoms
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Shapiro 2000.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: stated Withdrawals: stated (ITT)
Participants	484 adults and adolescents screened. 349 randomised (four treatment arm study; PLA: 93; FP: 84. Data from 13 participants excluded from the analysis due to poor procedure at one site). M/F %: PLA: 41/59; FP250: 54/46; age range: 12‐69; FEV1 mean % predicted (% reversibility): PLA: 68 (29); FP250: 66 (28); FEV1 L: PLA: 2.19 (SE 0.07); FP250: 2.12 (0.06); Symptom scores: PLA: 1.6 (SE 0.12); FP250: 1.6 (SE 0.12); SABA usage (puffs/d): PLA: 3.8 (0.3); FP250: 3.2 (0.3) Inclusion criteria: >/=12 years; ATS defined asthma of >/=6 mo duration requiring pharmacotherapy for at least 6 months; FEV1 between 40 and 85% predicted; >/=15% increase in FEV1 30 mins after 2 puffs of albuterol; use of ICS 12 weeks prior to the study. Exclusion criteria: Females with negative pregnancy tests; life‐threatening asthma; hypersensitivity to sympathomimetic drugs/steroids; smoking within previous year; smoking history of >10 pack years; use of oral/injectable steroid therapy within 1 month of study; use of daily oral steroids within 6 months prior to the study; use of any prescription or over the counter medication that could have affected asthma or course of treatment; abnormal CXR; clinically significant abnormal 12‐lead ECGs history of concurrent disease.
Interventions	PLA versus FP250 BID (500mcg/d) via Diskus inhaler. Duration: 12 weeks
Outcomes	FEV1; PEF; AUC; Symptoms; Rescue medication usage; Adverse Effects
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Identical inhaler devices used

Sheffer 1996.

Methods	Setting: Multicentre study USA, hospital outpatient clinics Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	307 patients: 185M 122F Age range: 12‐72 years Inclusion criteria: Diagnosis of asthma requiring at least 3 months of regular therapy FEV1 45‐75 (% predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist Exclusion criteria: More than 1 month's use of oral steroids in the past Any oral, topical or inhaled steroid or cromoglycate in last month Previous history of life threatening asthma Pregnancy or lactation
Interventions	FP: 1. 25 mcg 1 puff 2xdaily (50 mcg/d) 2. 50 mcg 1 puff 2xdaily (100 mcg/d) 3. 50 mcg 2 puffs 2xdaily (200 mcg/d) Placebo: 2xdaily Delivery device: MDI
Outcomes	Outcomes expressed as change compared to baseline: FEV1 Morning PEFR Evening PEFR Night‐time awakenings Daily wheeze score Daily cough score Daily breathlessness score Daily use of beta2 agonists Probability of remaining in study
Notes	Randomisation details confirmed by author For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning and evening PEFR, diurnal variability in PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer generated sequence
Allocation concealment?	Low risk	Off site by third party
Blinding? All outcomes	Low risk	Identical inhaler devices used

Sorkness 1999a.

Methods	Setting: Multicentre study Length of intervention period: 4 weeks Design: parallel group Excluded: not stated Withdrawals: stated (ITT)
Participants	168 adults randomised (N for treatment groups considered by the review: Placebo: 30; FP100: 27; FP500: 30); Mean age (SE): PLA: 27.9 (1.6); FP100: 27.7 (1.7); FP500: 28.2 (1.6); Gender (M/F): PLA: 26/4; FP100: 26/1; FP500: 24/6; Race (White/other %): PLA: 67/33; FP100: 81/19; FP500: 77/23; FEV1 % predicted (SE): PLA: 87 (2.5); FP100: 88 (3.1); FP500: 83 (3.9) Inclusion criteria: 18‐51 years of age; documented diagnosis of asthma (>/=6 months according to ATS criteria; FEV1 at least 50% predicted Exclusion criteria: Pregnancy or lactation; corticosteroid/immunosuppressive therapy for 3 months prior to study entry; use of 140mg prednisone or equivalent in any dosage or form in previous year; current/prior use of antiasthma medication other than beta‐agonists, theophylline or cromolyn sodium; historical or current evidence of significant concomitant disease; use of oral contraceptives or other hormonal therapy; current use of prescription or over the counter medication known to interact with corticosteroids or to cause an abnormal response to exogenous glucocorticoids or reversal of normal nocturnal sleeping hours
Interventions	FP100 versus FP500 versus Placebo. Delivery device: Rotadisk.
Outcomes	AUC; Plasma cortisol; withdrawals; adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer‐generated randomisation
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Sorkness 1999b.

Methods	Setting: Multicentre study Length of intervention period: 4 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	119 adults randomised (N for treatment groups considered by the review: PLA: 31; FP100: 29; FP250: 30); Mean age (SE): PLA: 32.1 (1.7); FP100: 31.4 (1.8); FP250: 33 (1.6); Gender (M/F): PLA: 25/6; FP100: 26/3; FP250: 26/4; Race (White/other %): PLA: 94/6; FP100: 93/7; FP250: 90/10; FEV1 % predicted (SE): PLA: 87 (2.7); FP100: 86 (2.7); FP250: 88 (3) Inclusion criteria: 18‐51 years of age; documented diagnosis of asthma (>/=6 months according to ATS criteria; FEV1 at least 50% predicted Exclusion criteria: Pregnancy or lactation; corticosteroid/immunosuppressive therapy for 3 months prior to study entry; use of 140mg prednisone or equivalent in any dosage or form in previous year; current/prior use of antiasthma medication other than beta‐agonists, theophylline or cromolyn sodium; historical or current evidence of significant concomitant disease; use of oral contraceptives or other hormonal therapy; current use of prescription or over the counter medication known to interact with corticosteroids or to cause an abnormal response to exogenous glucocorticoids or reversal of normal nocturnal sleeping hours
Interventions	FP100 versus FP500 versus Placebo. Delivery device: Rotadisk.
Outcomes	AUC; Plasma cortisol; withdrawals; adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer‐generated randomisation
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Sovijärvi 2003.

Methods	Setting: single centre study, Finland Length of intervention period: 6 weeks Design: parallel group Excluded: not stated Withdrawals: not stated
Participants	26 adults randomised. Age range: 21‐59; M/F: FP: 4/9; PLA: 7/6; Atopic asthma: FP: 9/13; PLA: 10/13; Mean duration of reversible airway obstruction (years): FP: 12.9 (0.1‐37); PLA: 8 (0.1‐33); FEV1 % pred: FP: 79.3 (70‐88); PLA: 84.3 (69‐100); am PEF: FP: 81 (64‐99); PLA: 92 (71‐112); pm PEF: FP: 83 (63‐99); PLA: 95 (72‐116); Symptoms (DAY): FP: 0.12; PLA: 0.27; Symptoms (NIGHT): FP: 0.46; PLA: 0.51. Rescue medication usage (puffs/week): FP: 3.8; PLA: 4.6 Inclusion criteria: >/=18 years; improvement by 15% in FEV1/PEF; FEV1 >/=65% predicted; 15% fall in FEV1 at a dose of </=0.6mg Exclusion criteria: Seasonal/unstable angina; RTI; exacerbation of asthma during 4 weeks prior to study entry; current smoking/cessation of smoking within year preceding study; history of pulmonary disease other than asthma; use of ICS/OCS, inhaled cromones, anti‐leux for 2 months prior to study; use of antihistamines within 2 weeks, and LABAs within 4 weeks of study entry; pregnancy or breast feeding; severe/chronic disease; alcohol or drug abuse
Interventions	FP250 BID (500) versus placebo. Inhaler device: MDI + spacer. Run‐in: 1‐2 weeks (usual asthma medication and monitoring symptoms)
Outcomes	PD15; FEV1 % predicted; PEF; Symptoms; rescue medication usage
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Identical inhaler devices used

Subburao 2005.

Methods	Setting: single centre Design: crossover study Length of intervention period: 1 week (3 week washout) Excluded: not stated Withdrawals: Stated
Participants	26 adults with mild asthma. Age range: 20‐52 Stable asthma Inclusion criteria: mild asthma (beta‐agonist less than twice weekly) Exclusion criteria: recent exacerbation
Interventions	FP200mcg BID (400mcg/d) BUD200mcg BID (400mcg/d) Placebo Inhaler device: DPI
Outcomes	EAR; LAR
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Double‐dummy design used

van Grunsven 2000.

Methods	Setting: Single centre study Design: parallel group Length of intervention period: 12 months Excluded: yes Withdrawals: stated
Participants	45 adults screened, 29 randomised (N for FP500mcg or Placebo not reported); Age range: 30‐70; 10M, 19F; FEV1 % predicted: 93 (SD 11); Pack years (mean): 7 (0‐31); PC20 histamine (mg/mL): 5.3 (SD 3.5); Reversibility FEV1 % predicted: 5 (SD 3); Symptoms: 0.6 (SD 0.9); Bronchodilators y/n: 2/27 Inclusion criteria: Bronchial hyperresponsiveness (concentration of Methcholine causing a 20% reduction in FEV1 histamine </= 8mg/mL and/or reversibility of obstruction (increase in FEV1 by 10% as percentage of FEV1 predicted after application of 800mcg inhaled salbutamol Exclusion criteria: Not reported
Interventions	FP500 or placebo via diskhaler.
Outcomes	Compliance
Notes	No outcomes of interest measured adequately in published trial report.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

van Rensen 1999.

Methods	Setting: Single centre study, Netherlands Length of intervention period: 4 weeks Design: parallel group Excluded: not stated Withdrawals: stated
Participants	25 adults randomised (FP 1500: 12; Placebo: 13); Mean age: FP 1500: 23.3 (SD 2.4); Placebo: 25.1 (SD 3.9); FEV % predicted: FP1500: 96.2 (SD 9); Placebo: 95.6 (SD 10.6); PC20: FP1500: 0.91 (SD 1.62); Placebo: 0.52 (SD 1.38); Eosinophils %: FP1500: 2.85 (SD 2.46); Placebo: 4.91 (SD 8.98); NO (ppb): FP1500: 6.30 (SD 3.34); Placebo: 7.47 (SD 4.37) Inclusion criteria: Stable (symptom free and free from RTI) for two weeks previously; Atopic disease (>3 mm weal); FEV1 % predicted >75% predicted; hyperresponsiveness to inhaled histamine
Interventions	FP 500mcg per day versus Placebo. Inhaler device: unclear
Outcomes	PC20; Sputum eosinophils; Exhaled NO
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Unclear risk	Information not available

van Schoor 2002.

Methods	Setting: Belgium, hospital outpatient clinic Length of intervention period: 2 weeks Design: crossover, one month washout Excluded: no details Withdrawals: no details Baseline characteristics: no demographic data presented
Participants	N=11. Mean FEV1: 3.2 (SEM 0.16); FEV1 % pred: 88 (SEM 3.44). Mean methacholine log2 PC20: ‐5.96 (SEM 0.2). Mean NKA (neurokronin A) log2 PC20 : ‐12.71 (SEM 0.63); Gender: 4M 11F; mean age: 27.5 years Inclusion criteria: Adults (no age threshold defined ‐ all participants recruited were over 18 years); mild to moderate asthma (NHLBI 1997 guideline definition); non‐ or ex‐smokers (</=5 pack years, and ceased smoking >/=1 year prior to study entry); females of child‐bearing required to be using reliable contraception Exclusion criteria: pregnant/lactating women.
Interventions	Inhaled FP500 BID versus PLA. Inhaler devices: Diskhaler. Study duration: 2 x 14 day treatment periods. Washout: 4 weeks. Only prn SABAs allowed as concomitant therapy.
Outcomes	FEV1; Methacholine BHR (PC20 FEV1); Neurokinin A BHR (log 10 PC20 FEV1)
Notes	Data on FEV1 presented at end of 1st arm
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Ward 2001.

Methods	Setting: single centre study, Australia Length of intervention period: Design: parallel group Excluded: stated Withdrawals: stated
Participants	35 adults enrolled, 34 randomised. Age range: 20‐70; Mean FEV1 % pred: 91.3 (SEM 3). No patients had received LABAs or ICS for at least 3 months prior to the study. 34/35 patients had not had OCS treatment in previous 12 months. 1 patient had received OCS treatment within 3 months before the study. Inclusion criteria: mild‐moderate symptomatic asthma Exclusion criteria: not reported
Interventions	Inhaled FP 1500 versus PLA. Inhaler device: MDI. Study duration: 12 months (preceded by 14‐day run in)
Outcomes	FEV1, MMFEF25‐75, withdrawals, adverse events, PD20, BAL inflammatory cell counts, membrane thickening
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer‐generated randomisation schedule
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Wasserman 1996.

Methods	Setting: Multicentre study USA, primary care and hospital outpatient clinics Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	331 adults randomised, 265 completed: 265M 66F Age range 12‐74 years Inclusion criteria: Diagnosis of asthma (ATS criteria 1987) for at least 6 months FEV1 50‐80 (% predicted) 15% or greater reversibility in FEV1 after inhaled beta2 agonist During run‐in: 12 or less puffs/day albuterol 4 or less mornings when PEFR decreased 20% or less than previous night PEFR 2 or less nights wakening requiring albuterol Good compliance Exclusion criteria: Smoking Use of any oral, inhaled or topical steroid within last month of study Oral steroids for 2 months or longer within last 6 month
Interventions	FP: 1. 50 mcg 1 actuation 2xdaily (100 mcg/d) 2. 100 mcg 1 actuation 2xdaily (200 mcg/d) 3. 250 mcg 1 actuation 2xdaily (500 mcg/d) Placebo: 1 actuation 2xdaily Delivery device: Diskhaler DPI
Outcomes	Outcomes expressed as change compared to baseline: FEV1 FVC FEF 25‐75% Morning PEFR Evening PEFR Daily asthma score Change in night time awakenings Daily use of beta2 agonist Probability of remaining in study Physician global assessment of efficacy Oro‐pharyngeal side effects
Notes	No reply from author to clarify details of randomisation method For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Wolfe 1996.

Methods	Setting: Multicentre study USA, hospital outpatient clinics Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated Baseline characteristics: comparable
Participants	304 adults: 169M 135F Age range: 12‐87 years Inclusion criteria: 12 years of age or older Diagnosis of moderate asthma, for at least 6 months Current treatment with inhaled corticosteroids and regular/as needed beta2 agonists Exclusion criteria: During run‐in period: More than 12 puffs albuterol daily for 3 or more days Diurnal variation in PEFR > 20% for 4 or more days Awakening more than 2 nights due to asthma symptoms And: Systemic steroids in last month Significant concurrent disease Pregnancy or lactation
Interventions	FP: 1. 100 mcg 2xdaily (200 mcg/d) 2. 250 mcg 2xdaily (500 mcg/d) 3. 500 mcg 2xdaily (1000 mcg/d) Placebo: 2xdaily Delivery device: MDI
Outcomes	Outcomes expressed as change compared to baseline: FEV1 Morning PEFR Evening PEFR Daily use of beta2 agonist Daily cough score Daily wheezing score Daily breathlessness score Daily asthma symptom score Probability of remaining in the study Physician related global assessment of efficacy Oro‐pharyngeal side effects Morning plasma cortisol
Notes	No reply from author to clarify details of randomisation method For continuous outcomes change scores from baseline to endpoint (i.e. point of withdrawal) were reported A priori criteria for withdrawal due to lack of efficacy were established based on FEV1, morning PEFR, night‐time awakenings or clinical exacerbation requiring emergency hospital treatment
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Described as randomised; no other information available
Allocation concealment?	Unclear risk	Information not available
Blinding? All outcomes	Low risk	Identical inhaler devices used

Wolfe 2000 ICS.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: stated Withdrawals: stated
Participants	358 adults and adolescents screened. 199 randomised; PLA: 69; FP100BID: 65; FP200QD: 65. Gender M/F (%): PLA: 58/42; FP100BID: 48/52; FP200QD: 60/40; Mean age: PLA: 36; FP100BID: 39; FP200QID: 36; FEV1 L: PLA: 2.35 (SEM 0.07); FP100BID: 2.26 (SEM 0.07); FP200QD: 2.38 (SEM 0.08); FEV1 (% predicted): PLA: 67.87 (SEM 1.17); FP100BID: 65.93 (SEM 1.19); FP200QD: 66.6 (SEM 1.02); am PEF (L/min): PLA: 408 (SEM 12); FP100BID: 396 (SEM 11); FP200QD: 421 (SEM 11); pm PEF (L/min): PLA: 426 (SEM 12); FP100BID: 411 (SEM 11); FP200QD: 438 (SEM 11); Symptoms: PLA: 2.62 (SEM 0.3); FP100BID: 2.91 (SEM 0.34); FP200QD: 2.82 (SEM 0.32); Nocturnal awakenings: 0.08 (SEM 0.02); FP100BID: 0.06 (SEM 0.01); FP200QD: 0.07 (SEM 0.02) Inclusion criteria: ICS >/=8 puffs day of BDP (42mcg/puff) or TAA (100mcg/puff) for three months; asthma stability defined as 0 days with >/= 12 puffs of SABA prn; </=4 mornings when PEF decreased by >/= 20% from previous pm's PEF; </=2 nights with awakenings caused by asthma requiring inhaled SABA; FEV1 between 50 & 80% predicted & +/‐15% screening value; adequate compliance during run‐in. Exclusion criteria: Exclusion criteria: pregnancy/lactation; use of methotrexate/gold; use inhaled cromolyn; use of oral, intranasal or parenteral steroids within 4 weeks of study start; significant concomitant illness; immunotherapy requiring change in dose within 12 weeks; concurrent use of prescription/over the counter medication that may affect course of asthma/interact with sympathomimetic amines. Use of loratadine/intranasal cromolyn for allergic rhinitis permitted if treatment started before screening visit and continued without change
Interventions	FP100BID versus FP200QD versus PLA. Inhaler device: Diskus. Run‐in period: 2 weeks (ICS dosage regimen maintained).
Outcomes	FEV1; am PEF; pm PEF; symptoms; rescue medication usage; nocturnal awakenings; withdrawals; adverse events
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double‐dummy design used

Wolfe 2000 SABA.

Methods	Setting: multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: stated Withdrawals: stated
Participants
Interventions	FP100BID (200mcg/d) versus FP200QD (200mcg/d) versus PLA. Inhaler device: Diskus. Study duration: 12 weeks, preceded by run‐in period ‐ placebo device for 2 weeks; prn SABA, SAL and XANTH continued (if SAL and XANTH used pre‐run‐in)
Outcomes	FEV1; am PEF; pm PEF; symptoms; rescue medication usage; nocturnal awakenings; withdrawals; adverse events
Notes	Additional data sourced from www.clinicalstudyresults.org
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double‐dummy design used

ZuWallack 2000.

Methods	Setting: Multicentre study, USA Length of intervention period: 12 weeks Design: parallel group Excluded: not stated Withdrawals: stated (ITT)
Participants	253 adults and adolescents randomised; Gender: M:F (%): FP500: 51:49; FP1000: 59:41; PLA: 58:42; Age range: 12‐69; FEV1 (L)*: FP500: 2.44 (SEM: 0.07); FP1000: 2.51 (SEM 0.08); PLA: 2.46 (SEM 0.06); FEV1 (% predicted): FP500: 68 (SEM: 0.9); FP1000: 66 (SEM 1); PLA: 67 (SEM 1); am PEF (L/min)*: FP500: 410 (SEM 9); FP1000: 402 (SEM 10); PLA: 418 (SEM 11); pm PEF (L/min)*: FP500: 434 (SEM 10); FP1000: 429 (SEM 10); PLA: 441 (SEM 11); Asthma symptom scores*: FP500: 1.13 (SEM 0.05); FP1000: 1.06 (SEM 0.06); PLA: 1.08 (SEM 0.07); ß‐2 agonist use (puffs/d)*: FP500: 2.82 (SEM 0.24); FP1000 2.67 (SEM 0.27) ; PLA: 3.04 (SEM 0.28); Nighttime awakenings/night*: FP500: 0.08 (SEM 0.02); FP1000: 0.11 (SEM 0.02); PLA 0.15 (0.02) *denotes efficacy population Inclusion criteria: Chronic asthma (ATS diagnosis); requirement of daily pharmacotherapy over 6 mo prior to study; FEV1 50‐80% predicted; >/= 15% increase in FEV1 <15 minutes after 2 puffs of ß‐2 agonist OR documented >/=15% variation in FEV1 within 6 mo prior to study. Open label extension: Participants completing DB phase eligible Exclusion criteria: History of life‐threatening asthma or other severe chronic disease; use of oral/intranasal/parenteral steroids; inhaled nedocromil or cromolyn sodium within 1 mo prior to start of study; ise of methotrexate/gold salts, any prescription/over the counter medication which could affect course of asthma; participation in previous study with Diskus device
Interventions	Inhaled FP 250mcg versus FP 500mcg versus placebo BID. Identical inhaler devices used (Diskus powder inhaler). Participants in FP500mcg given placebo inhaler for pm dose. Double‐blind phase duration: 12 weeks
Outcomes	Lung function (FEV1, PEF); Probability of remaining in study; Symptoms; Medication use; Safety; HPA axis function
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	See Appendix 2
Allocation concealment?	Low risk	See Appendix 2
Blinding? All outcomes	Low risk	Double‐dummy design used

ACTH: adrenocorticotropic hormone; ATS: American Thoracic Society; BAL: bronchoalveolar lavage; BDP: beclomethasone dipropionate; BID: twice daily; BHR: bronchial hyperresponsiveness; BUD: budesonide; DPI: dry powder inhaler; ECP: eosinophil cationic protein; EDN: eosinophil derived neurotoxin; FEF25‐75: forced expiratory flow at 25 to 75% of FVC; FEV1: forced expired volume in one second; FP: fluticasone propionate; FVC: forced vital capacity; HPA: hypothalamo‐pituitary‐adrenal; ICAM‐1: intercellular adhesion molecule‐1; ICS: inhaled corticosteroid; ITT: intension‐to‐treat; mcg/d: micrograms per day; MDI: metered dose inhaler; PD15 FEV1: provocative dose of inhalant required to produce a 15% fall in FEV1; PC20 FEV1: provocative concentration of inhalant required to produce a 20% fall in FEV1; PD20 FEV1: provocative dose of inhalant required to produce a 20% fall in FEV1; PEFR: peak expiratory flow rate; TA: triamcinolone acetonide

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Acuna 2001	Randomised study of the acute effects of inhalation of FP in mild asthmatics
Baitinger 2002	Comparison with combination product
Bisgaard 1999	This study assessed a group of young children including infants under the age of two years
Chervinsky 2001	Comparison between FP and LTRA
Cirule 2002	No clear diagnosis of asthma
Dal Negro 2001	FP as additional treatment to SAL
de Benedictis 2001	Comparison between FP and BDP
den Otter 2007	Administration of fluticasone to people without asthma or COPD
Dente 2001	No PLA control
Efthimiou 1998	Nebuliser delivery device
Eliraz 2002	Comparison with combination product
Falcoz 2000a	Wrong comparison (FP versus FP via different inhalers)
Faul 2002	Comparison between FP and LTRA
Fletcher 1999	Nebuliser delivery device
Fowler 2002	Comparison between different propellants
Harrison 2001	Comparison between FP and BDP
Kanniess 2001	Comparison between FP and LTRA
Kelly 2001	Not randomised
Lee 2002	Comparison with TAA
Leibman 2002	Comparison between SAL and LTRA as add on to FP
Lipworth 1997	Crossover study with intervention periods of only 4 days
Lujik 2004	Study of inadequate duration
Majer‐Teboul 2001	Comparison with BDP
Moore 1998	Wrong outcomes assessed
Overbeek 2002	Compaison with LTRA
Pao 2002	Participants had wheeze and not asthma
Srebro 1998	Wrong comparison
Su 2006	Treatments not given in random order
Szefler 2005	Study conducted in participants admitted as in patients.
Teper 1998	Study assesses infants
Wilson 1997	Placebo was not a randomised intervention
Wilson 1998a	Crossover design study with intervention periods of 4 days
Wilson 1998b	Placebo was not a randomised intervention
Wong 1997	Infant age group Assessing the effects of fluticasone in infants discharged from hospital following recent acute bronchiolitis

FP: fluticasone; SAL: salmeterol; BUD: budesonide; F: formoterol; TAA: triamcinolone; LTRA: anti‐leukotriene agent; PLA: placebo

Differences between protocol and review

No primary outcome was specified in the protocol, so FEV1 has been chosen as the primary outcome for this update (post hoc). We have decided against pooling lung function data expressed as absolutes (i.e. L/sec and L/min) for adults and children, in view of their different lung volumes. This is likely to affect the size of the effect for these subgroups, without providing valuable clinical information on differences between them. We have decided to retain pooled estimates for data expressed as % predicted, since this allows for the different lung volumes in both adults and children.

Contributions of authors

Nick Adams retrieved papers identified by electronic search, handsearched additional sources for relevant trials, assessed trials for methodological quality, contacted authors to clarify details of trial design and/or request missing data, extracted data from included trials and wrote text of review.

Janine Bestall retrieved papers identified by search, assessed trials for methodological quality, contacted authors for clarification or trial details and/or request missing data.

Toby Lasserson assessed trials for inclusion in the update of the review, contacted trialists, extracted and entered data and wrote‐up the findings.

Paul Jones provided guidance for the overall review and editorial support .

Chris Cates provided direction for reporting of results and discussion.

Sources of support

Internal sources

• NHS Research and Development, UK.

• Nederlands Astma Fonds, Netherlands.

External sources

• No sources of support supplied

Declarations of interest

None known.

Edited (no change to conclusions)