Cochrane Chronic Asthma Review (text extract)

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Cochrane Review

Published in:

The Cochrane Database of Systematic Reviews

2002, Issue 1

Outline

Fluticasone versus beclomethasone or budesonide for chronic asthma..............................................1 ABSTRACT ..........................................................................................................................................1 BACKGROUND...................................................................................................................................2 OBJECTIVES......................................................................................................................................3 CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW.......................................................3 SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES .............................................................3 METHODS OF THE REVIEW.............................................................................................................4 DESCRIPTION OF STUDIES ..............................................................................................................5 METHODOLOGICAL QUALITY..........................................................................................................8 RESULTS............................................................................................................................................8 DISCUSSION....................................................................................................................................17 REVIEWER'S CONCLUSIONS.........................................................................................................21 ACKNOWLEDGEMENTS..................................................................................................................22 POTENTIAL CONFLICT OF INTEREST...........................................................................................22 TABLES.............................................................................................................................................22 Characteristics of included studies........................................................................................22 Characteristics of excluded studies.......................................................................................57 Table 01 Outcome data not included in the meta−analysis...................................................58 Table 02 Delivery devices used.............................................................................................60 Table 03 Approximation of asthma severity...........................................................................61 REFERENCES..................................................................................................................................65 GRAPHS ............................................................................................................................................72 COVER SHEET.................................................................................................................................78 SOURCES OF SUPPORT .................................................................................................................80 SYNOPSIS........................................................................................................................................80 GRAPHS AND OTHER TABLES .......................................................................................................80 Fig. 01 FP v BDP or BUD, parallel group studies: dose ratio 1:2..........................................81 01.01 FEV1 (% predicted)..........................................................................................81 01.02 FEV1 (litres).....................................................................................................81 01.03 Change in FEV1 (litres) compared to baseline................................................81 01.04 Change in FVC (litres) compared to baseline..................................................82 01.05 Morning PEFR (L/min).....................................................................................82 01.06 Change in morning PEFR (L/min) compared to baseline .................................82 01.07 Evening PEFR (L/min).....................................................................................83 01.08 Change in evening PEFR (L/min) compared to baseline.................................83 01.09 Daily PEFR (% predicted)................................................................................83 01.10 Clinic PEFR (L/min) .........................................................................................84 . 01.11 Change in FEF 25−75 (L/second) compared to baseline .................................84 01.12 Change in daily asthma symptom score compared to baseline.......................84 01.13 Change in percentage of symptom free days compared to baseline...............85 01.14 Percentage of symptom free days...................................................................85 01.15 Change in daily use of rescue beta2 agonist (puffs/day) compared to baseline.....................................................................................................................85 01.16 Change in percentage of days with no rescue beta2 agonist requirement compared to baseline................................................................................................86 01.17 No change or reduction in daytime rescue beta2 agonist use (% of patients)....................................................................................................................86 01.18 Withdrawal due to asthma exacerbation (No. of patients)...............................86 i

Outline

01.19 One or more exacerbations (No. of patients)...................................................87 01.20 Sore throat/pharyngitis (No. of patients)..........................................................87 01.21 Hoarseness (No. of patients)...........................................................................87 01.22 Oropharyngeal Candidiasis (No. of patients)...................................................88 01.23 Morning plasma cortisol (nmol/L).....................................................................88 Fig. 02 FP v BDP or BUD, crossover studies: dose ratio 1:2 .................................................89 02.01 FEV1 (% predicted)..........................................................................................89 02.02 FEV1 (litres).....................................................................................................89 02.03 FVC (% predicted) ...........................................................................................89 . 02.04 Morning PEFR (L/min).....................................................................................90 02.05 Evening PEFR (L/min).....................................................................................90 02.06 Daytime breathlessness score.........................................................................90 02.07 Night−time breathlessness score.....................................................................91 02.08 Percentage of symptom free days...................................................................91 02.09 Percentage of symptom free nights.................................................................91 02.10 One or more night−time awaking due to asthma symptoms (No. of patients)....................................................................................................................92 02.11 Symptoms on wakening in the morning (No. of patients) ................................92 . 02.12 Percentage of rescue beta2 agonist free days (No. of patients)......................92 02.13 Morning plasma cortisol (nmol/L).....................................................................93 02.14 Plasma cortisol 30 min post 25U cosyntropin (nmol/L)....................................93 02.15 24 hour urinary free cortisol (nmol/L)...............................................................93 Fig. 03 FP v BDP or BUD, parallel studies: dose ratio 1:1 .....................................................94 03.01 FEV1 (% predicted)..........................................................................................94 03.02 FEV1 (litres).....................................................................................................94 03.03 FVC (litres).......................................................................................................94 03.04 Morning PEFR (L/min).....................................................................................95 03.05 Evening PEFR (L/min).....................................................................................95 03.06 Change in morning PEFR compared to baseline (L/min) ................................95 . 03.07 Change in evening PEFR compared to baseline (L/min).................................96 03.08 Clinic PEFR (L/min) .........................................................................................96 . 03.09 Daytime asthma symptom score......................................................................96 03.10 Night−time asthma symptom score ..................................................................97 03.11 Percentage of symptom free days...................................................................97 03.12 Percentage of symptom free days (No. of patients).........................................97 03.13 Percentage of symptom free nights (No. of patients).......................................98 03.14 Daytime rescue beta2 agonist use (puffs/daytime)..........................................98 03.15 Night−time rescue beta2 agonist use (puffs/night) ...........................................98 03.16 Percentage of rescue beta2 agonist free days (No. of patients)......................99 03.17 Withdrawal due to asthma exacerbation (No. of patients)...............................99 03.18 Requirement for one or more courses of oral steroid for asthma exacerbation (No. of patients)...................................................................................99 03.19 Sore throat (No. of patients)...........................................................................100 03.20 Hoarseness (No. of patients).........................................................................100 03.21 Oropharyngeal Candidiasis (No. of patients).................................................100 03.22 Change in morning plasma cortisol (nmol/L) compared to baseline..............101 Fig. 04 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by drug...........101 04.01 FEV1 (litres)...................................................................................................101 ii

Outline

04.02 Morning PEFR (L/min)...................................................................................102 04.03 Change in morning PEFR (L/min) compared to baseline ...............................102 04.04 Evening PEFR (L/min)...................................................................................103 04.05 Withdrawal due to asthma exacerbation (No. of patients).............................103 04.06 Sore throat/pharyngitis (No. of patients)........................................................104 04.07 Hoarseness (No. of patients).........................................................................104 04.08 Oropharyngeal Candidiasis (No. of patients).................................................105 Fig. 05 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by age .............105 05.01 FEV1 (litres)...................................................................................................105 05.02 Morning PEFR (L/min)...................................................................................106 05.03 Change in morning PEFR (L/min) compared to baseline ...............................106 05.04 Evening PEFR (L/min)...................................................................................107 05.05 Withdrawal due to asthma exacerbation (No. of patients).............................107 05.06 Sore throat/pharyngitis (No. of patients)........................................................108 05.07 Hoarseness (No. of patients).........................................................................108 05.08 Oropharyngeal Candidiasis (No. of patients).................................................109 Fig. 06 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by dose range...................................................................................................................................109 06.01 FEV1 (litres)...................................................................................................109 06.02 Morning PEFR (L/min)...................................................................................111 06.03 Change in morning PEFR (L/min) compared to baseline ...............................112 06.04 Evening PEFR (L/min)...................................................................................113 06.05 Withdrawal due to asthma exacerbation (No. of patients).............................114 06.06 Sore throat/pharyngitis (No. of patients)........................................................115 06.07 Oropharyngeal Candidiasis (No. of patients).................................................116 06.08 Hoarseness (No. of patients).........................................................................117 Fig. 07 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by asthma severity ................................................................................................................................118 07.01 FEV1 (litres)...................................................................................................118 07.02 Morning PEFR (L/min)...................................................................................119 07.03 Change in morning PEFR (L/min) compared to baseline ...............................119 07.04 Evening PEFR (L/min)...................................................................................120 07.05 Withdrawal due to asthma exacerbation (No. of patients).............................121 07.06 Sore throat/pharyngitis (No. of patients)........................................................123 07.07 Hoarseness (No. of patients).........................................................................124 07.08 Oropharyngeal Candidiasis (No. of patients).................................................125 Fig. 08 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by delivery device ..................................................................................................................................126 08.01 FEV1 (litres)...................................................................................................126 08.02 Morning PEFR (L/min)...................................................................................126 08.03 Change in morning PEFR (L/min) compared to baseline ...............................127 08.04 Evening PEFR (L/min)...................................................................................127 08.05 Withdrawal due to asthma exacerbation (No. of patients).............................128 08.06 Sore throat/pharyngitis (No. of patients)........................................................128 08.07 Hoarseness (No. of patients).........................................................................129 08.08 Oropharyngeal Candidiasis (No. of patients).................................................129

iii

Fluticasone versus beclomethasone or budesonide for chronic asthma

Adams N, Bestall JM, Jones PW

Date of most recent update: 15 November 2001 Date of most recent substantive update: 22 February 2000 This review should be cited as: Adams N, Bestall JM, Jones PW. Fluticasone versus beclomethasone or budesonide for chronic asthma (Cochrane Review). In: The Cochrane Library, Issue 1, 2002. Oxford: Update Software.

ABSTRACT Background Beclomethasone dipropionate (BDP) and budesonide (BUD) are commonly prescribed inhaled corticosteroids for the treatment of asthma, Fluticasone propionate (FP) is newer agent with greater potency in in−vitro assays. Objectives To compare the efficacy and safety of Fluticasone to Beclomethasone or Budesonide in the treatment of chronic asthma. Search Strategy We searched the Cochrane Airways Group Trial Register (1999) and reference lists of articles. We contacted trialists and pharmaceutical companies for additional studies and searched abstracts of major respiratory society meetings (1997−1999). Selection Criteria Randomised trials in children and adults comparing Fluticasone to either Beclomethasone or Budesonide in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality. Data collection and analysis One reviewer extracted data. Quantitative analyses where undertaken using Review Manager 4.0.3 with Metaview 3.1. Main Results 42 studies (>10,000 patients) met the inclusion criteria. Methodological quality was variable. When compared at a FP:BUD/BDP dose ratio of 1:2, fluticasone produced a significantly greater FEV1 (Weighted Mean Difference (WMD) 0.11 litres, 95% Confidence Interval (CI) 0.01, 0.20 litres), morning PEF (WMD 13 L/min, 95%CI 5, 22 L/min) and evening PEF (WMD 11 L/min, 95%CI 1, 20 L/min). This applied to all drug doses, age groups, and delivery devices, although subgroup analyses suggested that the relative benefit of FP may be greater in more severe patients treated with higher doses of inhaled corticosteroid. No difference between fluticasone and beclomethasone or budesonide were seen for trial withdrawals (Peto OR 0.77, 95%CI 0.54, 1.10). Symptoms and rescue medication use were widely reported but few trials provided sufficient data for analysis. A higher likelihood of pharyngitis (Peto Odds Ratio 2.16; 95% CI 1.42, 3.28) was apparent when patients were treated with fluticasone at twice the dose of BDP/BUD, although was unexplained heterogeneity in this effect between trials. There was no difference in the likelihood of oral Candidiasis. Plasma cortisol and 24 hour urinary cortisol were measured frequently but data presentation was limited. Reviewers' conclusions Fluticasone given at half the daily dose of beclomethasone or budesonide leads to small improvements in measures of airway calibre, but it appears to have a higher risk of causing

side−effects when given at the same daily dose . This review should be cited as: Adams N, Bestall JM, Jones PW. Fluticasone versus beclomethasone or budesonide for chronic asthma (Cochrane Review). In: The Cochrane Library, Issue 1, 2002. Oxford: Update Software.

BACKGROUND

Inhaled corticosteroids (ICS) have become the mainstay of therapy for chronic asthma, and are recommended for use in recent guidelines for all patients except those with mild, intermittent symptoms (BTS 1997, GINA 1995, NHLBI 1997). Fluticasone propionate (FP) is the most recently licensed ICS for the treatment of asthma in children and adults, and joins a stable of older agents including beclomethasone dipropionate (BDP) and budesonide (BUD). With an expanding range of drugs to choose from it is important to establish their relative efficacy and safety. All ICS's share close chemical and structural similarities. However, pharmacodynamic differences could lead to differences in their clinical effects. Potency, a measure of the microgram dose of drug required to produce a standard response, is greater for FP than either BDP or BUD. When assessed in the in−vitro skin blanching test FP is twice as potent as BDP (Phillipps 1990), and 25% more potent than BUD (Kelly 1998). Similar rank order potencies have been shown for other assays of anti−inflammatory activity including inhibition of basophil histamine release, eosinophil viability and expression of vascular cell adhesion molecule−1 in cultured bronchial epithelial cells (Stellato 1999). FP also exhibits considerably greater glucocorticoid receptor (GR) binding affinity when compared to BDP and BUD (Kelly 1998). These factors could lead to greater clinical potency of FP, i.e. a lower microgram dose required to produce equal or better asthma control compared to BDP or BUD due action at sites in the lung. However, potential advantages in this respect are only important if they are not achieved at the expense of increased systemic drug activity. Increased potency at active sites in the lung may be offset when FP becomes systemically available. Higher potency at the site of the pulmonary GR will be mirrored by higher potency at the site of systemic GR's. This factor, associated with the longer elimination half life (Thorsson 1997) and higher lipophilicity (Kelly 1998) of FP compared to the older inhaled steroids should lead to longer tissue retention times, and could lead to enhanced endogenous glucocorticoid suppression and increased exogenous steroid related side effects. Single dose and repeated dose short term studies (<1 week) have shown that FP leads to significantly greater reductions in morning plasma cortisol and overnight urinary cortisol excretion when compared to BUD at equal nominal daily dose (Clark 1996a, Clark 1996b, Clark 1997, Lipworth 1997). A previous systematic review has assessed the relative efficacy of FP versus BDP and BUD (Barnes 1998). However, this review has a number of weaknesses including the lack of a well−documented search strategy, clearly defined inclusion criteria or an assessment of methodological quality. In addition, a number of trials have become available since this review was published. Relative efficacy/side effect ratios need to be considered when the performance of ICS's is compared in clinical practice. The objectives of this review will be to compare efficacy and safety outcomes in studies that have compared FP to either BDP or BUD in the treatment of chronic asthma.

OBJECTIVES

To compare the efficacy and safety of FP to BDP or BUD in the treatment of chronic asthma.

CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW Types of studies Only prospective, randomised controlled trials were considered. Parallel group and crossover studies were eligible, in both children and adults. Studies assessing infants (under the age of two years) were excluded. A diagnosis of chronic asthma was necessary. Studies concerned with the treatment of acute asthma exacerbations were not considered. Studies could be in primary care, hospital outpatient or an institutional care setting. Types of participants Studies in children and/or adults were reviewed. Studies assessing infants (i.e. under the age of two years) were excluded. Patients needed to have a diagnosis of chronic asthma, studies concerning acute asthma were not considered. Studies conducted in primary care, hospital outpatient and institutional care were considered. Types of intervention FP delivered by mouth inhalation versus either BDP or BUD. Any dose of FP compared to any dose of either BDP or BUD was considered, but the nominal daily dose of each inhaled steroid had to be stated. Nominal daily dose was calculated as the actuator dose multiplied by the number of doses administered per day. Treatment periods had to be one week or longer. Delivery devices allowed including metered dose inhalers (MDI) with or without spacer/chamber and dry powder inhalers (DPI's). Trials using nebulisers were specifically excluded. Types of outcome measures All reported outcomes were considered. Outcomes identified a priori as important were as follows: 1. Measures of airway calibre: FEV1, diary and clinic PEF, diurnal PEF 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 lost from work/school 6. Safety assessment: hypothalamo−pituitary adrenal (HPA) function markers (plasma and urinary cortisol measures), oropharyngeal side effects, skin bruising

SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES See: Cochrane Airways Group search strategy Electronically Indexed Sources 1. An electronic Inhaled Steroid Register (ISR) was created by searching the Cochrane Airways Group Trials Register (1999) using the following terms: steroid* OR glucocorticoid* OR corticosteroid* OR beclomethasone OR budesonide OR fluticasone OR triamcinolone OR flunisolide OR Becotide OR Becloforte OR Pulmicort OR Flixotide

Abstracts of citations found from this search were imported into an electronic database to form the ISR. 2. Secondary searches of the ISR were undertaken using three separate sets of search terms: 1. Fluticasone OR Flixotide 2. Beclomethasone OR Becotide OR Becloforte 3. Budesonide OR Pulmicort The electronic abstracts of studies identified by these searches were imported into new databases to form three new registers termed the Fluticasone Register, the Beclomethasone Register and the Budesonide Register respectively. Each register was hand−searched for RCTs meeting the inclusion criteria. Studies were excluded if it was clear from the abstract that it was a) not concerned with asthma in humans, b) not an RCT c) did not include a treatment arm with inhaled corticosteroids. Where uncertainty existed the study was retrieved in full text form. There were no language restrictions to the search. 2. Other sources a) Reference lists of all included studies and relevant narrative reviews were searched for additional RCTs. b) The UK headquarters of Glaxo Wellcome (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 c) Authors of studies were asked if they were aware of further missed trials. d) The British Journal of Clinical Research and the European Journal of Clinical Research (journals not electronically indexed on Medline or EMBASE) were hand−searched. e) Proceedings of the British Thoracic Society (1997/1998), European Respiratory Society (1997−1999) and the American Thoracic Society (1997−1999) were searched for relevant trials.

METHODS OF THE REVIEW

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 and likely to be included were assessed by independently by the same reviewers, disagreement regarding eligibility was resolved by consensus. Included studies were assessed for methodological quality independently by two reviewers (NPA and JB) who were blinded to authors names, institution and funding sources. The studies were scored using two measures. Firstly according to the Cochrane approach: Grade A: adequate allocation concealment Grade B: unclear allocation concealment Grade C: clearly inadequate concealment Secondly, using a five point scoring instrument developed by Jadad 1996: a) Was the study described as randomised? (yes=1 no=0) b) Was the study described as double blind? (yes=1 no=0) c) Was there a description of withdrawals and dropouts? (yes=1 no=0) d) Was the method of randomisation well described and appropriate? (yes=1 no=0) e) Was the method of double blinding well described and appropriate? (yes=1 no=0) Deduct 1 point if method of randomisation or blinding inappropriate Inter−rater agreement was measured using the kappa statistic. Disagreement was resolved by consensus.

Data extraction One reviewer (NPA) 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. Data were extracted from graphical plots when presented in this form; attempt was made to verify such data by contacting authors. It should be noted that continuous outcome data are displayed using negative figures as the sign convention built into the software interprets smaller numbers as favourable (as is the case for dichotomous outcomes such as asthma exacerbation rates). This ensures that results favouring FP are consistently displayed to the left of the zero effect line in Metaview and results favouring BDP/BUD are consistently displayed to the right. Authors were written to (by mail, fax and/or electronic mail) to request absent or incompletely reported outcome data. Attempt was made to send requests to correct current addresses by searching MEDLINE, EMBASE and hospital World Wide Web (WWW) sites for up−to−date contact details. Data analysis A weighted treatment effect across trials was calculated using the Cochrane statistical package Revman 4.0.3 with Metaview 3.1. For continuous outcomes, a weighted mean difference (WMD) or standardised mean difference (SMD) was calculated as appropriate. For dichotomous outcomes Peto Odds Ratio's (OR) were calculated. Pooled treatments effects are expressed with their 95% confidence intervals (95% CI). A fixed effect model was used throughout. A number of a priori conditions were established regarding the comparisons made: 1. Studies were distinguished as those in which patients were a) not treated with regular oral corticosteroid (OCS), b) dependent upon regular OCS treatment prior to study. Trials involving OCS−dependent patients in which the efficacy of ICS are being assessed may have an 'OCS down−titration' design using reduction in the use of oral steroid as an outcome measure, whilst maintaining a given level of asthma control. However, studies in which patients were not treated with regular OCS are more likely to have a design aimed at detecting improvements in asthma control. It is inappropriate to combine trials with these different designs and objectives. 2. The results of parallel and crossover trials were not pooled. 3. Studies comparing FP versus BDP or BUD at a nominal daily dose ratio of 1:2 were not pooled with those making comparisons at equal nominal daily dose. Heterogeneity of effect size across pooled studies was calculated using a chi square test, with p< 0.05 used as the cut−off level for significance. Sensitivity analyses were planned based on methodological quality, as were subgroup analyses based upon the particular inhaled corticosteroid that was being ICS compared with FP (i.e. BDP or BUD), patient age (children or adult), delivery device (identical or different devices used for FP and BDP/BUD) and asthma severity.

DESCRIPTION OF STUDIES

57 publications were selected for inclusion in the review, consisting of 42 unique trials. One study published in Polish (Chlumsky 1998) requires translation and is awaiting assessment. We would like to draw the reader's attention to the additional eight citations listed under Studies awaiting assessment. Due to unforeseen delays in the publication of this review, a number of potentially relevant trials have been identified after an updated search of the electronic sources from April 1999 − August 2001. These studies will be fully evaluated and included as appropriate in a future update at the earliest possible

opportunity. Populations 26 trials (62%) were multi centre studies. These were conducted largely in Europe (Belgium, Denmark, Greece, Hungary, Italy, Norway, The Netherlands, UK). In nine of these studies, patients were also recruited from other areas of the world (Australia, Canada, Indonesia, South Africa and New Zealand). Two multi centre studies (Murray 1998, Raphael 1999a) were conducted in the USA, one (Berend 1997) in Australia. All single centre studies were conducted in either Australia, Canada or countries of Europe. Four studies recruited patients exclusively from primary care in the UK (Basran 1997, Connolly 1995, Langdon 1994a, Langdon 1994b); Rao 1999 recruited patients from both primary and secondary care. All other studies were conducted in a secondary care/hospital outpatient clinic setting. 14 studies (33%) were in children; all remaining studies were conducted in adolescents and adults. Study Design 31 studies (74%) employed a parallel group design, 11 studies (27%) were of crossover design. Only four crossover studies (Agertoft 1997b, Bootsma 1995, Ringdal 1998, Wolthers 1997) employed an inhaled steroid−free washout period between treatment periods. Eight studies (20%) had treatment periods of a month or less, 26 studies (63%) had treatment periods of between 6 weeks to 5 months, Two studies (Berend 1997, Pauwels 1998) has a treatment periods of six months, whilst six studies (de Benedictis 1998, Fabbri 1993, Hughes 1999b, Lorentzen 1996, Lundback 1998, Rao 1999) has treatment periods of 12 month or longer. Interventions In 20 studies (48%), patients were randomised to receive FP or BDP. In 21 studies (51%) patients received FP or BUD. In a single study (Berend 1997) patients were randomised to two parallel treatment arms: either FP, or BDP/BUD (depending on which ICS they had been receiving prior to randomisation). In the majority of studies, patients received the ICS to which they had been randomised, at a constant dose throughout the treatment period. In 30 studies (73%) patients were randomised to receive FP and either BDP or BUD in a nominal daily dose ratio of 1:2. In 11 studies (26%) FP and BDP or BUD were administered at an equal nominal daily dose ratio i.e. 1:1. Agertoft 1997a used a dose down−titration design. Patients were randomised to either FP or BUD. Over the course of the treatment period, the ICS dose was down−titrated to the minimum required to maintain asthma control at a pre−defined level. The main outcome measures in this study were the number of dose reduction steps and the minimal daily dose of ICS required to maintain acceptable control. Delivery device A tabulated summary of the devices used in each study in provided in Table 02. Aerosol metered dose inhalers (MDIs) and a variety of dry powder inhalers (DPIs) were used. In 18 studies (43%), the same delivery device was used for both FP and BDP/BUD treatment groups. This was mainly the case in studies that compared FP to BDP (14 studies). In only two studies of the that compared FP to BUD was the same delivery device used for both treatment arms (Langdon 1994b, Hughes 1999b). In the remainder of studies where the delivery device was stated, different devices were used for each ICS treatment arm. In the majority of studies that compared FP to BUD, FP treated patients used either the Diskhaler or Accuhaler DPI whilst BUD was administered using the Turbohaler/Turbuhaler DPI. In four studies (Ayres 1995, Fabbri 1993, Leblanc 1994, Pauwels 1998) all patients received treatment using a metered dose inhaler, but were given the option of using a large volume spacer, provided use

remained constant throughout the study. In five studies (Bisca 1997, Dal Negro 1997, Hughes 1999a, Johansson 1998, Murray 1998), the delivery device used was not stated. All of these studies were published in abstract form only and methodological details were limited.

Prior treatment with corticosteroids A single study (Lundback 1993) recruited oral steroid dependent asthmatics with the objective of assessing the relative prednisolone sparing effect of FP and BUD. One study (Ayres 1995) recruited severe asthmatics, a proportion of whom were receiving maintenance oral corticosteroids at the time of enrolment, but no attempt was made to taper prednisolone use during the trial. In all other studies, the patients were not receiving regular oral corticosteroids at the time of enrolment; indeed this was usually a specific exclusion criterion. In the majority of these studies (74%) however, some or all patients were using a regular inhaled corticosteroid at enrolment (see Table 03). In all cases, this was stopped at the point of randomisation when study medications were started. Asthma severity A summary of studies according to baseline FEV1 (% predicted), symptom frequency and prior use of oral/inhaled corticosteroids is given in Table 03. Using these features, along with the investigator's opinion an overall approximation of severity has been made for each study based on current GINA 1995/NHLBI 1997 criteria. This is summarised as follows Mild: 5 studies Agertoft 1997b, Connolly 1995, Dal Negro 1997, Hughes 1999a, Wolthers 1997 Mild to moderate: 8 studies Basran 1997, Hoekx 1996, Johansson 1998, Kemmerich 1999, Langdon 1994a, Langdon 1994b, Leblanc 1994, Williams 1997 Moderate: 8 studies Agertoft 1997a, Dahl 1993, Gustafsson 1993, Lundback 1993, Melaranci 1999, Murray 1998, Rao 1999, Steinmetz 1997 Moderate to severe: 12 studies Ayres 1995, Bisca 1997, Boe 1994, Bootsma 1995, Fabbri 1993, Ferguson 1999, Joubert 1998, Malo 1999, Pauwels 1998, Pickering 1996, Ringdal 1996, Ringdal 1998 Severe: 6 studies Barnes 1993, Berend 1997, Fitzgerald 1998, Lorentzen 1996, Lundback 1998, Yiallouros 1997 Mild to severe: 1 study Raphael 1999a/Raphael 1999b Unclear: 1 study de Benedictis 1998 Outcomes assessed A wide range of outcome measures was reported. All have been considered, except the following that were specified a priori as not being within the scope this review. These included growth assessment (Agertoft 1997b, Ferguson 1999, Wolthers 1997); biochemical markers of bone turnover (Ayres 1995, Berend 1997, Bootsma 1995, Hoekx 1996, Malo 1999, Pauwels 1998, Wolthers 1997); bone densitometry (Pauwels 1998, Rao 1999). A significant amount of data reported by trials could not be included in the meta−analysis, because it was not presented in a suitable form. This is listed in Table 01. Authors were asked for this data, but were either unable or unwilling to so. One study (Bootsma 1995) reported the effects of treatment on peripheral blood cell immunophenotype profiles. This outcome has not been considered, as inflammatory cell profiles are not a recognised clinical efficacy measure at the current time.

METHODOLOGICAL QUALITY

All studies were randomised, 27 were described as double blind. 17 studies clearly employed allocation concealment, in the majority of cases this information was only available after contact with the pharmaceutical company sponsors (Glaxo Wellcome), or authors (Bootsma 1995, Rao 1999). Methodological quality, as assessed by the Jadad scoring system, was variable. Three studies achieved a score of five (high quality), 11 studies a score of four (good quality), 12 studies a score of three (fair quality). 16 studies were scored poorly, only achieving a Jadad score of one or two. It should be noted however that 14 of these studies were published as abstracts from respiratory society meetings. Limited details concerning patients enrolled and trial methods were available. It is likely therefore that these scores are an underestimation of the true methodological quality. Requests were made to authors for further information, but this was unsuccessful in all cases.

RESULTS

Search summary for FP v BDP/BUD

1. Initial electronic search: 6494 citations retrieved, 2162 unique citations FP Register BDP Register BUD Register Total citations 258 1149 1036 Studies excluded on abstract: Not RCT 150 379 331 Not chronic asthma in humans 30 190 195 No inhaled corticosteroid arm 187 129 Not assessing FP v BDP or BUD 118 40 Studies retrieved in full text 78 290 341 Excluded on full paper: Not RCT 6 89 46 Not assessing FP v BDP or BUD 47 166 268 Device comparison 1 20 10 Dose scheduling comparison 2 6 Treatment period < 1 week 5 5 Included 19 13 (FP v BDP) 6 (FP v BUD) The 19 trials identified from the FP Register were an identical set to the 13 studies from the BDP Register and the 6 studies from the BUD Register. In other words a total of 19 unique trials were included as a result of searching all three Registers.

2. Other sources Thirteen studies (Berend 1997, Bisca 1997, Dal Negro 1997, de Benedictis 1998, Hughes 1999a, Johansson 1998, Joubert 1998, Kemmerich 1999, Lundback 1998, Melaranci 1999, Murray 1998, Ringdal

1998, Steinmetz 1997) were identified as a result of searching respiratory society meeting proceedings. Four studies (Basran 1997, Connolly 1995, Langdon 1994a, Langdon 1994b) were identified as a result of hand−searching the British Journal of Clinical Research and the European Journal of Clinical Research. Six studies (Ferguson 1999, Hughes 1999b, Malo 1999, Pickering 1996, Raphael 1999a/Raphael 1999b, Rao 1999) were identified by Glaxo Wellcome. The majority of these studies were published after the date of the final electronic search. A total of 42 studies were therefore included. Agreement between the two independent assessments of study quality were as follows: Randomised? kappa=1 Double blind? kappa=0.9 Description of withdrawals kappa=0.7 Method of randomisation kappa=0.4 Method of double blinding kappa=0.9

A structured approach has been used to report results. Studies were initially categorised based on the following features: a) Oral corticosteroid use b) Study design (parallel group or crossover) c) Nominal daily dose ratios used in comparisons of FP to BDP or BUD (1:1 or 1:2 respectively) Categorisation of studies based on these features resulted in the generation of five main comparison groups: Group 1. Parallel group studies in non−OCS treated asthmatics, comparing FP to BDP/BUD at a 1:2 nominal daily dose ratio. Group 2. Crossover studies in non−OCS treated asthmatics, comparing FP to BDP/ BUD at a 1:1 nominal daily dose ratio. Group 3. Parallel group studies in non−OCS treated patients comparing FP to BDP/BUD at 1:1 nominal daily dose ratio. Group 4. Crossover studies in non−OCS treated patients comparing FP to BDP/BUD at 1:1 nominal daily dose ratio. Group 5. Parallel group studies in oral steroid treated asthmatics comparing FP to BDP or BUD at a 1:2 nominal daily dose ratio. No crossover studies in OCS treated subjects met the inclusion criteria. Results of meta−analysis of studies with the characteristics defined by Groups 1, 2 and 3 are shown in Comparisons 01, 02 and 03 respectively. Few studies had the characteristics defined by Groups 4 and 5, and it was not appropriate to pool their results in a meta−analysis. The results of these studies are discussed below. The single dose reduction design study (Agertoft 1997a) was considered separately and its results are discussed below. Sensitivity analyses based on methodological quality were undertaken and the data were re−analysed using only studies of higher quality (Jadad score 3 to 5). Subgroup analyses (as outlined under Methods) were planned. However, this could only be undertaken for some of the outcomes reported in the parallel group studies in non−OCS treated patients that compared FP to BDP/BUD at a nominal daily dose ratio of 1:2 (Group 1 studies). These analyses are shown in Comparisons 05 to 08. Too few studies reported common outcomes with the characteristics defined by Groups 2 and 3 to allow meaningful subgroup analyses.

NON−ORAL STEROID TREATED ASTHMATICS FP v BDP/BUD AT 1:2 NOMINAL DAILY DOSE RATIO EFFICACY MEASURES FEV1: parallel group studies FP resulted in a significantly greater FEV1 compared to BDP/BUD: WMD 0.11 litres (95% CI 0.01 to 0.20 litres, 3 studies n=1107). No heterogeneity was present when studies were pooled. When reported as change compared to baseline, FP also resulted in a significantly greater improvement in FEV1 compared to BDP/BUD: WMD 0.14 litres (95% CI 0.05 to 0.23 litres, n=399). No heterogeneity was apparent. Two studies reported FEV1 as a percent predicted value (Dahl 1993, Rao 1999). No difference between FP and BDP/BUD was apparent: WMD −1.93% (95% CI −7.41 to 3.56 %). There was no heterogeneity. FEV1: crossover studies Two studies (Bootsma 1995, Wolthers 1997) reported FEV1 (litres). Results from these studies were pooled. No significant difference between FP and BDP/BUD treated groups was apparent: WMD 0.02 litres (95% CI −0.23 to 0.26 litres, 2 studies n=76). Two crossover studies (Malo 1999, Pauwels 1998) reported FEV1 (% predicted). Results could not be aggregated as only one study presented complete numerical data (Malo 1999). However, no difference between FP and BDP treated subjects was apparent in either study. FVC: parallel studies Four studies reported FVC. Because only one (Ringdal 1996) provided data in a form suitable for inclusion in the meta−analysis, calculation of a pooled treatment effect was not possible. In three studies (Basran 1997, Leblanc 1994, Lorentzen 1996), no difference between treatment groups was apparent. In a single study (Ringdal 1996) a small effect in favour of FP was reported (FP 3.52 litres v BUD 3.37 litres, p=0.02). A range of dose comparisons and delivery devices were used in these studies, with patients of different ages and different degrees of disease severity. Change in FVC compared to baseline was reported by Raphael 1999a/Raphael 1999b. A significantly greater improvement favouring FP compared to BDP was seen: WMD 0.13 litres (95% CI 0.01 to 0.25 litres, n=399). FVC: crossover studies Two crossover studies reported FVC, either as an absolute value (Pauwels 1998), or as a percent−predicted value (Malo 1999). No significant difference between FP and BDP treatment groups was apparent in either study. PEF: parallel studies Diary card PEF was reported widely. Treatment with FP led to a significantly greater morning PEF compared to BDP/BUD: WMD 13 L/min (95% CI 5 to 22 L/min, 7 studies n=2087). A number of trials expressed this outcome as a change compared to baseline. FP treatment resulted in significantly greater improvements in morning PEF compared to BDP/BUD: WMD 13 L/min (95% CI 7 to 17 L/min, 3 studies n=831). FP treatment also resulted in significantly higher diary card evening PEF compared to BDP/BUD at half nominal daily dose: WMD 11 L/min (95% CI 1 to 20 L/min, 5 studies n=1698). One study, incorporating two separate comparisons (Raphael 1999a/Raphael 1999b) reported evening PEF as a change compared to baseline. No difference between FP and BDP was apparent (n=399). Clinic measured PEF was less frequently reported. Two studies provided data in a form suitable for inclusion in a meta−analysis (Langdon 1994b, Ringdal 1996). FP treatment led to significantly greater clinic PEF compared to BDP/BUD: WMD 18 L/min (95% CI 1 to 34 L/min, 2 studies n=675).

No heterogeneity was present when studies were pooled for any of these outcomes. Diurnal variability in PEF was reported in five studies whose Jadad scores were 3 or greater. However full outcome data (with endpoint mean and standard deviation values) were only available for one study (Ringdal 1996). Consistent effects were not seen for this outcome. In two studies (Barnes 1993, Ringdal 1996) significant reductions in diurnal variability favouring FP over BDP/BUD were seen, in others (Gustafsson 1993, Lundback 1993, Williams 1997) no difference between treatment groups was apparent. PEF: crossover studies Two crossover studies presented data in a form suitable for inclusion in the meta−analysis (Bootsma 1995, Wolthers 1997). These studies were pooled. No difference between FP and BDP treatment groups was apparent (WMD 3 L/min 95% CI −28 to 34 L/min). Two further studies (Fitzgerald 1998, Yiallouros 1997) also reported morning PEF but did not present data in a form that could be included in a meta analysis. In both studies however, no difference between FP and BDP treated groups was apparent. Diary card evening PEF was reported in the same set of crossover studies. Similar results were found, with no difference between FP and BDP treated groups. Diurnal variability in PEF was reported in only one crossover study (Bootsma 1995). No difference between FP and BDP treated subjects was found. SYMPTOMS: parallel group studies Asthma symptoms were reported frequently. However, the use of different scales across the studies limited the possibilities for combining results to derive a pooled treatment effect. A single study incorporating two separate comparisons (Raphael 1999a/Raphael 1999b) reported the change in daily asthma symptom score compared to baseline; a significantly greater reduction in symptom score was seen for FP treated patients compared to BDP: WMD −0.16 (95% CI −0.26 to −0.06, n=399). Two studies reported the percentage of symptom free days experienced by patients (Dahl 1993, Steinmetz 1997) . No significant difference between FP and BDP/BUD treatment groups was apparent: WMD 4.9 % (95% CI −1 to 11%, n=699). A number of individual studies with a Jadad quality score of 3 or greater (Barnes 1993, Gustafsson 1993, Leblanc 1994, Lundback 1993, Williams 1997) reported the percentage of symptom free days and nights. Meta−analysis was not possible because the data were either not in a form suitable for analysis, and/or the original studies analysed their data using non−parametric tests. In all studies, no significant differences between FP and BDP/BUD treatment groups were reported for these outcomes. Three studies (Ferguson 1999, Rao 1999, Ringdal 1996) reported the change in daytime and nighttime symptoms scores compared to baseline. Complete numerical data were not available. No significant difference between FP and BDP/BUD treatment groups was apparent for either of these measures in any study. SYMPTOMS: crossover studies Two studies (Pauwels 1998, Wolthers 1997) reported the percentage of symptom free days and nights, these studies were pooled. No significant difference between FP and BDP treated patients was seen. Individual studies reported symptoms using different methods, including day and night−time breathlessness scores (Bootsma 1995), number of patients experiencing one or more night−time awakening due to symptoms (Malo 1999) and number of patients experiencing cough and wheeze free days and nights (Yiallouros 1997). No significant difference between FP and BDP treatment groups was seen in any study. RESCUE BETA2 AGONIST USE: parallel studies

Rescue beta2 agonist use was a widely reported outcome. The number of patients experiencing rescue beta2 agonist free days and nights was reported in six studies (Barnes 1993, Gustafsson 1993, Leblanc 1994, Lundback 1993, Ringdal 1996, Williams 1997), however a number of factors precluded pooling of data. In each study however, no significant differences were reported between FP and BDP/BUD treatment groups. Two studies (Basran 1997, Ferguson 1999) reported daytime and nighttime beta2 agonist use scores. Again, complete numerical data were not presented. No significant differences between FP and BDP/BUD treatment groups were seen in either study. RESCUE BETA2 AGONIST USE: crossover studies Rescue beta2 agonist use was assessed infrequently . Pauwels 1998 reported the percentage of rescue beta2 agonist free days; Yiallouros 1997 reported daytime and nighttime rescue beta2 agonist use. Significant treatment group differences were not reported. ASTHMA EXACERBATIONS A number of parallel group studies reported withdrawal due to asthma exacerbation. The criteria for withdrawal varied between studies. In one study (Raphael 1999a/Raphael 1999b) the criteria were based upon a pre−defined deterioration in FEV1 or PEF of 20% compared to baseline. Clinical need for oral corticosteroid was also used, either one course (Dahl 1993) or two courses (Ferguson 1999). In one study (Lundback 1993) deterioration in asthma prompting any change in asthma medication was the criterion for withdrawal. In six studies (Barnes 1993, Connolly 1995, Gustafsson 1993, Langdon 1994a, Langdon 1994b, Leblanc 1994) withdrawal criteria were not stated. Results from these studies were pooled. No significant difference in the likelihood of withdrawal was seen for FP compared to BDP or BUD: Peto OR 0.77 (95% CI 0.54 to 1.10, 11 studies n=2824).There was no heterogeneity between the studies. Two studies (Ferguson 1999, Ringdal 1996) reported the number of patients who experienced asthma exacerbations during the trial, but which did not necessarily lead to trial withdrawal. The findings of these studies were pooled. No significant difference in the likelihood of experiencing an exacerbation was seen when comparing treatment groups: Peto OR 0.70 (95% CI 0.45 to 1.09, 2 studies n=851). No heterogeneity was apparent when studies were pooled. EFFICACY: other measures Parallel studies A number of outcome measures were reported by individual studies with a Jadad score of 3 or greater. A single parallel group study (Rao 1999) reported post exercise challenge drop in FEV1 and histamine BHR (PC20 FEV1). However, FP and BDP treatment groups were not compared directly. Langdon 1994b reported patient and investigator assessment of treatment success, no difference between FP and BUD treatment groups was observed. Crossover studies A number of outcome measures were reported in individual crossover studies, comparing FP and BDP/BUD administered at a 1:2 nominal daily dose ratio. Bootsma 1995 assessed the effects of treatment on histamine BHR (PC20 FEV1) and ultrasonically nebulised distilled water BHR (PD20 FEV1). Fitzgerald 1998 reported patient and physician assessments of efficacy. No difference between FP and BDP treatment groups was seen in either study for any of these outcomes. Malo 1999 reported the frequency and severity of patient assessed skin bruising using a questionnaire at clinic visits, and a physician assessed score for frequency and severity of bruising based on direct skin examination at clinic visits. No difference between FP and BDP was apparent for patient reported scores, although a significantly lower bruising score was seen for FP treated patients compared to BDP. A single crossover study (Pauwels

1998) reported health status as measured using a disease specific instrument, the Living with Asthma Questionnaire (LWAQ). Significantly greater (i.e. better) scores were seen for FP treated patients when compared to BDP (mean difference 0.02, 95% CI 0.00 to 0.04).

SAFETY MEASURES OROPHARYNGEAL SIDE EFFECTS The incidence of oropharyngeal side effects was reported in a number of parallel group studies. The incidence of sore throat/pharyngitis was significantly higher in patients treated with FP compared to BDP/BUD (in 1:2 nominal daily dose ratio): Peto OR 2.16 (95% CI 1.42 to 3.28, 6 studies n=1859). However, significant heterogeneity was present when the studies were pooled (Chi square 11.31, df=5). No significant difference between FP and BDP/BUD treatment groups was apparent in terms of the numbers of patients experiencing hoarseness: Peto OR 0.92 (95% CI 0.38 to 2.22, 5 studies n=1524). No heterogeneity was apparent when studies were pooled. No significant difference between FP and BDP/BUD treated groups was apparent in terms of the incidence of oral Candidiasis: Peto OR 1.11 (95% CI 0.63 to 1.96, 10 studies, n=2748), although heterogeneity was present when studies were pooled (Chi square 12.71, df=6). HYPOTHALAMO−ADRENAL−PITUITARY (HPA) FUNCTION Morning plasma cortisol: parallel studies Morning plasma cortisol levels were reported in a number of studies. However only two studies (Berend 1997, Rao 1999) reported data suitable for inclusion in the meta−analysis. These studies were pooled. No significant difference between FP and BDP/BUD treated groups was apparent: WMD 12 nmol/L (95% CI −38 to 62 nmol/L). Six further studies reported morning plasma cortisol levels. Attempts were made to obtain data from authors, but were unsuccessful. Five studies (Dahl 1993, Ferguson 1999, Gustafsson 1993, Hughes 1999b, Lundback 1993) found no significant differences between treatment groups, whilst three studies (Leblanc 1994, Lorentzen 1996, Ringdal 1996) found small, statistically significant differences between FP and BDP/BUD treatment groups that favoured FP. Because results could not be combined in a pooled analysis it was not possible to determine whether treatment responses across trials were determined by such factors as differences in doses compared, age of patients, delivery device, length of treatment or asthma severity. Morning plasma cortisol: crossover studies Three studies that reported morning plasma cortisol levels had data in a form suitable for inclusion in the meta−analysis (Bootsma 1995, Malo 1999, Pauwels 1998). No significant difference between FP and BDP/BUD treatment groups was apparent when the studies were pooled: WMD −0.34 nmol/L (95% CI −28 to 27 nmol/L, 3 studies n=782). No heterogeneity was present.

HPA function: other measures 24 hour urinary free cortisol levels were reported in a single parallel group study (Hughes 1999b), and four crossover studies (Fitzgerald 1998, Malo 1999, Wolthers 1997, Yiallouros 1997). In only one study (Wolthers 1997) was a difference in response to treatments seen, with a small but significant difference in urinary cortisol levels in favour of FP compared to BDP. In all other studies, no significant difference between FP and BDP/BUD treatment groups was apparent. Because only one study (Malo 1999) presented data suitable for inclusion in the meta−analysis, it was not possible to calculate an overall pooled treatment effect for the crossover studies.

A single parallel group study (Dahl 1993) and two crossover studies (Fitzgerald 1998, Malo 1999) reported plasma cortisol levels following a short synthetic ACTH (cosyntropin) test. Data was not in a format that allowed a pooled estimate to be calculated. No difference between FP and BDP/BUD treatment groups was apparent in any study.

FP v BDP OR BUD AT 1:1 NOMINAL DAILY DOSE RATIO Parallel group studies Seven studies (Basran 1997, Boe 1994, Dahl 1993, Fabbri 1993, Hoekx 1996, Joubert 1998, Melaranci 1999) assessed FP and either BDP or BUD administered at equal nominal daily dose. FEV1 was assessed in most studies. However numerical data were not always reported, and different scales (absolute value in litres, change compared to baseline and % predicted values) were used in different studies. This meant that results could not be pooled. When expressed as an absolute value (Basran 1997, Boe 1994, Hoekx 1996) or as a % predicted value (Dahl 1993) no significant difference between FP and BDP/BUD treatment groups were found. Fabbri 1993 expressed FEV1 as a change compared to baseline. In this single study (n=274) FP resulted in a significantly greater improvement in FEV1 compared to BDP (mean difference 0.15 litres, 95% CI 0.01 to 0.29 litres). Diary card PEF was reported, but again limited numerical data were available, thus restricting the number of studies that could be pooled to calculate an overall treatment effect. Two studies with available data reported diary card morning PEF (Basran 1997, Dahl 1993). There was no significant difference between FP and BDP/BUD treated groups (WMD 15 L/min 95% CI −6 to 36 L/min). However, a single large study (Fabbri 1993, n=274) which did not report complete data found a significant difference in favour of FP compared to BDP after 12 weeks of treatment (mean difference 15 L/min, 95% CI 6 to 25 L/min). Change in morning PEF compared to baseline was reported by one study (Boe 1994). No difference between FP and BUD treatment groups was seen. Two studies with available data (Basran 1997, Dahl 1993) reported diary card evening PEF; no difference between FP and BDP/BUD treatment groups was apparent (WMD 14 L/min 95% CI −7 to 35 L/min). However, a single large study (Fabbri 1993) which did not provide data in a form that could be included found a significant effect in favour of treatment with FP compared to BDP after 12 weeks of treatment (mean difference 10 L/min, 95% CI 6 to 25). A single study (Boe 1994) reported change in evening PEF compared to baseline. No difference between FP and BDP treated patients was apparent. Symptom frequency and rescue beta2 agonist use were often reported in these studies. However, different measures were used so a pooled treatment effect could not be calculated. No difference between FP and BUD treatment groups was apparent when symptoms were expressed as a daytime or nighttime score (Basran 1997, Boe 1994), the percentage of symptom free days (Dahl 1993) or as the number of patients experiencing symptom free days and nights (Fabbri 1993, Hoekx 1996). Similar considerations applied to reported use of rescue beta2 agonist, no study found a difference between FP and BDP/BUD treatment groups. Trial withdrawal due to asthma exacerbation was reported in four studies. Results from these studies were pooled. Criteria for withdrawal varied. In one study (Dahl 1993) patients were withdrawn if they required a single course of rescue oral prednisolone due to a clinical exacerbation. In one study (Fabbri 1993) patients were withdrawn if they failed to improve following a course of oral prednisolone. In two studies (Basran 1997, Hoekx 1996) withdrawal criteria were simply 'worsening asthma' or withdrawal due to 'asthma related events' respectively, no further definition was given. No significant difference between FP and BDP/BUD treatment groups was apparent in terms of the likelihood of withdrawal: Peto OR 0.68 (95% CI 0.36 to 1.28, 4 studies n=947). No heterogeneity was present when studies were pooled.

Two studies (Boe 1994, Fabbri 1993) reported the numbers of patients requiring a course of oral prednisolone for a clinical asthma exacerbation. The studies were pooled. A significantly lower likelihood of need for rescue oral steroid was apparent in FP treated subjects compared to BDP: Peto OR 0.28 (95% CI 0.13 to 0.60, 2 studies n=408). A single parallel group study (Hoekx 1996) conducted in children assessed FP and BDP at a 1:1 nominal daily dose ratio (400 mcg/d. It) reported the number of days missed from school (patients), and the number of days missed from work (parents) due to asthma related events. No difference between treatment groups was apparent for these outcomes. A questionnaire centred on the experience of sleep disturbance, and interference with physical activities (sports, games, visiting friends) was administered to parents of children included in this study. FP treatment resulted in significantly lower (i.e. better) activity limitations scores compared to BDP. Safety Four studies assessed aspects of HPA function. Data were not in a form suitable for inclusion in a meta−analysis. No difference between FP and BDP/BUD treatment groups were apparent for morning plasma cortisol (Fabbri 1993, Hoekx 1996), plasma cortisol following a short synthetic ACTH stimulation test (Dahl 1993, Fabbri 1993) or 24 hour urinary free cortisol levels (Fabbri 1993). A single study (Boe 1994) reported change in morning plasma cortisol and ACTH levels compared to baseline. In that study, FP 2000 mcg/d was compared to BDP 1600 mcg/d over a 12 week treatment period. A significant difference in favour of BDP treated patients was observed in terms of reduction in morning plasma cortisol levels (FP −133 nmol/L v BDP +40.4 nmol/L, p<0.001), although no difference in ACTH levels was seen (FP −10.6 ng/L v BDP 02.0 ng/L, p=0.06). The incidence of sore throat and hoarseness was reported in a number of studies (Boe 1994, Dahl 1993, Fabbri 1993, Hoekx 1996, Williams 1997). Results of these studies were pooled. No significant difference between FP and BDP was apparent in terms of the likelihood of sore throat (Peto OR 1.81, 95% CI 0.99 to 3.32, 3 studies n=637), or oral Candidiasis (Peto OR 0.85, 95% CI 0.51 to 1.39, 4 studies n=1122); however a significantly higher likelihood of hoarseness was apparent for patients treated with FP compared to BDP/BUD (Peto OR 2.43, 95% CI 1.10 to 5.39, 3 studies n=676). Crossover studies Two crossover design studies assessed FP compared to BUD at a 1:1 nominal daily dose ratio. Both had two week treatment periods and compared FP to BUD. Agertoft 1997b assessed children with moderately severe asthma. Patients were randomised to receive either FP or BUD at a dose of 200 mcg/d, with a second treatment group who were randomised to receive either FP or BUD at 400 mcg/d. Clinic measured FEV1, diary card morning and evening PEF, symptoms, rescue beta2 agonist use and 24 hour urinary cortisol excretion were assessed. No significant difference was seen between the two drugs in this study. Ringdal 1998 assessed the effects of FP 1500 mcg/d and BUD 1600 mcg/d in adults with moderate to severe asthma and reported morning plasma cortisol and overnight urinary cortisol. No significant difference between treatment groups was apparent for these measures.

DOSE DOWN−TITRATION DESIGN A single study (Agertoft 1997a) met the inclusion criteria for this review. In this carefully conducted study, 219 children with moderately severe asthma first entered an evaluation period during which time their usual daily dose of BUD administered via MDI+Nebuhaler spacer was titrated to the point at which deterioration in control was considered to have occurred. Criteria for loss of control were specified a priori, and were based around daytime, night−time and exercise−related symptoms, rescue beta2 agonist use or clinical

deterioration as judged by investigators. Patients requiring BUD at a daily dose of 400 or 800 mcg/d were then randomised to receive half the nominal daily baseline dose of either FP or BUD i.e. 200 or 400 mcg/d. FP was administered using a Diskhaler DPI, BUD using a Turbohaler DPI. During the first five weeks of the study patients received treatment at the dose to which they were randomised. Following this, dose reduction was attempted. Using pre−defined criteria for acceptable control (based around symptoms, rescue beta2 agonist use, morning PEF and post exercise fall in FEV1/FEF25−75 compared to baseline) a 50% dose reduction was attempted at 5 weekly intervals. Doses were reduced until either control deteriorated, or a daily dose of 100 mcg was reached. The primary outcome measures were the mean number of dose reductions steps achievable, and the minimal effective dose of ICS. No significant difference was apparent between FP and BUD treatment groups either in terms of dose reduction steps (FP 1.65 v BUD 1.59) or in terms of the minimal effective dose of ICS (FP 180 mcg/d v BUD 188 mcg/d).

ORAL STEROID TREATED ASTHMATICS ORAL STEROID SPARING DESIGN A single parallel group study (Lundback 1998) assessed the relative oral steroid sparing effects of FP and BUD in oral steroid dependent asthma. This study has only been published in abstract form. 74 adult asthmatics requiring treatment with at least 5 mg/d of oral prednisolone and 800 mcg/d of inhaled steroid were randomised to treatment with either FP 1500 mcg/d via the Diskhaler DPI or BUD 1600 mcg/d via the Turbohaler DPI. Few methodological details were available, including whether or not a run−in period to establish the minimal effective dose of prednisolone was employed, or whether pre−defined criteria for oral steroid dose reduction were used. A significantly greater number of patients (37 out of 40) were able to discontinue oral prednisolone with FP compared to BUD treated subjects (25 out of 34), although no difference between treatment groups was apparent in terms of the daily oral prednisolone dose. NON ORAL STEROID SPARING DESIGN A single parallel group study (Ayres 1995) of fair methodological quality (Jadad score 3) was conducted in adult asthmatic patients with moderate to severe asthma. 11% of patients were also receiving oral prednisolone (<10 mg/d) at the time of enrolment. Patients were randomised to receive FP 1000 mcg/d, FP 2000 mcg/d or BUD 1600 mcg/d over a six week treatment period. They used a MDI delivery device, and were given the option of using a large volume spacer. No attempt was made to taper oral steroid use in patients treated with prednisolone. A number of outcome measures were reported. Both daily doses of FP led to significant improvements in a number of measures when compared to BUD:

FP 1000 v BUD 1600 FP 2000 v BUD 1600 Morning PEF (L/min) 9 (95% CI 2 to 17) 13 (95% CI 6 to 21) Diurnal variation in PEF (L/min) 6 (95% CI 1 to 11) 6 (95% CI 1 to 11) FEV1 (litres) 0.10 (95% CI 0.02 to 0.18) 0.17 (95% CI 0.80 to 0.25) No significant differences between FP 1000 mcg/d and BUD 1600 mcg/d were apparent in terms of daytime and night−time symptoms although FP 2000 mcg/d led to a significantly greater reduction in daytime and night−time symptom scores and use of night−time rescue beta2 agonist. No significant differences were seen between either daily dose of FP and BUD in terms of oropharyngeal side effects, although FP 2000 mcg/d led to a significantly greater reduction in morning plasma cortisol level compared to BUD 1600 mcg/d.

SENSITIVITY AND SUBGROUP ANALYSES

Sensitivity analyses based on study quality excluded two studies (Berend 1997, Connolly 1995). This did not lead to a significant difference in the size or direction of effect for any of the pooled estimates to which these studies contributed. Subgroup analyses were undertaken for a number of outcomes reported in the parallel group studies in non−oral steroid treated asthmatics that compared FP to BDP/BUD at a nominal daily dose ratio of 1:2. These included FEV1, morning PEF, change in morning PEF compared to baseline, evening PEF, withdrawal due to asthma exacerbation, hoarseness, sore throat and oral Candidiasis. These were done with the purpose of a) identifying potential groups who appeared to show differences in response to treatment b) exploring sources of heterogeneity. FEV1 and PEF measures were significantly better in FP treated patients compared to BDP/BUD treated patients. These studies included children and adults (treated with both BDP and BUD), patients with asthma of mild to moderate/severe disease, delivery devices that were same in the the two treatment groups (e.g. FP and BDP/BUD via MDI) or different between groups (e.g. FP via Diskhaler or Accuhaler and BUD via Turbohaler). No heterogeneity was found in the pooled treatment effect and subgroup analyses did not identify any groups that showed a clear difference in response to treatment. However there did appear to be a trend for higher dose range comparisons (FP 500 vs BDP/BUD 1200 mcg/d, FP 800 vs BDP/BUD 1600 mcg/d) to show a greater difference in favour of FP. The studies that contributed to these subgroup analyses (Ringdal 1996, Steinmetz 1997) were also conducted in patients with moderate/moderately severe asthma. Although such factors may be important in determining response, this conclusion can only be speculative. No difference in the likelihood of withdrawal was seen when comparing FP to BDP/BUD. Subgroup analyses did not identify any potential groups of patients in which significant treatment differences were apparent. Significant heterogeneity was apparent when studies that reported the incidence of sore throat/pharyngitis and oral Candidiasis were pooled. Subgroup analyses were unhelpful in identifying the potential sources of this heterogeneity. A number of different groupings did reduce the heterogeneity in these outcomes, including age, dose range and asthma severity. However, this was often because the subgroups often contained only a single study. These analyses cannot be interpreted reliably and the causes of heterogeneity cannot be explained.

DISCUSSION

This review has assessed the relative efficacy and safety of fluticasone propionate when compared to beclomethasone and budesonide in the treatment of chronic asthma. Only randomised, prospective trials were included. 42 studies met the inclusion criteria for this review, comprising over 10,000 patients. EFFICACY: Airway Calibre The largest group of patients assessed were those in which FP was compared to either BDP or BUD at a 1:2 nominal daily dose ratio, in non−oral steroid treated asthmatics. In the studies of this type that used a parallel group design, FP resulted in significantly higher measurements of airway calibre compared to BDP/BUD. These included FEV1 (WMD 0.11 litres, 95% CI 0.01 to 0.20 litres n=1107), morning PEF (WMD 13 L/min, 95% CI 5 to 22 L/min n=2087) and evening PEF (WMD 11 L/min, 95% CI 1 to 20 L/min n=1698). Children and adults, with asthma ranging in severity from mild to severe, treated with both BDP and BUD were included. No heterogeneity was present when the studies were pooled, suggesting that the differences in treatment efficacy between FP and BDP/BUD apply to all patients. Subgroup analyses suggested the possibility that effects in favour of FP may be greater in patients with more severe disease treated at higher dose comparisons. Some support for this hypothesis comes from the single, large parallel study that assessed the relative efficacy of FP vs BUD in adults with severe asthma, some of whom were

oral steroid treated at the time of enrolment (Ayres 1995): FP 1000 mcg/d resulted in significantly greater improvements in FEV1 and morning PEF compared to BUD 1600 mcg/d. Few crossover studies assessed airways function in a way that could be analysed. No difference between FP and BDP/BUD was apparent, but few studies could be pooled. Although all studies were of high methodological quality, washout periods between treatments were not always used and the possibility of carryover effects that masked true treatment differences could not be excluded. In summary, the results of the parallel group study analysis are more reliable. Symptoms and rescue beta2 agonist use It is difficult to draw conclusions concerning the relative efficacy of FP and BDP/BUD in reducing symptoms and rescue beta2 agonist use. Few numerical outcome data were available, different scales of measurement were used and the possibilities for pooling results across studies was limited. However, no individual studies (either of parallel group design or crossover design) demonstrated a significant difference between FP and BDP/BUD at a 1:2 dose ratio or at a 1:1 dose ratio. For the few instances in which data could be pooled where two studies reported symptoms measured using the same metric scale, no overall difference between treatment groups was seen. Asthma exacerbations A number of parallel group studies reported trial withdrawal due to an asthma exacerbation. Although varying criteria for withdrawal were used, the underlying nature of the outcome assessed (worsening asthma control) was the same. It was considered appropriate therefore to pool these studies. No difference between FP and BDP/BUD at a 1:2 nominal daily dose ratio was apparent (Peto OR 0.77, 95% CI 0.54 to 1.10, 11 studies n=2824) and there was no heterogeneity, suggesting a consistent response across studies independent of the criteria used to define withdrawal. The likelihood of withdrawal due to asthma exacerbation cannot be considered equivalent to asthma exacerbations leading to emergency dept or GP attendance, but may be a reasonable surrogate for these. In summary, data from trials that compared FP to BDP/BUD at a 1:2 nominal daily dose ratio suggest that FP and the older corticosteroids cannot be considered equivalent with respect to clinical efficacy. The greater improvements in FEV1 and PEF when administered at half the nominal daily dose of BDP/BUD suggest that the higher potency of FP demonstrated in laboratory studies is reflected in certain outcomes relevant to clinical practice. Against this, no studies found significant differences in terms of symptoms, rescue beta2 agonist use or asthma exacerbations. Although this cannot be taken to mean that FP at half daily dose is equivalent to BDP/BUD at full dose, it does suggest that clinically relevant differences in effect are unlikely to be seen when FP and BDP/BUD are used at a 1:2 daily dose ratio. Previous reviews have examined the dose response relationships for BDP, BUD and FP (Adams 2001a, Adams 2001b, Adams 2002). Although each ICS is effective in improving airway function compared to placebo, no dose response effect for daytime symptom scores, rescue beta2 agonist use or withdrawal due to lack of efficacy was apparent for any of these agents over wide dose ranges in non−oral steroid treated asthmatics. In the light of this fact it should not be surprising that differences between FP and BDP/BUD were not seen in the studies included in this review, irrespective of dose ratios compared. In a previous review, we have shown that FP exhibits a dose response effect for FEV1 and morning PEF (Adams 2002). Larger daily doses lead to greater improvements compared to lower doses. A logical expectation would be for even greater benefits favouring FP to be seen when given at equal nominal daily dose to BDP or BUD. This has not been clearly demonstrated in the current review. However, fewer studies made such a comparison and an overall pooled analysis across studies was not possible. Less weight should therefore be given to these findings, and they do not undermine the more powerful analysis that was possible for the studies that compared FP to BDP/BUD at a 1:2 dose ratio. The findings for the parallel group studies that compared FP to BDP/BUD at the 1:2 dose ratio also appear to be inconsistent with the single dose reduction study (Agertoft 1997a). In that study, acceptable asthma control was maintained with mean daily doses of FP and BUD that were not significantly different. Given the results from the FP v BDP/BUD 1:2 ratio analysis, one would expect to see lower doses of FP necessary to maintain control. A

possible explanation for the discrepancy is that in Agertoft 1997a a minimum daily dose threshold of 100 mcg was set at which no further dose reduction were attempted. Although the investigators speculate that deterioration in control was likely if doses had been reduced below this threshold, this was not directly tested, so it is not possible to exclude the possibility that further dose reduction steps could have been achieved. This could have masked a difference in the dose of FP and BUD required to achieve equivalent asthma control. Health status Only one fair quality study (Pauwels 1998) reported health status measured using an asthma−specific instrument, the Living with Asthma Questionnaire (LWAQ). In this crossover study FP and BDP were compared in a daily dose ratio of 1:2. The study was undertaken in asthmatics with moderate to severe disease, who were randomised to receive FP and BDP at doses corresponding to their pre−study requirement for BDP/BUD. Dose ranges included FP 500−1000 mcg/d vs BDP 1000−2000 mcg/d. Significantly better scores were seen for patients receiving FP compared to BDP, suggesting that FP and BDP/BUD cannot be considered equivalent with respect to their effects on health status in this group of patients. However, no other studies with a Jadad score of three or greater reported health status, and it not known whether this difference in effect holds true for different dose comparisons in patients with less severe disease. Oral steroid sparing effect Little trial evidence exists regarding the relative oral steroid−sparing efficacy of FP and BDP or BUD. Only one included study (Lundback 1998) addressed this question. This study has only been published in abstract form to date, and limited details regarding trial design are available. Important design characteristics of such trials should include a) a prolonged run−in period to allow patients to have their prednisolone dose weaned to the minimum required to maintain asthma control prior to randomisation; b) prednisolone dose reduction should be undertaken according to pre−defined criteria based around acceptable asthma control. Only in this manner can unbiased estimations be made of the relative efficacy of different interventions. Although Lundback 1998 found that FP 1500 mcg/d allowed significantly more patients to discontinue oral prednisolone when compared to BUD 1600 mcg/d, it is unclear if this study incorporated these design features. Authors did not respond to requests for further information. Interpretation of these results therefore requires caution. SAFETY Adrenal function Accurate assessment of the relative effects of FP versus BDP/BUD on markers of adrenal function were difficult to make using the data available for this review. When comparisons of FP to BDP/BUD at a nominal daily dose ratio of 1:2 were made, a meta−analysis of the few parallel group studies (Berend 1997a, Rao 1999) and crossover studies (Bootsma 1995, Malo 1999, Pauwels 1998) did not find a significant differences between treatment groups. The few individual studies that assessed this outcome when FP and BDP/BUD were compared at equal nominal doses did not find any difference. It was not possible to calculate a pooled treatment effect across studies because numerical data were reported incompletely. This also meant that assessment of the relative influence of FP vs BDP/BUD across the a range inhaled corticosteroid doses(e.g. 100 FP vs 200 BDP/BUD, 500 FPvs 1000 BDP/BUD, 1000 FP vs 2000 BDP/BUD) could not be done. Single dose and short term (< 1 week) studies have demonstrated that FP results in a significantly greater suppression of plasma cortisol than BUD when compared at equal nominal daily dose over a range of 400 to 2000 mcg/d (Clark 1996a, Clark 1996b, Wilson 1998). A recent meta−regression analysis (Lipworth 1999) that included these studies also concluded that FP is significantly more potent that BUD in suppressing morning plasma cortisol, in other words that FP leads to greater suppression of levels than BUD when given at equal daily dose. This effect was more pronounced at higher nominal daily doses. The findings of this review are consistent with that analysis. The absence of differences between FP and BDP/BUD when compared at a dose ratio of 1:2 are consistent with a higher potency of FP in terms of cortisol suppression. The absence of significant differences between FP and BDP/BUD in the individual studies that assessed the drugs at a 1:1 nominal daily dose ratio may be explained by issues related to the

timing of cortisol measurements. In all of the longer term studies included in this review, cortisol measurements were made within a 2 hour time window between 8am and 10.00am. In the short term studies that were not eligible for inclusion, cortisol measurements were taken at a strictly standardised time of either 7.30 or 8.00 am. Estimations over a time frame of 2 hours have been shown to be substantially less sensitive in detecting change compared to those taken at closely controlled times, with up to three fold differences in levels occurring between 8.00 am and 10.00 am in healthy volunteers (Lonnebo 1996). The greater variability introduced into estimations made over a 2 hour time frame may have masked any true differences between FP and BDP/BUD in terms of their effects on morning cortisol levels. 24 hour urinary cortisol, a more sensitive assay of basal adrenocortical activity than morning plasma cortisol, was not reported frequently. This measurement should not be subject to the same difficulties in interpretation as plasma cortisol. The majority of studies (both parallel group and crossover), that assessed FP versus BDP/BUD at either a 1:1 or 1:2 nominal daily dose ratio did not find significant differences betweenFP and the other two drugs. A recent meta−regression analysis of a different group of short term studies (Lipworth 1999) suggested that FP is more potent than BDP/BUD in suppressing 24 hour urinary cortisol levels. The findings of the individual studies included here are not consistent with this. This difference may be a real phenomenon, however, these relatively small trials may not have had sufficient power to detect true differences. Since we were unable to calculate an overall pooled treatment effect due to limitations in the presentation of the primary trial results, this remains uncertain. In summary, this review does not permit firm conclusions to be drawn with regard to the relative effect of FP versus BDP/BUD on morning plasma cortisol or 24 hour urinary cortisol levels in randomised trials with treatment periods of one week or longer. Oropharyngeal side effects When compared to BDP/BUD at a nominal daily dose ratio of 1:1, FP results in a significantly greater likelihood of hoarseness (Peto OR 2.43, 95% CI 1.10 to 5.39), although no difference was apparent when FP and BDP/BUD were compared at a dose ratio of 1:2. This suggests that the greater potency of FP, reflected in a number of measures of efficacy, also leads to greater likelihood of this pharmacologically predictable side effect when FP is given at an equal nominal dose compared to either BDP or BUD. No difference between FP and BDP/BUD in terms of the likelihood of oral Candidiasis was seen when given at either a 1:2 or a 1:1 nominal daily dose ratio (Peto OR 0.85, 95% CI 0.51 to 1.39), suggesting a greater margin of safety exists when considering this outcome. FP was significantly more likely to result in sore throat when compared to BDP/BUD given in a nominal dose ratio of 1:2 (Peto OR 2.16, 95% CI 1.42 to 3.28, 6 studies n=1859), but there was no difference between FP and BDP/BUD when given at a dose ratio of 1:1 (Peto OR 1.81, 95% CI 0.99 to 3.32, 3 studies n=637). This discrepancy is difficult to account for. A larger number of studies assessed the 1:2 dose ratio comparison and a more powerful meta−analysis was possible. Whilst differences in analytical power may account for this discrepancy, this suggestion can only be speculative, especially since there significant heterogeneity in the 1:2 dose ration studies. Overall the results provide a sufficient level of evidence to suggest that FP is more likely to lead to sore throat when used in clinical practice when compared to BDP/BUD. METHODOLOGICAL LIMITATIONS A number of included studies have been presented at respiratory society meetings, and published in abstract form only. At the time of writing, these had not been published as full journal papers, and include the following: Berend 1997, Bisca 1997, Dal Negro 1997, de Benedictis 1998, Hughes 1999a, Joubert 1998, Kemmerich 1999, Melaranci 1999, Murray 1998 and Pickering 1996. Limited details were available concerning the characteristics of the patients enrolled and trial methodology. Clinically relevant outcomes were reported, but numerical data were rarely presented. Grading of these studies using the Jadad scoring system has generally resulted in low scores (1 or 2). However, this is likely to be an underestimation of their

true quality and is probably a reflection of the limited information presented in meeting abstracts. Many studies published as full papers reported clinically relevant outcomes, but a substantial amount of data could not be included in the meta−analyses due to the format in which results were presented (Table 01). This was often because standard deviation values around means were not reported. Requests were made to authors for this data, but response was disappointing. It is not been possible to judge whether inclusion of these data would have influenced the overall conclusions of the review. A comprehensive search for relevant studies was undertaken. It is possible that additional studies were missed, or were not retrieved because they have not been published in any of the sources examined. However, this possibility seems unlikely as Glaxo Wellcome, who market Flixotide and have sponsored many of the studies included, did not identify further relevant trials. SUMMARY The results of this review suggest that FP, when used at half the nominal daily dose of BDP or BUD leads to greater improvements in FEV1, morning PEF and evening PEF in non−oral steroid treated asthmatics. This appears to be the case for both children and adults, with disease ranging in severity from mild to severe, irrespective of the delivery devices used for each drug. These differences are likely to be a reflection of the higher potency exhibited by FP in laboratory assays of anti−inflammatory activity. There appears to be little if any difference between FP and BDP/BUD with regard to their effects on symptoms, rescue beta2 agonist requirement or the likelihood of exacerbations, when given at any nominal daily greater than FP 200 mcg/d and BDP/BUD 400 mcg/d. Although this conclusion needs to be viewed with some caution, since a pooled treatment effect across studies was not easily calculated, it is consistent with the lack of dose response seen for these outcomes demonstrated in other reviews of inhaled corticosteroids (Adams 2001a, Adams 2001b, Adams 2002). Too few studies have reported functional health status to draw clear conclusions regarding the relative efficacy of FP and BDP/BUD. However, the single fair quality study that has reported the results of a validated, disease−specific instrument did find improvements in favour of FP when compared to BDP at a 1:2 nominal daily dose ratio. Further studies are needed to confirm the findings of a single study that FP at 1000 mcg/d is more effective than BUD in allowing a larger proportion of oral steroid dependent patients to stop treatment without deterioration in asthma control. The clinical significance of the small improvements that can be expected in FEV1 and morning PEF when patients are treated with FP is hard to assess. If this were accompanied by a lower risk of systemic side effects, in terms of interference with HPA function, there would be a case for recommending FP as a first line anti−inflammatory corticosteroid in non−oral steroid asthmatics. However, the trial evidence concerning the relative effects of FP v BDP/BUD at any nominal daily dose comparison on morning plasma cortisol levels or 24 hour urinary cortisol excretion is difficult to interpret. An overall therapeutic ratio (i.e. advantageous efficacy effects versus systemic side effects) cannot be constructed for each ICS. A clear recommendation for FP over the older agents cannot be made from the findings of this review, but in the most severe patients FP may confer an advantage over its comparators. This would need to be judged on an individual patient basis, however.

REVIEWER'S CONCLUSIONS Implications for practice Current asthma management guidelines (BTS 1997, GINA 1995, NHLBI 1997) recommend inhaled corticosteroids for all asthmatics except those with mild, intermittent symptoms. Acknowledgement is made that FP given at equal nominal daily dose to BDP and BUD may result in greater clinical efficacy. However, this is an assumption largely based on differences in potency when ICS's are compared in in−vitro assays. The results of this review lend support to the recommendation that when initiating the use of an inhaled steroid, FP can be given at half the daily dose compared to either BDP or BUD without clinically significant differences in asthma control being encountered, and may even lead to small additional improvements in certain measures, including FEV1 and diary card PEF. However, it is not possible to assess whether this is associated with a reduced risk of HPA function disturbance. The additional recommendation that individual

patients have dose titrated to the minimum required to maintain control and thereby minimise any potential (unknown) risk of long−term systemic side effects seems sensible. Implications for research The development of a standardised, validated scoring system for the assessment of symptoms is needed in order that better comparisons across studies can be made. Assessment of health status using disease−specific instruments may be a more sensitive tool for detecting variations in efficacy when comparing inhaled steroids. This has rarely been reported, and future studies need to include this measure. Hospital and GP attendance rates due to asthma exacerbation have not been reported. Future studies comparing inhaled steroids need to consider such outcomes, which will be important in health economic evaluations. A complete picture of the relative value of different inhaled steroids can only be gained if efficacy/systemic side effect ratios can be constructed for each agent. Disturbance of HPA function is one aspect of systemic activity. Complete reporting of data for overnight and 24−hour urinary cortisol measures, and more precise measurements of morning cortisol levels in primary studies would improve the accuracy of future updates of this review, and allow a better understanding of these issues.

ACKNOWLEDGEMENTS

We would like to thank the support staff of the Cochrane Airways Group, Anna Bara and Jane Dennis for assistance in the electronic search and retrieval of papers, and Steve Milan for statistical support. We would like to thank Julia Earnshaw who coordinated efforts of behalf of Glaxo Wellcome to search for additional studies, and provided further information regarding a number of included trials that were sponsored by the company. We would like to thank Dr G.P. Bootsma and Dr R.K. Gregson who were kind enough to provide additional information concerning their trials.

POTENTIAL CONFLICT OF INTEREST

None

TABLES

Characteristics of included studies

Study Methods Agertoft 1997a Setting: Denmark, paediatric outpatient clinic Design: parallel group, dose down−titration design Length of intervention period: variable (see notes) Randomisation: yes, computer generated sequence Allocation concealment: unclear Masking: double blind (double dummy) Excluded: stated Withdrawals: stated

Baseline characteristics: comparable Jadad score: 4 Participants 219 children: 136M 83F Age range: 5−16 years Inclusion criteria: Children with asthma aged 5−16 years Requiring BUD 400 or 800 mcg/d via MDI+Nebuhaler spacer for asthma control at end of evaluation period Able to use Turbuhaler/Diskhaler delivery devices Exclusion criteria: Systemic corticosteroids/theophylline/cromoglycate use in last month Asthma exacerbation in last 2 months Respiratory tract infection in last month Poor complicance FP: half (100 or 200) mcg/d baseline dose BUD via Diskhaler DPI BUD: half (100 or 200) mcg/d baseline dose BUD via Turbuhaler DPI Patients treated for 5 weeks on above regimen. Dose reduction was then attempted at five weekly intervals. A priori defined criteria for deterioration in asthma and acceptable asthma control were applied. Patients with acceptable control had their daily dose of ICS reduced by 50% until deterioration in control occurred or ICS dose of 100 mcg/d was achieved. Outcomes Following dose down−titration period: Dose reduction steps from baseline Minimal effective ICS dose (mcg/d)

Interventions

Notes Allocation concealment B Study Methods Agertoft 1997b Setting: Denmark, paediatric outpatient clinic Design: crossover, 2 week washout Length of intervention period: 2 weeks Randomisation: yes, computer generated random sequence with balanced blocks Masking: double−blind Excluded: stated (none) Withdrawals: stated (one child from low dose group due to sore throat) Baseline characteristics: comparable between groups Jadad score: 5 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 Group 1 FP: 200mcg/d via Diskhaler DPI

Participants

Interventions

BUD: 200 mcg/d via Turbuhaler DPI Group 2 FP: 400mcg/d via Diskhaler DPI BUD: 400 mcg/d via Turbuhaler DPI Outcomes FEV1 Morning PEFR Evening PEFR Daily asthma symptom score Daily use of beta2agonist 24 hour urinary cortisol excretion Growth by lower leg knemometry

Notes Allocation concealment B Study Methods Ayres 1995 Setting: multicentre study worldwide, hospital outpatient clinics Design: parallel group Length of intervention period: 6 weeks Randomisation: computer generated random sequence Allocation concealment: yes (central coding by pharmaceutical company sponsor) Masking: double blind Excluded: stated Withdrawals: adverse event rates reported, unclear if any led to patient withdrawal Baseline characteristics: comparable between groups Jadad score: 3 862 adults enrolled, 671randomised Age range: 18−70 years Inclusion criteria: Adults with a clinical history of severe asthma Requiring BDP 1−2 mg/d or BUD 0.8−1.6 mg/d BUD for asthma control During run−in period: Asthma symptom scores of 1 or more on 4 out of last 7 days and either: 1. At least 15% reversibility FEV1 post beta2 agonist or: 2. Diurnal variation in PEFR 15% or greater on 4 out of last 7 days or: 3. Need for 2 or more doses beta2 agonist each of last 7 days with either a). % predicted FEV1 80% or greater b) Mean morning PEFR 80% or greater in last 7 days Exclusion criteria: Alteration of normal asthma medication during run−in period Hospital admission due to asthma exacerbation in last month Systemic corticosteroids > 10mg daily Suspected of being steroid hypersensitive Concomitant disease likely to complicate evaluation of drug Current smokers

Participants

Interventions

FP: 1. 125 mcg 4 puffs 2xdaily (1000 mcg/d) 2. 250 mcg 4 puffs 2xdaily (2000 mcg/d) BUD: 200 mcg 4 puffs 2xdaily (1600 mcg/d) Delivery device: MDI +/− spacer Outcomes Outcomes expressed as a change compared to baseline: FEV1 FVC Clinic PEFR Morning PEFR Evening PEFR Diurnal variation in PEFR Symptom free days Symptom free nights Daytime symptom score Night−time symptom score Rescue beta2 agonist free days Asthma exacerbations Morning plasma cortisol Biochemical markers of bone turnover Notes Details concerning randomisation method provided by Glaxo Wellcome Patients were given the option of using spacer device Allocation concealment A Study Methods Barnes 1993 Setting: multicentre study Europe, hospital outpatient clinic Design: parallel group Length of intervention period: 6 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (coded, sealed envelopes) Masking: double blind Excluded: stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 4 154 subjects: 85M 69F Age range: 18−78 years Inclusion criteria: Severe chronic asthma Requirement for BDP or BUD 1500 to 2000 mcg/d During last 7 days of run−in period: Mean morning PEFR 70 (% predicted) or less 15% or greater FEV1 reversibility following beta2 agonist 20% or greater variation in PEFR on at least 4 of last 7 days of run in period Symptoms on at least 4 of last 7 days of run−in period

Participants

Exclusion criteria: Systemic corticosteroids within last month or on more than 4 occasions during last 6 months Hypersensitivity to inhaled corticosteroids Co−existent serious disease Interventions FP: 250 mcg 2 puffs 2xdaily (1000 mcg/d) BDP: 250 mcg 4 puffs 2xdaily (2000 mcg/d) Delivery device: MDI Outcomes FEV1 (% predicted) FVC (% predicted) PEFR (% predicted) Morning PEFR Evening PEFR Diurnal variation in PEFR % symptom−free days % symptom−free nights % beta2−agonist free days % beta−2 agonist nights Daytime beta2 agonist use (puffs) Night−time beta2 agonist use (puffs) Oral candidiasis Upper respiratory tract infection Oropharyngeal side effects Plasma cortisol (sample time during day not specified) Details concerning randomisation method provided by Glaxo Wellcome

Notes

Allocation concealment A Study Methods Basran 1997 Setting: multicentre study UK, primary care and hospital outpatient clinics Design: parallel group Length of intervention period: 8 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (central coded schedule prepared by pharmaceutical company sponsors) Masking: open, no blinding Excluded: stated Withdrawals: stated Jadad score: 3 229 subjects enrolled, 176 randomised Age range: 18−60 years Inclusion criteria: FEV1 > 40 (% predicted) Current ICS therapy 400 of 800 mcg/d During 2 week run−in period one or more of the following: 1) 20% or greater diurnal PEFR variability 2) 7 or more puffs beta2 agonist daily for 7 consecutive days 3) night time awakening 2 out of 7 nights Exclusion criteria:

Participants

Respiratory tract infection in last month Serious concurrent disease Interventions FP: half pre−study nominal daily dose (200 or 400 mcg/d) via Diskhaler DPI BUD: half pre−study nominal daily dose (200 or 400 mcg/d) via Turbohaler DPI Outcomes FEV1 FVC Morning PEFR Evening PEFR Diurnal variation in PEFR Daytime asthma symptom score Night−time asthma symptom score Daytime beta2 agonist use Night−time beta2 agonist use

Notes Allocation concealment A Study Methods Berend 1997 Setting: multicentre study Australia, hospital outpatient clinics Design: parallel group Length of intervention period: 6 months Randomisation: yes, method not stated Allocation concealment: unclear Masking: open, non−blinded Excluded: not stated Withdrawals: not stated Baseline characteristics: comparable Jadad score: 1 133 adults: 64M 69F Age range: 20−78 years Inclusion criteria: Adults requiring BDP or BUD > 1750 mcg/d for asthma control One or more of following: 190ml or greater FEV1 reversibilty after inhaled beta2 agonist Asthma symptoms on 2 or more days/week for 2 weeks in last month Night−time symptoms 2 or more nights/week Diurnal PEFR variability 15% or greater Exclusion criteria: Regular oral steroids therapy Significant co−existent disease FP: half usual maintainance dose (mcg/d) via MDI+spacer BDP or BUD: usual maintainance dose via MDI+ spacer or Turbuhaler DPI Outcomes FEV1 FVC Morning PEFR Clinic PEFR HRQOL: Change in Asthma Quality of Life Questionnaire domain scores compared to baseline

Participants

Interventions

HRQOL: Change in Short−form 36 questionnaire domain scores compared to baseline Morning plasma cortisol Urine cortisol:creatinine ratio (1 hour post waking sample) Asthma exacerbations Local oral side−effects Extent and ease of skin bruising Biochemical markers of bone turnover Notes Study in abstract form only

Allocation concealment B Study Methods Bisca 1997 Setting: Romania, hospital outpatient clinic Design: parallel group Length of intervention period: 8 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: not stated Excluded: not stated Withdrawals: not stated Jadad score: 1 48 children Age range: 4−18 years Inclusion criteria: Children with asthma, no further details Exclusion criteria: Not stated Baseline asthma control FEV1 (% predicted): Mean FP group 52.3, mean BDP group 48.8 Interventions FP: 200 mcg/d BDP: 400 mcg/d Delivery device: not stated Outcomes FEV1 (% predicted) FVC Clinic PEFR (% predicted) MEF50 (% predicted) Airways resistance Morning PEFR Evening PEFR Asthma symptoms score Rescue beta2 agonist use Study in abstract form only

Participants

Notes

Allocation concealment B Study Boe 1994

Methods

Setting: multicentre study Norway, hospital outpatient clinic Design: parallel group Length of intervention period: 3 months Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 3 134 adults: 80M 54F Age range: 20−75 years Inclusion criteria: Patients > 18 years with a clinical diagnosis of asthma Receiving 400 − 2000 mcg/d of BDP or BUD for at least 4 weeks After run−in period at least 2 of following: 1. FEV1 < 80 (% predicted) 2. Mean morning PEFR during last 7 days < 80 (% predicted) 3. 20% or greater diurnal variability in PEFR on at least 4 of last 7 days 4. Asthma symptoms on at least 4 of last 7 days Exclusion criteria: Oral corticosteroids with in the last 4 weeks FP: 500 mcg 2 actuations 2xdaily (2000 mcg/d) BDP: 400 mcg 2 actuations 2xdaily (1600 mcg daily) Delivery device: Diskhaler DPI

Participants

Interventions

Outcomes

Change in morning PEFR compared to baseline Change in evening PEFR compared to baseline Daytime symptom score Night−time symptom score Beta2 agonist use daytime (puffs) Beta2 agonist use night−time (puffs) Clinic PEFR FEV1 FVC Change in morning serum cortisol compared to baseline Change in serum ACTH compared to baseline Oral candidiasis Oropharyngeal side effects No reply from author to clarify details of randomisation procedure

Notes

Allocation concealment B Study Methods Bootsma 1995 Setting: The Netherlands, hospital outpatient clinic Design: crossover, 3 week washout Length of intervention period: 3 weeks Randomisation: yes, by computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company sponsors)

Masking: double blind Excluded: stated Withdrawals: stated (none) Baseline characteristics: comparable Jadad score: 4 Participants 21 adults: 10M 11F Mean age 30.2 years Inclusion criteria: Adults with asthma (ATS criteria 1987) During run−in period: 4 or more symptomatic days during at least 7 days of last 2 weeks FEV1 at least 50 (% predicted) Histamine BHR (PC20 FEV1) < 4mg/ml Exclusion criteria: Subjects with seasonal allergy Use of systemic steroids in last 6 months Lower respiratory tract infection in last 6 weeks FP: 125 mcg 3 puffs 2xdaily (750 mcg/d) BDP: 250 mcg 3 puffs 2xdaily (1500 mcg/d) Delivery device: MDI Outcomes FEV1 Morning PEFR Evening PEFR Diurnal variability PEFR (%) Daytime breathlessness score Night−time breathlessness score Daily use of rescue beta2 agonist (puffs/day) Histamine BHR (PC20 FEV1) UNDW BHR (PC20 FEV1) Morning serum cortisol Serum and urinary markers of bone turnover Blood inflammatory cell profiles Blood eosinophil count Serum ECP Author provided details of randomsation method and data for morning plasma cortisol measurements Carryover effects were tested for and excluded Allocation concealment A Study Methods Connolly 1995 Setting: multicentre study UK, primary care Design: parallel group Length of intervention period: 8 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: open, no blinding Excluded: stated

Interventions

Notes

Withdrawals: stated Baseline characteristics: comparable Jadad score: 2 Participants 283 adults enrolled, 190 randomised: 43M 39F Age range: 18−70 years Inclusion criteria: Adult asthmatic patients Receiving BDP or BUD 200 mcg/d or less During 2 week run−in period: Symptom score 1 or greater on 10 successive days FEV1 > 50 (% predicted) Able to use delivery devices Exclusion criteria: Current treatment with OCS or > 6 courses in last year Change in asthma therapy in last 6 weeks Serious coexistent illness FP: 100 mcg 1 actuation 2xdaily (200 mcg/d) via Diskhaler DPI BUD: 200 mcg 1 actuation 2xdaily (400 mcg/d)via Tubuhaler DPI Outcomes Change in morning PEFR compared to baseline Change in diurnal variation in PEFR compared to baseline % symptom free days % symptom free nights % rescue beta2 agonist free days % rescue beta2 agonist free nights Physician assessed level of overall asthma control Patient assessed level of overall asthma control Morning plasma cortisol

Interventions

Notes Allocation concealment B Study Methods Dahl 1993 Setting: world−wide multicentre study, hospital outpatient clinic Design: parallel group Length of intervention period: 4 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 4 825 adults: 297M 528F Age range: 17−74 years Inclusion criteria: Adults with moderately severe chronic asthma requiring BDP 1000 mcg/d or less. During run−in period: Daytime or night−time symptoms during at least 4 days or:

Participants

Diurnal variation in PEFR of 20% or more Exclusion criteria: Systemic steroids within the last month Serious concurrent disease Interventions FP: 1. 100 mcg/d 2. 200 mcg/d 3. 400 mcg/d 4. 800 mcg/d BDP: 400 mcg/d Delivery device: MDI Outcomes Change in morning PEFR compared to baseline Change in evening PEFR compared to baseline Morning PEFR Evening PEFR Diurnal variation in PEFR FEV1 (% predicted) FVC Clinic PEFR (% predicted) % symptom free days Rescue beta2 agonist use (puffs/day) Plasma cortisol Plasma cortisol 30 mins after 250 mcg ACTH Incidence of oral candidiasis Incidence of oropharyngeal side effects Details of randomisation method and data provided by Glaxo Wellcome

Notes

Allocation concealment A Study Methods Dal Negro 1997 Setting: Italy, hospital outpatient clinic Design: crossover, 6 week 'washout' when patients treated with BDP Length of intervention period: 6 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind (double dummy) Excluded: not stated Withdrawals: not stated Jadad score: 2 8 adults: 4M 4F Age range: 19−39 years Inclusion criteria: Adult asthmatics No further details Exclusion criteria: Smokers Baseline asthma control FEV1 (% predicted): > 80

Participants

Symptom frequency: asymptomatic Interventions FP: 250 mcg 2xdaily (500 mcg/d) BUD: 400mcg 2xdaily (800 mcg/d) Delivery device: not stated Outcomes Notes Methacholine BHR (PD20 FEV1) Study in abstract form only

Allocation concealment B Study Methods Fabbri 1993 Setting: multicentre study Europe and Australia, hospital outpatient clinic Design: parallel group Length of intervention period: 12 months Randomisation: yes, computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company) Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 4 274 adults: 155M 119F Age range: 17−80 years Inclusion criteria: Patients with symptomatic moderate to severe asthma Receiving BDP or BUD 1000 mcg/d or greater During run−in period at least 2 of following: 1. Mean morning PEFR on last 7 days 70 (% predicted) or less 2. 15% or greater reversibility in FEV1 after inhaled beat2 agonist 3. Diurnal variability in PEFR 20% or greater in 4 out last 7 days 4. Asthma symptoms on 4 or more days out last 7 days Exclusion criteria: Requirement for treatment with 2000 or more mcg daily BDP/BUD or systemic steroids within last month or on more than 3 occasions in the last 6 months Hypersensitivity to inhaled corticosteroids Severe coexistent disease FP: 750 mcg 2xdaily (1500 mcg/d) BDP: 750 mcg 2xdaily (1500 mcg/d) Delivery device: MDI +/− spacer Outcomes Change in FEV1 compared to baseline Change in clinic PEFR compared to baseline Morning PEFR Evening PEFR % symptom free days % symptom free nights % beta2 agonist free days Asthma exacerbations

Participants

Interventions

Withdrawal due to asthma exacerbation (No. of patients) Morning plasma cortisol 24 hour urinary free cortisol Plasma cortisol 30 and 60 mins post 250 mcg tetracosactrin Oral Candidisasis Oropharyngeal side effects Notes Details of randomisation method provided by Glaxo Wellcome

Allocation concealment A Study Methods Ferguson 1999 Setting: multicentre study (Canada, Denmark, Indonesia, South Africa, The Netherlands), paediatric outpatient clinics Design: parallel group Length of intervention period: 20 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind (double dummy) Excluded: stated Withdrawals: stated Baseline characteristics: comparable age, height, duration of asthma Jadad score: 3 442 children enrolled, 333 randomised: 223M 110F Mean (SD) age: 8.2 (2) years FP group, 7.9 (2) years BUD group Inclusion criteria: Children with moderate to severe asthma Requiring BDP or BUD 400−800 mcg/d or FP 200−400 mcg/d for asthma control for one month or longer Ability to use inhaler device and complete diary card with parental assistance During 7 run−in period: daily symptom score of 1 or greater on 4 consecutive days, and mean morning PEFR < 85 (% predicted) over last 4 days or 15% or greater reversibility in PEFR after inhaled beta2 agonist Exclusion criteria: Patients with seasonal or exercise−induced symptoms only Hospital admission due to asthma in last month Previous systemic corticosteroid use Co−existent serious illness FP: 200 mcg 2xdaily (400 mcg/d) via Diskus/Accuhaler DPI BUD: 400 mcg 2xdaily (800 mcg/d) via Turbuhaler DPI Outcomes Morning PEFR Change in daytime symptom score compared to baseline Change in night−time symptom score compared to baseline Daytime rescue beta2 agonist use Night−time rescue beta2 agonist use Change in height compared to baseline Change in morning plasma cortisol compared to baseline Asthma exacerbations Oro−pharyngeal side effects Height assessment

Participants

Interventions

Notes Allocation concealment B Study Methods Fitzgerald 1998 Setting: Australia, paediatric outpatient clinic Design: crossover, no washout Length of intervention period: 12 weeks Randomisation: yes, computer generated sequence Allocation concealment: unclear Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: female preponderance in BDP−FP sequence group, otherwise comparable Jadad score: 4 34 children randomised, 30 completed study: 19M 11F Age range: 5−15 years Inclusion criteria: School aged children with persistent severe asthma defined as requiring 1000−2000 mcg/d of BDP or BUD to control asthma symptoms Exclusion criteria: None stated FP: 375 mcg 2xdaily (750 mcg/d) BDP: 750 mcg 2xdaily (1500 mcg/d) Delivery device: MDI+large volume spacer Outcomes Morning PEFR Evening PEFR Daytime asthma symptom score Night−time asthma symptom score 24 hour urinary free cortisol Plasma ACTH 8 am plasma cortisol Plasma 1 hour post synathsen (0.5mcg/1.73m2 body surface area) Patient assessed efficacy scale Physician assessed efficacy scale No. of asthma exacerbations No. of asthma exacerbations requiring oral steroids No reply from author to clarify details of randomisatation method

Participants

Interventions

Notes

Allocation concealment B Study Methods Gustafsson 1993 Setting: multicentre study Europe and Canada, paediatric outpatient clinic Design: parallel group Length of intervention period: 6 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company sponsors)

Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 4 Participants 398 children: 225M 173F Age range: 4−19 years Inclusion criteria: Children with a clinical diagnosis of asthma Asthma controlled using BDP 400 mcg/d or demonstrating inadequate control on less than 400 mcg/d such that during run−in period: Night−time symptoms or 1 or more days out of 7 or: Daytime symptoms on 3 or more days out of 7 or: PEFR 80 (% predicted) or less 3 or more days out of 7 or: 15% or greater reversibility FEV1 after inhaled beta2 agonist Exclusion criteria: Use of oral steroids within previous month More than 3 courses of oral steroids within previous 3 months Respiratory tract infection within previous 2 weeks FP: 100 mcg 2xdaily (200 mcg/d) BDP: 200 mcg 2xdaily (400 mcg/d) Delivery device: MDI+ large volume spacer Outcomes FEV1 (% predicted) Change in FEV1 (% predicted) compared to baseline Clinic PEFR (% predicted) Change in clinic PEFR (% predicted) compared to baseline Morning PEFR (% predicted) Change in morning PEFR (% predicted) compared to baseline Evening PEFR (% predicted) Change in evening PEFR (% predicted) compared to baseline Diurnal variation in PEFR % symptom free days % symptom free nights % beta2 agonist free days Oral Candidiasis Oropharyngeal side effects Morning plasma cortisol Details of randomisation method provided by Glaxo Wellcome

Interventions

Notes

Allocation concealment A Study Methods Hoekx 1996 Setting: multicentre study Europe, hospital outpatient clinics Design: parallel group Length of intervention period: 8 weeks Randomisation: yes, computer generated random sequence (PACT programme) Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: double blind

Excluded: stated Withdrawals: stated, 8 patients in total, 3 due to failure to meet inclusion criteria. 5 others (2 in FP group, 3 in BUD group) due to 'asthma and related events'. Baseline characteristics: comparable between groups Jadad score: 4 Participants 285 children enrolled, 229 randomised: 156M 73F Age range: 4−13 years Inclusion criteria: Mild to moderate asthma receiving ICS 200−400 mcg/d During run−in period 2 of 4 criteria: Daytime or night−time symptoms on at least 4 of 7 consecutive days One or more awakenings due to asthma symptoms on one or more night/early morning PEFR (% predicted) 75 or less on 4 of 7 days 15% or greater reversibility in FEV1 following beta2 agonist Exclusion criteria: Systemic steroids within last 3 months Unable to use delivery devices or peak flow meter Known or suspected corticosteroid hypersensitivity Seasonal allergy Infection or concurrent disease considered likely to affect asthma Any investigational drug within previous month FP: 100 mcg 2 actuations 2xdaily (400 mcg/d) via Diskhaler DPI BUD: 200 mcg 1 actuation 2xdaily (400 mcg/d) via Turbuhaler DPI Outcomes FEV1 Clinic PEFR Morning PEFR Evening PEFR Daytime asthma symptom score % symptom free days % symptom free nights Days missed from school (patients) Days missed from work (parents) Parent completed, patient−centred assessment of physical and social activity Morning serum cortisol Biochemical markers of bone turnover

Interventions

Notes Allocation concealment A Study Methods Hughes 1999a Setting: USA, primary/secondary care unclear Design: parallel group Length of intervention period: 4 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: open, no blinding Excluded: not stated Withdrawals: not stated Jadad score: 1

Participants

71 subjects Age range: not stated Inclusion criteria: Patients with asthma controlled on low dose ICS (dose range not specified) FEV1 > 70 (% predicted) 12% or greater reversibility in FEV1 after inhaled beta2 agonist Exclusion criteria: Not stated Baseline asthma control Mean FEV1 85.8−87.6 (% predicted) in each treatment group Symptom frequency: not stated

Interventions

FP: 88 mcg 2xdaily (176 mcg/d) BUD: 200 mcg 2xdaily (400 mcg/d) Delivery device: not stated

Outcomes Notes

Rescue free days (No use of beta2 agonist, oral steroid use or physician visit) Rescue beta2 agonist use (puffs/day) Study in abstract form only A montelukast treatment arm was assessed: results not considered in this review

Allocation concealment B Study Methods Hughes 1999b Setting: UK, hospital outpatient clinic Design: parallel group Length of intervention period: 12 months Randomisation: yes, stratified randomisation (using minimisation routine) Allocation concealment: unclear Masking: open, non−blinded Excluded: stated Withdrawals: stated Baseline characteristics: comparable age, sex distribution, ICS use between treatment groups Jadad score: 3 62 adults enrolled, 59 randomised: 36M 23F Age range: 21−70 years Inclusion criteria: Asthmatic patients receiving BDP or BUD 1500−2000 mcg/d FEV1 > 30 (% predicted) Exclusion criteria: Oral corticosteroid use in last 3 months 3 or more courses of oral steroids in last 12 months HRT therapy, fractures, arthritis, metabolic bone disease FP: 500 mcg 2xaily (1000 mcg/d) BUD: 800 mcg 2xdaily (1600 mcg/d)

Participants

Interventions

Delivery device: MDI+spacer Outcomes Bone mineral density assessment Biochemical markers of bone turnover Change in urinary free cortisol level compared to baseline Change in plasma cortisol level (time not specified) compared to baseline

Notes Allocation concealment B Study Methods Johansson 1998 Setting: Sweden, primary/secondary care unclear Design: parallel group Length of intervention period: 12 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind Excluded: not stated Withdrawals: not stated Baseline characteristics: no demographic data presented Jadad score: 2 219 subjects Age range: not stated Inclusion criteria: Asthmatic patients symptomatic despite treatment with BDP or BUD 400 mcg/d Exclusion criteria: Not stated FP: 200 mcg/d (once daily) BUD: 400 mcg/d (once daily) Delivery device: not stated Outcomes Change in morning PEFR compared to baseline Asthma symptom score Daily use of beta2 agonists Study in abstract form only Study also included a treatment arm with FP 100 mcg 2xdaily: results not considered Allocation concealment B Study Methods Joubert 1998 Setting: multicentre study South Africa, Greece, Spain, Hungary Primary/secondary care unclear Design: parallel group Length of intervention period: 8 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind

Participants

Interventions

Notes

Excluded: not stated Withdrawals: not stated Baseline characteristics: no demographic data presented Jadad score: 2 Participants 258 adults Age range: not stated Inclusion criteria: Adult asthmatics with symptoms despite treatment with ICS (mean dose 825 mcg/d) Exclusion criteria: Not stated FP: 375 mcg 2xdaily (750 mcg/d) via MDI BUD: 400 mcg 2xdaily (800 mcg/d) via Turbuhaler DPI Outcomes Change in morning PEFR compared to baseline Daily beta2 agonist use Asthma symptom score 24 hour area under curve serum cortisol Study in abstract form only

Interventions

Notes

Allocation concealment B Study Methods Kemmerich 1999 Setting: multicentre study Germany, primary/secondary care setting unclear Design: crossover, no washout Length of intervention period: 4 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: not stated Excluded: not stated Withdrawals: not stated Baseline characteristics: no demographic data presented Jadad score: 1 100 subjects Age range: not stated Inclusion criteria: Asthmatic patients with mild disease (not further defined) No further details Exclusion criteria: Not stated FP: 200 mcg/d via Diskus/Accuhaler DPI BUD: 400 mcg/d via Turbuhaler DPI Outcomes Notes Morning PEFR Rescue beta2 agonist free days Study in abstract form only

Participants

Interventions

Allocation concealment B

Study Methods

Langdon 1994a Setting: multicentre study UK, primary care Design: parallel group Length of intervention period: 8 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: open, no blinding Excluded: stated Withdrawals: stated Baseline characteristics: comparable age, asthma duration, baseline ICS use between treatment groups Jadad score: 2 397 adults enrolled, 281 randomised Age range: 18−70 years Inclusion criteria: Adult asthmatic patients Treatment with BDP or BUD 600 mcg/d or less FEV1 > 50 (% predicted) During 2 week run−in period: Diurnal variation PEFR 15% or greater on 4 successive days and/or daytime asthma symptoms on 4 successive days 15% or greater reversibility in FEV1 after inhaled beta2 agonist Exclusion criteria: Current or recent treatment with oral corticosteroids Change in asthma therapy in last 6 weeks Respiratory tract infection in last 6 weeks FP: 200 mcg 2xdaily (400 mcg/d) via Diskhaler DPI BUD: 400 mcg 2xdaily (800 mcg/d) via Turbuhaler DPI

Participants

Interventions

Outcomes

Morning PEFR Evening PEFR Diurnal variation in PEFR Daily asthma symptom score Daytime rescue beta2 agonist use Night−time rescue beta2 agonist use Patient assessed degree of asthma control Physicican assessed success of treatment Morning plasma cortisol

Notes Allocation concealment B Study Methods Langdon 1994b Setting: multicentre study UK, primary care Design: parallel group Length of intervention period: 8 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (central centre coding of randomisation schedules) Masking: open, unblinded Excluded: stated

Withdrawals: stated Baseline characteristics: comparable age, asthma duration and severity between treatment groups Jadad score: 3 Participants 214 adults enrolled, 157 randomised: 83M 74F Mean (SD) age: 48 (15) years FP group, 46 (17) years BUD group Inclusion criteria: Adult asthmatics 16 years of age or over 15% or greater reversibility in FEV1 after inhaled beta2 agonist Receiving ICS for asthma control FEV1 >50 (% predicted) During 2 week run−in: asthma symptoms on an least 4 of last 12 days Exclusion criteria: Current use of OCS, > 6 courses OCS in last 12 months or course OCS in last 6 weeks Change in asthma therapy in last 6 weeks Respiratory tract infection in last 4 weeks FP: 50 mcg 2 puffs 2xdaily (200 mcg/d) BUD: 200 mcg 1 puff 2xdaily (400 mcg/d) Delivery device: MDI Outcomes FEV1 FVC Clinic PEFR Morning PEFR Evening PEFR Daily asthma symptom score Daytime rescue beta2 agonist use Night−time rescue beta2 agonist use Morning plasma cortisol Patient assessed degree of asthma control Physicican assessed success of treatment

Interventions

Notes Allocation concealment A Study Methods Leblanc 1994 Setting: multicentre study Europe and Canada, hospital outpatient clinic Design: parallel group Length of intervention period: 4 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: double blind Excluded: stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 4 261 adults

Participants

Age range: 18−80 years Inclusion criteria: Patients with mild to moderate asthma During run−in period: Variability in PEFR > 20% PEFR bronchodilator response > 15% Asthma symptoms on at least 4 days or nights of the run−in period Exclusion criteria: Requirement of > 400 mcg BDP or BUD on a regular basis in preceding month Oral steroids within preceding month Severe concurrent disease Interventions FP: 100 mcg 2xdaily (200 mcg/d) BDP: 200 mcg 2xdaily (400 mcg/d) Delivery device: MDI +/− spacer Outcomes FEV1 FEV1 (% predicted) FVC (% predicted) FVC Morning PEFR Evening PEFR % symptom free days % symptom free nights % beta2 agonist free days Morning plasma cortisol Oral candidiasis Oropharyngeal side effects Details of randomisation method provided by Glaxo Wellcome

Notes

Allocation concealment A Study Methods Lorentzen 1996 Setting: multicentre study Europe, hospital outpatient clinic Design: parallel group Length of intervention period: 12 months Randomisation: yes, computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 5 213 patients randomised 104 male 109 female Age range: 18−77 years Inclusion criteria: Clinical history of severe chronic asthma Requiring and responding to inhaled beta2 agonists and high doses of ICS No change in regular asthma medication for at least one month Exclusion criteria:

Participants

Recent hospital admission due to asthma Systemic corticosteroids or respiratory tract infection within last month Hypersensitivity to corticosteroids Pregancy Inability to use aersol MDI Interventions FP: 250 mcg 2 puffs 2xdaily (1000 mcg/d) BDP: 250mcg 4 puffs 2xdaily (2000 mcg/d) Delivery device: MDI Outcomes Morning plasma cortisol FEV1 FVC Clinic PEFR Oral Candidiasis Oropharyngeal side effects Asthma exacerbations (No. of patients) Details of randomisation method provided by Glaxo Wellcome

Notes

Allocation concealment A Study Methods Lundback 1993 Setting: multicentre study Europe and Canada, hospital outpatient clinic Design: parallel group Length of intervention period: 6 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company) Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 4 585 adults: 306M 279F Age range: 18−90 years Inclusion criteria: Clinical diagnosis of moderately severe asthma Using 400−1000 mcg/d ICS During run−in period: Patients on 400−600 mcg ICS daily: 4 or more days of asthma symptoms, or at least 15% reversibility in FEV1 following beta2 agonist Patients on 600−1000 mcg ICS daily: stable symptoms during run−in period Exclusion criteria: Change in prophylactic treatment in last month Hospital admission due to respiratory disease in month preceding study Systemic steroids within preceding month 3 or more courses of systemic steroids in 6 months Concurrent serious illness FP: 1. 500 mcg/d via MDI 2. 500 mcg/d via Diskhaler DPI

Participants

Interventions

BDP: 1000 mcg/d via MDI Outcomes FEV1 FVC Morning PEFR Evening PEFR Diurnal variation PEFR % patients with no change/improvement in daytime symptom score % patients with no change/improvement in night−time symptom score % patients with same/reduced daytime requirement for beta2 agonists % patients with same/reduced night−time requirement for beta2 agonists Morning plasma cortisol Oral Candidiasis Oropharyngeal side effects Details of randomisation method and standard deviation values for outcomes not reported in original paper provided by Glaxo Wellcome Randomised study followed by an open 46 week treatment period: results not considered in this review Allocation concealment A Study Methods Lundback 1998 Setting: Sweden, hospital outpatient clinic Design: parallel group Length of intervention period: 12 months Randomisation: yes, method not stated Allocation concealment: unclear Masking: no details Excluded: no details Withdrawals: no complete details Baseline characteristics: no details Jadad score: 1 74 subjects Age range: not stated Inclusion criteria: Diagnosis of "chronic severe asthma" Treatment with prednisolone 5mg/d and ICS 800 mcg/d or greater Exclusion criteria: Not stated FP: 750 mcg 2xdaily (1500 mcg/d) via Diskhaler DPI BUD: 800 mcg 2xdaily (1600 mcg/d) via Turbuhaler DPI Outcomes Discontinuation of oral prednsiolone (% of patients) Oral prednisolone consumption over treatment period FEV1 Morning PEFR Asthma symptom score Health status (scale not stated)

Notes

Participants

Interventions

Notes Allocation concealment B Study Methods Malo 1999 Setting: Canada, hospital outpatient clinic Design: crossover, no washout Length of intervention period: 4 months Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind Excluded: stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 3 69 adults: 30M 39F Mean (SD) age: 48.4 (14.5) years Inclusion criteria: Adults with asthma (ATS criteria) Moderate to severe disease (no definition) Stable for 3 months or longer (no definition) Requiring BDP or BUD 800−2000 mcg/d for asthma control 15% or greater variability in FEV1 over preceding 2 years Exclusion criteria: Regular oral steroid use Any oral steroid use within last 3 months Use of aspirin, non−steroidals or anticoagulants, history of bleeding disorders, smokers 1. FP at nominal daily dose half normal mcg dose of BDP 2. BDP usual nominal maintenance dose Delivery device: MDI Outcomes FEV1 (% predicted) FVC (% predicted) Diary card assessed skin bruising severity score Diary card assessed skin bruising frequency score Clinic assessed skin bruising score One or more night−time awakening due to symptoms (No. of patients) Symptoms on wakening in morning (No. of patients) 24 hour urinary cortisol Plasma cortisol Plasma cortisol post synthetic ACTH Urinary calcium Urinary phosphorous Serum osteocalcin Serum bone specific alkaline phosphatase

Participants

Interventions

Notes Allocation concealment B Study Melaranci 1999

Methods

Setting: Italy, paediatric outpatient clinic Design: parallel group Length of intervention period: 15 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind Excluded: not stated Withdrawals: not stated Baseline characteristics: no details Jadad score: 2 143 children Age range: 3−11 years Inclusion criteria: Children with asthma (not otherwise defined) Exclusion criteria: Not stated FP: 100 mcg 2xdaily (200 mcg/d) BDP: 100 mcg 2xdaily (200 mcg/d) Delivery device: MDI+Babyhaler spacer

Participants

Interventions

Outcomes

Morning PEFR Evening PEFR Wheeze score Cough score Study in abstract form only

Notes

Allocation concealment B Study Methods Murray 1998 Setting: multicentre study USA, hospital outpatient clinics Design: parallel group Length of intervention period: 12 weeks Randomisation: yes, method not stated Allocation concealment: not stated Masking: double blind Excluded: not stated Withdrawals: not stated Baseline characteristics: no demographic data presented Jadad score: 2 790 adults Age range: not stated Inclusion criteria: Adult asthmatics using BDP or TA 8 puffs/d or greater FEV1 45−80 (% predicted) Exclusion criteria: Not stated FP: 1. 88 mcg 2xdaily (176 mcg/d) 2. 220 mcg 2xdaily (440 mcg/d)

Participants

Interventions

BDP: 1. 168 mcg 2xdaily (336 mcg/d) 2. 336 mcg 2xdaily (672 mcg/d) Delivery device: not stated Outcomes FEV1 Morning PEFR Daily beta2 agonist use (puffs/d) Asthma symptom score Withdrawal due to lack of efficacy Study in abstract form only

Notes

Allocation concealment B Study Methods Pauwels 1998 Setting: multicentre study Belgium, hospital outpatient clinic Design: crossover, no washout Length of intervention period: 6 months Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind Excluded: stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 3 340 adults: 196M 144F Age range: 18−75 years Inclusion criteria: Moderate to severe asthma Requiring 800−2000 mcg/d BDP or BUD for asthma control 15% or greater reversibility in FEV1 after inhaled beta2 agonist FEV1 > 40 (% predicted) Exclusion criteria: > 6 weeks of oral corticosteroids within last year Oral steroids, hospitalisation due to asthma or respiratory tract infection in last month Use of any drugs affecting bone metabolism Patients randomised to receive FP or BDP in a nominal daily dose ratio of 1:2 Dose was individualised depending on pre−study daily ICS dose: Pre−study: BDP 1000 /BUD 800 mcg/d Randomised to: BDP 1000 or FP 500 mcg/d Pre−study: BDP 1500/ BUD 1200 mcg/d Randomised to: BDP1500 or FP 750 mcg/d Pre−study: BDP 2000/ BUD 1600 mcg/d Randomised to: BDP 2000 or FP 1000 mcg/d Outcomes FEV1 (% predicted)

Participants

Interventions

FVC % symptom free days % symptom free nights % rescue salbutamol free days Hyland Living With Asthma Questionnaire (LWAQ) Serum cortisol Serum osteocalcin Serum calcium Urinary hydroxyproline Bone mineral density by dual photon x−ray absorbitometry (DEXA) Withdrawal due to asthma (No. of patients) Oropharyngeal side effects Notes No reply from author to clarify details of randomisatation method Patients had the choice of using either an MDI or an MDI with large volume spacer, provided they continued to use the same device throughout the trial Allocation concealment B Study Methods Pickering 1996 Setting: multicentre study Europe, primary/secondary care unclear Design: parallel group Length of intervention period: 4 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: open, no blinding Excluded: not stated Withdrawals: not stated Baseline characteristics: no demographic data presented Jadad score: 1 277 adults Age range: 18−87 years Inclusion criteria: Asthma patients treated with ICS 400−1200 mcg/d No further details Exclusion criteria: Not stated FP: 250 mcg 2xdaily (500 mcg/d) via Diskus DPI BUD: 600 mcg 2xdaily (1200 mcg/d) via Turbuhaler DPI Outcomes Notes Morning PEFR Morning plasma cortisol Study in abstract form only

Participants

Interventions

Allocation concealment B Study Methods Rao 1999 Setting: UK, paediatric outpatient and primary care Design: parallel group Length of intervention period: 20 months Randomisation: yes, computer generated sequence

Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: double blind Excluded: not stated Withdrawals: stated (none) Baseline characteristics: comparable Jadad score: 4 Participants 23 children: 15M 8F Age range: 5−10 years Inclusion criteria: Pre−pubertal children with moderately severe asthma defined by episodic breathlessness and wheeze with symptom relief following bronchodilator and symptoms during run−in period Exclusion criteria: Previous regular use of inhaled corticosteroid Systemic corticosteroid in last 2 weeks Respiratory tract infection in last 2 weeks FP: 100 mcg 2xdaily (200 mcg/d) BDP: 200 mcg 2xdaily (400 mcg/d) Delivery device: MDI+spacer Outcomes Morning plasma cortisol FEV1 (% predicted) FEF25−75 Post exercise fall in FEV1 Histamine BHR (log 10 PC20 FEV1) Daily asthma symptom score Bone mineral density by dual energy x−ray absorptometry Serum and urine markers of bone turnover Height assessment Details of randomisation method provided by authors

Interventions

Notes

Allocation concealment A Study Methods Raphael 1999a Setting: multicentre study USA, primary care and hospital outpatient clinics Design: parallel group Length of intervention period: 12 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 5 399 adolescents and adults: 167M 232F Age range: 12−83 years Inclusion criteria:

Participants

12 years of age or older with established diagnosis of asthma (no further details) At end of run−in period: FEV1 of 45−65 (% predicted), or if FEV1 65−80 (% predicted) additional evidence of sub−optimal control (> 8 puffs rescue beta2 agonist/week, diurnal PEFR variability > 20%, any night−time wakening due to asthma symptoms requiring beta2 agonist) 12% or greater increase in FEV1 after inhaled beta2 agonist Regular treatment with BDP or TA 8−12 puffs/day for one month or longer Exclusion criteria: Use of systemic steroids, leukotreine modifiers, sodium cromoglycate or nedocromil within last month Smokers Asthma exacerbation during run−in period Interventions FP 44 mcg 2 puffs 2xdaily (176 mcg/d) BDP: 42 mcg 4 puffs 2xdaily (336 mcg/d) Delivery device: MDI Outcomes Outcomes expressed as a change compared to baseline: FEV1 FEF25−75 FVC Morning PEFR Evening PEFR Rescue beta2 agonist use Daily asthma symptom score % days with no rescue beta2 agonist use % days with no symptoms Asthma exacerbations Oropharyngeal side effects Oropharyngeal Candidiasis Notes Allocation concealment A Study Methods Participants Interventions Raphael 1999b See Raphael 1999a See Raphael 1999a FP: 110 mcg 2 puffs 2xdaily (440 mcg/d) 4. BDP 42 mcg 8 puffs 2xdaily (672 mcg/d) Delivery device: MDI Outcomes Notes Allocation concealment A Study Ringdal 1996 See Raphael 1999a

Methods

Setting: multicentre study New Zealand and Scandinavia, hospital outpatient clinics Design: parallel group Length of intervention period: 12 weeks Randomisation: yes, computer generated random sequence (PACT programme) Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable between groups Jadad score: 4 518 adults: 279M 239F Age range: 18−75 years Inclusion criteria: Clinical history of reversible airways obstruction Requirement for regular inhaled corticosteroids at constant dosage for at least 4 weeks FEV1 (% predicted) 45−90 During run−in period: Mean morning PEFR 90% or less of the response obtained following inhaled salbutamol at start of study, over last 7 days Requiring 2 or more doses beta2 agonist, or 2 or greater asthma symptom score on at least 4 of last 7 days Exclusion criteria: Oral steroids within last month Respiratory tract infection or admission to hospital with respiratory disease within the last month Severe concomitant disease, pregnancy or lactation FP: 800 mcg/d via Diskhaler DPI BUD: 1600 mcg/d via Turbuhaler DPI

Participants

Interventions

Outcomes

FEV1 FVC Morning PEFR Evening PEFR Diurnal variation in PEFR Daily PEFR (% predicted) Clinic PEFR Daytime symptom score Night−time symptom score % symptom free days % symptom free nights % rescue beta2 agonist free days % rescue beta2 agonist free nights Morning plasma cortisol Details of randomisation procedure confirmed by Glaxo Wellcome

Notes

Allocation concealment A Study Ringdal 1998

Methods

Setting: Sweden, primary/secondary care setting unclear Design: crossover, 2 week washout Length of intervention period: 2 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind (double dummy) Excluded: not stated Withdrawals: 3 dropouts, reasons not stated Baseline characteristics: Jadad score: 2 48 adults randomised, 45 completed study: 31M 14F Mean age: 50 years Inclusion criteria: Adult asthmatics treated with BDP or BUD 1500−1600 mcg/d No further details Exclusion criteria: Not stated FP: 750 mcg 2xdaily (1500 mcg/d) via Diskus/Accuhaler DPI BUD: 800 mcg 2xdaily (1600 mcg/d) via Turbuhaler DPI

Participants

Interventions

Outcomes Notes

Morning serum cortisol (AUC 0830−1030) 12 hour night time urinary cortisol Study in abstract form only Carryover effects were tested for and excluded

Allocation concealment B Study Methods Steinmetz 1997 Setting: multicentre study Germany, hospital outpatient clinics Design: parallel group Length of intervention period: 6 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: open, no blinding Excluded: stated Withdrawals: not stated Baseline characteristics: stated that patients in each group were of comparable age, asthma duration, baseline FEV1/PEFR but no tabulated demographic data presented Jadad score: 1 497 adults recruited, 457 randomised: 224M 233F Age range: 18−74 years Inclusion criteria: Patients with asthma Documented asthma symptoms and/or 15% or greater diurnal variability in diary card recorded PEFR on at least 4 days of 2 week run−in period FEV1 or morning PEFR 50−80 (% predicted) Exclusion criteria: Use of any corticosteroid within last 3 weeks

Participants

Current use of sodium cromoglycate, nedocromil or ketotifen Respiratory tract infection within last 2 weeks Interventions FP: 125 mcg 2 puffs 2xdaily (500 mcg/d) via MDI BUD: 200 mcg 3 actuations 2xdaily (1200 mcg/d) via Turbuhaler DPI Outcomes FEV1 Morning PEFR Evening PEFR % symptom free days Evaluation of treatment as ''very effective'' (No. of physicians) Oropharyngeal side−effects Primary citation translated from German

Notes

Allocation concealment B Study Methods Williams 1997 Setting: multicentre study UK, hospital outpatient clinic Design: parallel group Length of intervention period: 4 weeks Randomisation: yes, computer generated random sequence Allocation concealment: yes (central coding by pharmaceutical company sponsors) Masking: non−blinded Excluded: stated Withdrawals: stated, 9 in FP group 11 BUD group, exact reasons unclear, but some related to asthma exacerbations Baseline characteristics: comparable between groups Jadad score: 3 338 subjects enrolled, 323 randomised Age range: 4−11 years Inclusion criteria: Children with a clinical diagnosis of asthma Receiving or had symptoms indicating a clinical requirement for, inhaled corticosteroids at a daily dose of 400 mcg BUD or BDP, or 200 mcg FP. Able to use delivery devices and peak flow meter Exclusion criteria: Any medication via the Turbohaler within the last 12 months or previous use of Accuhaler FP: 100 mcg 2xdaily (200 mcg/d) via Accuhaler DPI BUD: 200 mcg 2xdaily (400 mcg/d) via Turbohaler DPI Outcomes Change in morning PEFR compared to baseline Diurnal variation in PEFR Symptom free nights (No. of patients) Symptom free days (No. of patients) Rescue beta2 agonist free days (No. of patients) Rescue beta2 agonist free nights (No. of patients) Details of randomisation method and data for morning PEFR provided by Glaxo Wellcome

Participants

Interventions

Notes

Allocation concealment A Study Methods Wolthers 1997 Setting: Denmark, hospital outpatient clinic Design: crossover, 2 week washout Length of intervention period: 2 weeks Randomisation: yes, computer generated sequence Allocation concealment: yes Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: comparable Jadad score: 4 19 children: 15M 4F Age range: 7−14 years Inclusion criteria: Children with mild asthma requiring treatment with beta2 agonists only Exclusion criteria: Treatment with either inhaled or oral corticosteroids in the preceding 2 months 1.FP 100 mcg 1 actuation 2xdaily (200 mcg/d) 2. BDP 200 mcg 1 actuation 2xdaily (400 mcg/d 3. BDP 400 mcg 1 actuation 2xdaily (800 mcg/d) Delivery device: Diskhaler DPI Outcomes FEV1 Morning PEFR Evening PEFR % symptom free days % symptom free nights Urinary free cortisol/creatinine ratio Growth by lower leg knemometry Serum markers of bone and collagen turnover

Participants

Interventions

Notes Allocation concealment A Study Methods Yiallouros 1997 Setting: UK, paediatric outpatient clinic Design: crossover, no washout Length of intervention period: 6 weeks Randomisation: yes, method not stated Allocation concealment: unclear Masking: double blind Excluded: not stated Withdrawals: stated Baseline characteristics: authors state well matched for sex ratio, height, duration of asthma, history of atopy Jadad score: 3

Participants

34 children: 23M 11F Age range: 5−13.1 years Inclusion criteria: Children with severe but clinically stable chronic asthma Established on either inhaled BDP or BUD for at least 3 months prior to study Exclusion criteria: Oral steroids in previous 3 months Oral steroids for 10 or more consecutive days or for 20 days in total in previous year Co−existing respiratory disease Respiratory tract infection in previous 2 weeks Seasonal pattern to asthma FP: half daily mcg dose of pre study ICS via MDI+spacer BDP: dose equal to pre−study ICS via MDI+spacer

Interventions

Outcomes

24 hour urinary cortisol Morning PEFR Evening PEFR % cough free days % wheeze free days % symptom free activity days % cough free nights Daytime beta2 agonist use Night−time beta2 agonist use No reply from author to clarify details of randomisation method

Notes

Allocation concealment B Study Methods de Benedictis 1998 Setting: multicentre study Europe, hospital outpatient clinic Design: parallel group Length of intervention period: one year Randomisation: yes, method not stated Allocation concealment: unclear Masking: no details Excluded: no details Withdrawals: no details Baseline characteristics: no details Jadad score: 1 343 children Age range: 4−11 years Inclusion criteria: Pre−pubertal children with asthma, no further details Exclusion criteria: No details FP: 200 mcg 2xdaily (400 mcg/d) BDP: 200 mcg 2xdaily (400 mcg/d) Delivery device: Diskhaler DPI

Participants

Interventions

Outcomes

Growth velocity FEV1 Morning PEFR Evening PEFR Daily asthma symptom score Rescue beta2 agonist use Overnight urinary cortisol Study in abstract form only

Notes

Allocation concealment B

ACTH: adrenocorticotropic hormone; BDP: beclomethasone dipropionate; BHR: bronchial hyperresponsiveness; BUD: budesonide; DPI: dry powder inhaler; ECP: eosinophil cationic protein; 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; HRQOL: health−related quailty of life; ICS: inhaled corticosteroid; mcg/d: micrograms per day; MDI: metered dose inhaler; OCS: oral corticosteroid; 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; UNDW: ultrasonically nebulised distilled water

Characteristics of excluded studies

Study Barnes 1999a Barnes 1999b Clark 1996a Clark 1996b Clark 1997 Egan 1999 Ericsson 1999 Harmanci 1998 Harrison 1999 Lipworth 1997 Lofdahl 1999 Medici 1998 O'Reilly 1998 Price 1998 Primhak 1999 Spelman 1999 Stempel 1999 Thorsson 1999 Reason for exclusion Health economic analysis Health economic analysis Treatment period less than one week Treatment period less than one week Treatment periods of less than one week RCT assessing effects of BDP and FP on bone mineral density and biochemical markers of bone turnover. No other outcomes reported. Health economic analysis Unclear if RCT Not RCT Study < 1 week duration Study conducted in asthmatic and healthy volunteers, < 1 week duration Only outcomes assessed concerned with bone density and biochemical markers of bone turnover Nebuliser delivery device employed Health economic analysis Knemometry and biochemical markers of bone turnover only assessed. Health economic analysis Health economic analysis Healthy volunteers assessed

Thwaites 1997 Tsoi 1998 Wilson 1998

Health economic analysis Daily dose of FP unclear Crossover study with intervention periods of 4 days

ADDITIONAL TABLES

Table 01 Outcome data not included in the meta−analysis

Study ID Agertoft 1997a Jadad score 5 Missing data FEV1 FVC FEF25−75 % fall in FEV1 after 6 minute treadmill exercise test % fall in FEF25−75 after 6 minute exercise treadmill test Morning PEFR Evening PEFR Daytime asthma symptom score Night−time asthma symptom score Rescue beta2 agonist use (puffs/d) 24 hour urinary free cortisol No SD values available for above outcomes Morning PEFR Evening PEFR 24 hour urinary cortisol excretion No SD values available for above outcomes Daily asthma symptoms score Daily beta2 agonist use No numerical data available Symptom free days and nights Rescue beta2 agonist free days and nights Daytime and night−time symptom scores Above outcomes analysed by investigators using non−parametric tests Change in FEV1 compared to baseline Change in FVC compared to baseline Change in morning PEFR compared to baseline Change in evening PEFR compared to baseline Change in diurnal variability in PEFR compared to baseline Change in clinic PEFR compared to baseline No SD values available for above outcomes Morning plasma cortisol Data log transformed and reported using geometric means by investigators: log transformed values not available Morning PEFR Evening PEFR Diurnal variability in PEFR daytime salbutamol use night−time salbutamol use No standard deviation values for above outcomes FEV1 FVC Diurnal variation in PEFR Daytime asthma symptom score Night−time asthma symptom score Daytime beta2 agonist use Night−time beta2 agonist use No SD values available for above outcomes FEV1 FVC Clinic PEFR No numerical data available for above outcomes Change in Asthma Quality of Life Questionnaire domain scores compared to baseline Change in SF−36 questionnaire domain scores compared to baseline SD values available for above outcomes FEV1 (% predicted) Clinic PEFR (% predicted) Airway resistance (% predicted) MEF50 (% predicted) Numbers randomised to each treatment group not stated FVC Dairy card morning PEFR Diary card evening PEFR Symptom score Rescue beta2 agonist use No data presented for above outcomes Histamine BHR log 10 PC20 FEV1 UNDW BHR log 10 PC20 FEV1 No SD values available for above outcome Change in diurnal variation in PEFR compared to baseline % symptom free days % symptom free nights % rescue beta2 agonist free days % rescue beta2 agonist free nights Physician assessed level of overall asthma control Patient assessed level of overall asthma control Morning plasma cortisol Non−parametric tests used by investigators to examine treatment differences for above outcomes Morning plasma cortisol Plasma cortisol 30 min post 250 mcg ACTH Diurnal variation in PEFR Daily beta2 agonist use (puffs/day) No SD values available for above outcomes Methacholine BHR (PD20 FEV1) Log transformed data not available FEV1 Morning PEFR Evening PEFR Daily symptom score Rescue beta2 agonist use Overnight urinary cortisol No numerical data available for above outcomes

Agertoft 1997b

Ayres 1995

Barnes 1993 Basran 1997

4 3

Berend 1997

Bisca 1997

Bootsma 1995 Connolly 1995

4 2

Dahl 1993 dal Negro 1997 de Benedictis 1998 Fabbri 1993

4 2 1 4

Morning PEFR Evening PEFR Morning plasma cortisol Plasma cortisol post ACTH No SD values available for above outcomes Ferguson 1999 3 Evening PEFR Change in daytime symptom score compared to baseline Change in night−time symptom score compared to baseline Daytime rescue beta2 agonist use No SD values available for above outcomes Morning plasma cortisol Log transformed values not available Morning PEFR Evening PEFR 24 hour urinary free cortisol Plasma ACTH 8 am plasma cortisol Plasma 1 hour post synathsen (0.5mcg/1.73m2 body surface area) No SD values available for above outcomes Patient assessed efficacy scale Physician assessed efficacy scale Daytime asthma symptom scores − no data presented Night−time asthma symptom scores − no data presented FEV1 (% predicted) Change in FEV1 (% predicted) compared to baseline Clinic PEFR (% predicted) Change in clinic PEFR (% predicted) compared to baseline Morning PEFR (% predicted) Change in morning PEFR (% predicted) compared to baseline Evening PEFR (% predicted) Change in evening PEFR (% predicted) compared to baseline Diurnal variation in PEFR % symptom free days/nights % beta2 agonist free days Morning plasma cortisol No SD values available for above outcomes Daytime asthma symptom score % symptom free days % symptom free nights Days missed from work/school Parent completed, patient−centred assessment of physical and social activity Above outcomes analysed by investigators using non−parametric statistics Morning plasma cortisol Data log transformed and reported using geometric means FEV1 Clinic PEFR No numerical data available for above outcomes Rescue free days (No use of beta2 agonist, oral steroid use or physician visit) Rescue beta2 agonist use (puffs/day) Data for above outcomes reported using medians with interquartile range Change in urinary free cortisol level compared to baseline Change in plasma cortisol level (time not specified) compared to baseline No SD values available for above outcomes Change in morning PEFR compared to baseline No SD values available for above outcomes Asthma symptom score Daily use of beta2 agonists No data presented for above outcomes Change in morning PEFR compared to baseline Daily beta2 agonist use Asthma symptom score 24 hour area under curve serum cortisol No numerical data presented for above outcomes Morning PEFR Rescue beta2 agonist free days No data presented for above outcomes Diurnal variation in PEFR % symptom free days % symptom free nights Rescue beta2 agonist use Above outcomes analysed by investigators using non−parametric tests Morning PEFR Morning plasma cortisol No SD values available for this outcome Daily asthma symptom score Daytime rescue beta2 agonist use Night−time rescue beta2 agonist use Patient assessed degree of asthma control Above outcomes analysed by investigators using non−parametric test Morning plasma cortisol No SD values available for this outcome FEV1 FEV1 (% predicted) FVC (% predicted) FVC Morning PEFR Evening PEFR % symptom free days % symptom free nights % beta2 agonist free days Morning plasma cortisol Plasma cortisol 30min post ACTH No SD values available for above outcomes Morning plasma cortisol (log transformed) FEV1 FVC Clinic PEFR No SD values for above outcomes Morning PEFR Evening PEFR Diurnal variation in PEFR Morning plasma cortisol Plasma cortisol post ACTH No SD values available for above outcomes Morning PEFR Evening PEFR Wheeze score Cough score No numerical data available FEV1 (% predicted) FVC No SD values available for above outcomes Morning PEFR Morning plasma cortisol

Fitzgerald 1998

Gustafsson 1993

Hoekx 1996

Hughes 1999a

Hughes 1999b Johansson 1998

3 2

Joubert 1998

Kemmerich 1999 Langdon 1994a

1 3

Langdon 1994b

Leblanc 1994

Lorentzen 1996 Lundback 1993 Melaranci 1999 Pauwels 1998 Pickering 1996

5 3 2 3 1

Rao 1999 Ringdal 1996

4 4

FEF25−75 Post exercise fall in FEV1 Histamine BHR (log 10 PC20 FEV1) Daily asthma symptom score No SD values for above outcomes Daytime symptom score Night−time symptom score % symptom free days % symptom free nights % rescue beta2 agonist free days % rescue beta2 agonist free nights Above outcomes analysed by investigators using non−parametric tests Morning plasma cortisol Data log transformed and reported using geometric means Diurnal variation in PEFR No SD values available for this outcome % symptom free days and nights (No. of patients) % rescue beta2 agonist free days and nights (No. of patients) Above outcomes analysed by investigators using non−parametric statistics Morning PEFR: no SD values available Evening PEFR: no numerical data available % cough free days: effect size expressed as median % wheeze free days % symptom free activity days % cough free nights Daytime beta2 agonist use Night−time beta2 agonist use No numerical data presented for above outcomes

Williams 1997

Yiallouros 1997

Table 02 Delivery devices used

Study ID Barnes 1993 Bootsma 1995 Dahl 1993 Lorentzen 1996 Malo 1999 Raphael 1999a/Raphael 1999b Boe 1994 de Benedictis 1998 Wolthers 1997 Fitzgerald 1998 Gustafsson 1993 Melaranci 1999 Rao 1999 Yiallouros 1997 Fabbri 1993 Leblanc 1994 Pauwels 1998 Lundback 1993 Comparison FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP v BDP FP device MDI MDI MDI MDI MDI MDI DISKHALER DISKHALER DISKHALER MDI+SPACER MDI+SPACER MDI+SPACER MDI+SPACER MDI+SPACER MDI+/− SPACER MDI+/− SPACER MDI+/− SPACER MDI AND DISKHALER (2 treatment arms) BDP/BUD device MDI MDI MDI MDI MDI MDI DISKHALER DISKHALER DISKHALER MDI+SPACER MDI+SPACER MDI+SPACER MDI+SPACER MDI+SPACER MDI+/− SPACER MDI+/− SPACER MDI+/− SPACER MDI

Agertoft 1997a Agertoft 1997b Basran 1997

FP v BUD FP v BUD FP v BUD

DISKHALER DISKHALER DISKHALER

TURBOHALER TURBOHALER TURBOHALER

Connolly 1995 Hoekx 1996 Langdon 1994a Lundback 1998 Ringdal 1996 Ferguson 1999 Kemmerich 1999a Pickering 1996 Ringdal 1998 Williams 1997 Joubert 1998 Steinmetz 1997 Langdon 1994b Hughes 1999b Ayres 1995 Bisca 1997 Murray 1998 Dal Negro 1997 Hughes 1999a Johansson 1998

FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BUD FP v BDP FP v BDP FP v BUD FP v BUD FP v BUD

DISKHALER DISKHALER DISKHALER DISKHALER DISKHALER ACCUHALER ACCUHALER ACCUHALER ACCUHALER ACCUHALER MDI MDI MDI MDI+SPACER MDI+/− SPACER NOT STATED NOT STATED NOT STATED NOT STATED NOT STATED

TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER TURBOHALER MDI MDI+SPACER MDI +/− SPACER NOT STATED NOT STATED NOT STATED NOT STATED NOT STATED

Berend 1997

FP v BDP/BUD

MDI+SPACER

MDI+SPACER OR TURBOHALER

Table 03 Approximation of asthma severity

Study ID IC FEV1 BL FEV1 (% pred) BL symptoms Oral steroids ICS at at BL BL Author opinion Approx severity

BL= baseline IC= inclusion criterion OCS= oral corticosteroid ICS= inhaled corticosteroid Agertoft 1997a Not stated 92−94 Not stated No Yes: requiring Moderate Moderate

BUD 400−800 mcg/d Agertoft 1997b Ayres 1995 Not stated Not stated Not stated Morning PEFR 73−77 No Need for 2 or more doses beta2 agonist on 2 out of 7 days of run in period No Proportion of patients using OCS (<10 mg/d) Not stated Mild Mild Moderate to severe

Yes: BDP Moderate to 1−2 mg/d severe or BUD 0.8−1.6 mg/d Yes: BDP Severe or BUD 1.5 to 2 mg/d Yes: 400−800 mcg/d ICS Mild to moderate

Barnes 1993

Not stated

57−61

Symptoms on at least 4 out No of 7 days of run−in period

Severe

Basran 1997

>40

80−82

Night−time awakening on 2 No or more out of 7 during run−in Symptoms on at least 2 days/week, night−time symtoms on at least 2 nights/week No details On at least 4 out of 7 days of run−in period No

Mild to moderate

Berend 1997

No details

Yes: BDP Severe or BUD 1750 mcg/d or greater No details Moderate to severe

Severe

Bisca 1997 Boe 1994

No details <80

48.8−52.3 Not stated

No No

Moderate to severe Moderate to severe

Yes: BDP Not stated or BUD 400−2000 mcg/d Yes: Not stated mean daily dose of ICS 790 mcg/d Some: BDP or BUD 200 mcg/d or less Mild

Bootsma 1995

50 or greater

75−85

On at least 4 out of 7 days of run−in period

Moderate to severe

Connolly 1995

>50

Not stated

Symptoms on at least 2 out No of last 10 days

Mild

Dahl 1993

Not stated

73−75

Daytime wheezing or No night−time symptoms on at least 4 days of 7 day run−in period or PEFR variability 20% or greater Asymptomatic No details No No

Yes: BDP Moderate 1000 mcg/d or less No details No details Mild Not stated

Moderate

Dal Negro 1997 de Benedictis 1998 Fabbri 1993

No details No details Not stated

No details No details Morning PEFR 73−74

Mild Unclear Moderate to severe

Symptoms on at least 4 out No of 7 days of run−in period

Yes: BDP Moderate to or BUD severe 1000 mcg/d or greater

Fergusson 1999

Not stated

Symptoms on at least 4 out No of 7 days of run−in period

Yes: BDP Moderate to or BUD severe 400−800 mcg/d or FP 200−400 mcg/d Yes: BDP Severe or BUD 1−2 mg/d Yes: BDP Moderate up to 400 mcg/d Yes: ICS 200−400 mcg/d Mild to moderate

Moderate to severe

Fitzgerald 1998

Not stated

Severe

Gustafsson 1993 Hoekx 1996

Not stated Not stated >70

Morning PEFR 100 Morning PEFR 97−98 FEV1 86−88

If using BDP < 400 mcg/d: No symptoms on at least 3 out of 7 days of run−in period Symptoms on at least 4 out No of 7 days of run−in period No details No

Moderate

Mild to moderate Mild

Hughes 1999a

Some Mild using low dose ICS, no further details Yes: BDP Moderate to or BUD severe 1500−2000 mcg/d Yes: BDP Mild to or BUD moderate 400 mcg/d Yes: Not stated mean daily dose ICS 825 mcg/d No details Yes: majority using BDP or BUD, up to 600 mcg/d Yes: majority using an ICS, no further details Mild to moderate Not stated

Hughes 1999b

>30

Not stated

Moderate to severe

Johansson 1998

No details

Symptomatic despite ICS 400 mcg/d, no further details Symptomatic despite ICS

Mild to moderate

Joubert 1998

No details

FEV1 75

Moderate to severe

Kemmerich 1999 Langdon 1994a

No details > 50

No details Not stated

No details

Mild to moderate Mild to moderate

Symptoms on at least 4 out No of 12 days of run−in period

Langdon 1994b

>50

Not stated

Symptoms on at least 4 out No of 12 days of run−in period

Mild to moderate

Leblanc 1994

Not stated

FEV1 71−73

Symptoms on at least 4 out No of 14 days of run−in period

Some Mild to using moderate BDP or BUD (no more than 400

Mild to moderate

mcg/d) Lorentzen 1996 Not stated Not stated Not stated No Yes: BDP Severe or BUD 1−2 mg/d Yes: ICS 800 mcg/d or greater Severe Severe

Lundback 1998

No details

Yes: prednisolone 5 mg/d or greater

Severe

Lundback 1993

Not stated

Symptoms on 4 out of 14 No days of run−in period for patients using ICS 400−600 mcg/d Not stated No

Yes: ICS Moderate 400−1000 mcg/d Yes: BDP Moderate to or BUD severe 800−2000 mcg/d No details Moderate

Moderate

Malo 1999

Not stated

FEV1 75.8

Moderate to severe

Melaranci 1999 Murray 1998

No details No details

No details FEV1 range 45−80

No details No details

No No

Moderate Moderate

Yes: BDP Moderate or TA 8 puffs/d or greater Yes: BDP Moderate to or BUD severe 800−2000 mcg/d Yes: ICS Moderate to 400−1200 severe mcg/d No Moderate

Pauwels 1998

>40

FEV1 78−80

Not stated

Moderate to severe

Pickering 1996

50−90

No details

Moderate to severe Moderate

Rao 1999 Raphael 1999a/Raphael 1999b

Not stated 45−65

FEV1 79−91 FEV1 64.7−65.7

Symptoms on at least 2 out No of 7 days of run−in period > 8 puffs/week beta 2 No agonist or diurnal variability in PEFR > 20% during run−in if FEV > 65−80 (% predicted) Symptoms on at least 4 out No of 7 days of run−in period

Yes: BDP Mild/moderate Mild/moderate or TA and severe and severe 8−12 puffs/d Yes: BDP Moderate to or BUD severe 400−2400 mcg/d Yes: BDP Moderate or BUD 1500−1600 mcg/d No Moderate Moderate to severe

Ringdal 1996

45−90

Not stated

Ringdal 1998

No details

Symptoms and need to No rescue beta2 agonist during 2 week run−in Symptoms on at least 4 out No of 14 days of run−in period "Symptoms indicating a clinical requirement for ICS" if not already using one, no further details No

Moderate to severe

Steinmetz 1997

50−80

Not stated

Moderate

Williams 1997

Not stated

Some: BDP or BUD 400 mcg/d or less, FP

Not stated

Mild to moderate

200 mcg/d or less Wolthers 1997 Yiallouros 1997 Not stated Not stated Not stated Not stated Not stated Not stated No No No Mild Mild Severe

Yes: BDP Severe or BUD 400−909 mcg/m2/d

REFERENCES

References to studies included in this review Agertoft 1997a {published data only} Agertoft L, Pedersen S. A randomized, double−blind dose reduction study to compare the minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler. Journal of Allergy & Clinical Immunology 1997;99:773−80. Agertoft 1997b {published data only} Agertoft L, Pedersen S. Short−term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study. European Respiratory Journal 1997;10:1507−12. Ayres 1995 {published data only} Ayres JG, Bateman ED, Lundback B, Harris TAJ. High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. European Respiratory Journal 1995;8:579−586. Barnes 1993 {published data only} Barnes NC, Marone G, Di Maria GU, Visser S, Utama I, Payne SL. A comparison of fluticasone propionate, 1 mg daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of severe asthma. International Study Group. European Respiratory Journal 1993;6:877−85. Basran 1997 {published data only} Basran G, Campbell M, Knox A, Scott R, Smith R, Vernon J, Wade A. An open study comparing equal doses of budesonide via Turbohaler with fluticasone propionate via Diskhaler in the treatment of adult asthmatic patients. European Journal of Clinical Research 1997;9:185−97. Berend 1997 {published data only} *Berend N. A six month comparison of the efficacy of high dose fluticasone propionate (FP) with beclomethasone dipropionate (BDP) and budesonide (BUD) in adults with severe asthma. European Respiratory Journal. ;101997:105S. Gibson P, Rutherford C, Price M, Lindsay P. Comparison of the quality of life differences in severe asthma after treatment with beclomethasone dipropionate or budesonide and fluticasone propionate at approximately half the microgram dose. European Respiratory Journal. ;121998:35S. Jenkins C. High dose inhaled steroids and skin bruising. European Respiratory Journal. ;121998:435S. Bisca 1997 {published data only} Bisca N. Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe childhood asthma. European Respiratory Journal. ;101997:219S.

Boe 1994 {published data only} Boe J, Bakke P, Rodolen T, Skovlund E, Gulsvik A. High−dose inhaled steroids in asthmatics: moderate efficacy gain and suppression of the hypothalamic−pituitary−adrenal (HPA) axis. European Respiratory Journal 1994;7:2179−84. Bootsma 1995 {published data only} Bootsma GP, Dekhuijzen PN, Festen J, Mulder PG, Swinkels LM, van Herwaarden CL. Fluticasone propionate does not influence bone metabolism in contrast to beclomethasone dipropionate. American Journal of Respiratory & Critical Care Medicine 1996;153:924−30. *Bootsma GP, Dekhuijzen PN, Festen J, Mulder PG, van Herwaarden CL. Comparison of fluticasone propionate and beclomethasone dipropionate on direct and indirect measurements of bronchial hyperresponsiveness in patients with stable asthma. Thorax 1995;50:1044−50. Bootsma GP, Koenderman L, Dekhuijzen PN, Festen J, Lammers JW, van Herwaarden CL. Effects of fluticasone propionate and beclomethasone dipropionate on parameters of inflammation in peripheral blood of patients with asthma. Allergy 1998;53:653−61. Connolly 1995 {published data only} Connolly A. A comparison of fluticasone propionate 100 mcg twice daily with budesonide 200 mcg twice daily via their respective powder devices in the treatment of mild asthma. European Journal of Clinical Research 1995;7:15−29. Dahl 1993 {published data only} Dahl R, Lundback B, Malo JL, Mazza JA, Nieminen MM, Saarelainen P, Barnacle H. A dose−ranging study of fluticasone propionate in adult patients with moderate asthma. International Study Group. Chest 1993;104:1352−8. Dal Negro 1997 {published data only} Dal Negro R, Micheletto C, Turco P, Pomari C. Fluticasone prop. 500 mcg, budesonide 800 mcg, and beclomethasone dip. 1000 mcg: different protection degrees against the methacholine−induced bronchoconstriction. American Journal of Respiratory & Critical Care Medicine. ;1551997:A153. de Benedictis 1998 {published data only} de Benedictis FM, Medley HV, Williams L. Long−term study to compare safety and efficacy of fluticasone propionate (FP) with beclomethasone dipropionate (BDP) in asthmatic children. European Respiratory Journal. ;121998:142S. Fabbri 1993 {published data only} *Fabbri L, Burge PS, Croonenborgh L, Warlies F, Weeke B, Ciaccia A, Parker C. Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. Thorax 1993;48:817−23. Payne SL, Thwaites RMA, Collins N. Estimation from clinical trial data of direct costs associated with asthma exacerbations treated in hospital. European Respiratory Journal 1997;10(Suppl 28):106S. Ferguson 1999 {published data only} *Ferguson AC, Spier S, Manjra A, Versteegh FG, Mark S, Zhang P. Efficacy and safety of high−dose inhaled steroids in children with asthma: a comparison of fluticasone propionate with budesonide. Journal of Pediatrics 1999;134(4):422−7. Manjra AI, Versteegh FGA, Mehra S, Zhang P, Mark S. Clinical equivalence of fluticasone propionate (FP) 400 mcg daily via the Diskus inhaler and budesonide (B) 800 mcg daily via the Turbuhaler in asthmatic children. European Respiratory Journal. ;121998:87S. Fitzgerald 1998 {published data only} Fitzgerald D, Van Asperen P, Mellis C, Honner M, Smith L, Ambler G. Fluticasone propionate 750 micrograms/day versus beclomethasone dipropionate 1500 micrograms/day: comparison of efficacy and adrenal function in paediatric asthma. Thorax 1998;53(8):656−61. Gustafsson 1993 {published data only} Gustafsson P, Tsanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma. Archives of Disease in Childhood 1993;69:206−11.

Hoekx 1996 {published data only} Hoekx JC, Hedlin G, Pedersen W, Sorva R, Hollingworth K, Efthimiou J. Fluticasone propionate compared with budesonide: a double−blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(−1). European Respiratory Journal 1996;9:2263−72. Hughes 1999a {published data only} Hughes GL, Edelman J, Turpin J, Liss C, Weeks K, Schweiger D, Rand C. Randomized, open−label pilot study comparing the effects of montelukast sodium tablets, fluticasone aerosol inhaler and budesonide dry powder inhaler on asthma control in mild asthmatics. American Journal of Respiratory & Critical Care Medicine. ;1591999:A641. Hughes 1999b {published data only} Hughes JA, Conry BG, Male SM, Eastell R. One year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density. Thorax 1999;54(3):223−9. Johansson 1998 {published data only} *Johansson LO. A comparison of once−daily of fluticasone propionate (FP) 200 mcg and budesonide (BUD) 400 mcg twice−daily of fluticasone (FP) 100 mcg. American Journal of Respiratory & Critical Care Medicine. ;1571998:A404. Johansson LO. A comparison of once−daily regimen of fluticasone propionate (FP) 200 mcg and budesonide (BUD) 400 mcg and twice−daily regimen of fluticasone propionate (FP) 100 mcg. European Respiratory Journal. ;121998:38S. Joubert 1998 {published data only} Joubert J, Boszormenyi G, Sanchis J, Siafakas N. A comparison of the efficacy and systemic activity of budesonide and fluticasone propionate in asthmatic patients. European Respiratory Journal. ;121998:37S. Kemmerich 1999 {published data only} Kemmerich B, Bruckner OJ, Petro W. Superiority of fluticasone powder from the Diskus over budesonide from the Turbuhaler in mild and moderate asthma. American Journal of Respiratory and Critical Care Medicine. ;1591999:A627. Langdon 1994a {published data only} Booth PC, Capsey LJ, Langdon CG, Wells NEJ. A comparison of the cost−effectiveness of alternative prophylactic therapies in the treatment of adult asthma. British Journal of Medical Economics 1995;8:65−72. *Langdon CG, Capsey LJ. Fluticasone propionate and budesonide in adult asthmatics: a comparison using dry−powder inhaler devices. British Journal of Clinical Research 1994;5:85−99. Langdon 1994b {published data only} Langdon CG, Thompson J. A multicentre study to compare the efficacy and safety of inhaled fluticasone propionate and budesonide via metered−dose inhalers in adults with mild−to−moderate asthma. British Journal of Clinical Research 1994;5:73−84. Leblanc 1994 {published data only} Leblanc P, Mink S, Keistinen T, Saarelainen PA, Ringdal N, Payne SL. A comparison of fluticasone propionate 200 micrograms/day with beclomethasone dipropionate 400 micrograms/day in adult asthma. Allergy 1994;49:380−5. Lorentzen 1996 {published data only} Lorentzen KA, Van Helmond JL, Bauer K, Langaker KE, Bonifazi F, Harris TA. Fluticasone propionate 1 mg daily and beclomethasone dipropionate 2 mg daily: a comparison over 1 yr. Respiratory Medicine 1996;90:609−17. Lundback 1993 {published data only} Lundback B, Alexander M, Day J, Hebert J, Holzer R, Van Uffelen R, Kesten S, Jones AL. Evaluation of fluticasone propionate (500 micrograms day−1) administered either as dry powder via a Diskhaler inhaler or pressurized inhaler and compared with beclomethasone dipropionate (1000 micrograms day−1) administered by pressurized inhaler. Respiratory Medicine 1993;87:609−20. Lundback 1998 {published data only} Lundback B, Sandstrom T, Ekstrom T, Hermansson BA, Alton M, Tunsater A. Comparison of the oral corticosteroid sparing effect of inhaled fluticasone propionate (FP) 750 mcg bd via the Diskhaler with

budesonide (BUD) 800 mcg bd via the Turbuhaler in patients with chronic severe asthma. American Journal of Respiratory & Critical Care Medicine. ;1571998:A456. Malo 1999 {published data only} Malo JL, Cartier A, Ghezzo H, Mark S, Brown J, Laviolette M, Boulet LP. Skin bruising, adrenal function and markers of bone metabolism in asthmatics using inhaled beclomethasone and fluticasone. European Respiratory Journal 1999;13(5):993−8. Melaranci 1999 {published data only} Melaranci C. Fluticasone propionate vs beclomethasone dipropionate in pediatric patients with moderate asthma. American Journal of Respiratory & Critical Care Medicine. ;159:A631. Murray 1998 {published data only} Murray JJ, Friedman B, Chervinsky P, Fogarty C, Baker JW, Rogenes PR, Edwards WR. Fluticasone propionate (FP) is more effective than higher doses of beclomethasone dipropionate (BDP) in patients with moderate asthma. American Journal of Respiratory & Critical Care Medicine. ;1571998:A407. Pauwels 1998 {published data only} Pauwels RA, Yernault JC, Demedts MG, Geusens P. Safety and efficacy of fluticasone and beclomethasone in moderate to severe asthma. Belgian Multicenter Study Group. American Journal of Respiratory & Critical Care Medicine 1998;157:827−32. Pickering 1996 {published data only} Backman R, Pickering CAC, Baumgarten C, Huskisson SC. A comparison of fluticasone propionate via Diskus (Accuhaler) inhaler and budesonide via Turbuhaler inhaler in adult asthmatics. Journal of Allergy & Clinical Immunology. ;2491997:249. Pickering CAC, Backman R, Baumgarten C, Huskisson SC. Fluticasone propionate 250 mcg bd compared to budesonide 600 mcg bd in adult asthmatics. European Respiratory Journal. ;91996:79S. Rao 1999 {published data only} Gregson RK, Rao R, Murrills AJ, Taylor PA, Warner JO. Effect of inhaled corticosteroids on bone mineral density in childhood asthma: comparison of fluticasone propionate with beclomethasone dipropionate. Osteoporosis International 1998;8(5):418−22. *Rao R, Gregson RK, Jones AC, Miles EA, Campbell MJ, Warner JO. Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone. European Respiratory Journal 1999;13:87−94. Raphael 1999a {published data only} Raphael GD, Lanier RQ, Baker J, Edwards L, Rickard K, Lincourt WR. A comparison of multiple doses of fluticasone propionate and beclomethasone dipropionate in subjects with persistent asthma. Journal of Allergy & Clinical Immunology 1999;103(5 Pt 1):796−803. Raphael 1999b {published data only} Raphael GD, Lanier RQ, Baker J, Edwards L, Rickard K, Lincourt WR. A comparison of multiple doses of fluticasone propionate and beclomethasone dipropionate in subjects with persistent asthma. Journal of Allergy & Clinical Immunology 1999;103(5 Pt 1):796−803. Ringdal 1996 {published data only} Ringdal N, Swinburn P, Backman R, Plaschke P, Sips AP, Kjaersgaard P, Bratten G, Harris TAJ. A blinded comparison of fluticasone propionate with budesonide via powder devices in adult patients with moderate−to−severe asthma: a clinical evaluation. Mediators of Inflammation 1996;5:382−389. Ringdal 1998 {published data only} *Ringdal B, Lundback M, Alton M, Rak S, Eivindson A, Bratten G, Kjaersgaard P. Comparison of the effect on HPA−axis of inhaled fluticasone propionate (FP) 1500 mcg/day via Diskus and budesonide (BUD) 1600 mcg/day via Turbuhaler in adult asthmatic patients. American Journal of Respiratory & Critical Care Medicine. ;1571998:A406. Ringdal N, Lundback B, Alton M, Rak S, Evindson A, Bratten G, Kjaersgaard P. Comparison of the effect on HPA−Axis of inhaled fluticasone propionate (FP) 1500 mcg/day via Diskus and budesonide (BUD) 1600 mcg/day via Turbuhaler in adult asthmatic patients. European Respiratory Journal. ;121998:37S. Steinmetz 1997 {published data only}

*Steinmetz KO. [Vergleich der Wirksamkeit und Verträglichkeit von fluticasonpropionat−dosieraerosol und budesonid−pulverinhalat bei mittelschwerem asthma] [Comparative efficacy and safety of fluticasone propionate MDI versus budesonide powder inhalation in the treatment of moderate asthma]. Atemwegs Und Lungenrankheiten 1997;23(12):730−5. Steinmetz KO, Trautmann M. Efficacy of fluticasone propionate (0.5mg daily) via MDI and budesonide (1.2 mg daily) via Turbuhaler in the treatment of steroid−naïve asthmatics. American Journal of Respiratory & Critical Care Medicine. ;1531996:A338. Steinmetz KO, Volmer T, Trautmann M, Kielhorn A. Cost effectiveness of fluticasone and budesonide in patients with moderate asthma. Clinical Drug Investigation 1998;16(2):117−23. Williams 1997 {published data only} Williams J, Richards KA. Ease of handling and clinical efficacy of fluticasone propionate Accuhaler/Diskus inhaler compared with the Turbohaler inhaler in paediatric patients. British Journal of Clinical Practice 1997;51:147−53. Wolthers 1997 {published data only} *Wolthers OD, Hansen M, Juul A, Nielsen HK, Pedersen S. Knemometry, urine cortisol excretion, and measures of insulin−like growth factor axis and collagen turnover in children treated with inhaled glucocorticosteroids. Pediatric Research 1997;41:44−50. Wolthers OD, Pedersen S. Short−term growth during treatment with inhaled fluticasone propionate and beclomethasone dipropionate. Archives of Disease in Childhood 1993;68:673−6. Yiallouros 1997 {published data only} Yiallouros PK, Milner AD, Conway E, Honour JW. Adrenal function and high dose inhaled corticosteroids for asthma. Archives of Disease in Childhood 1997;76:405−10.

References to studies excluded from this review Barnes 1999a Barnes NC, Price MJ, Thwaites RMA. Impact of disease severity on the cost−effectiveness of fluticasone propionate and budesonide in asthma. European Respiratory Journal 1999;14(Suppl 30):371S. Barnes 1999b Barnes NC, Thwaites RM, Price MJ. The cost−effectiveness of inhaled fluticasone propionate and budesonide in the treatment of asthma in adults and children. Respiratory Medicine 1999;93(6):402−7. Clark 1996a Clark DJ, Clark RA, Lipworth BJ. Adrenal suppression with inhaled budesonide and fluticasone propionate given by large volume spacer to asthmatic children. Thorax 1996;51:941−3. Clark 1996b Clark DJ, Grove A, Cargill RI, Lipworth BJ. Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients. Thorax 1996;51:262−6. Clark 1997 Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997;52:55−8. Egan 1999 Egan JJ, Maden C, Kalra S, Adams JE, Eastell R, Woodcock AA. A randomized, double−blind study comparing the effects of beclomethasone and fluticasone on bone density over two years. European Respiratory Journal 1999;13(6):1267−75. Ericsson 1999 Ericsson A, Leuenberger P, Perruchoud D, Cheung C, Grassi C. Budesonide Turbohaler gave lower health care costs than fluticasone propionate. European Respiratory Journal. ;141999:508S. Harmanci 1998 Harmanci E, Colak O, Ozdemir N, Alatas O, Isik R. Fluticasone propionate and budesonide does not influence bone metabolism in the long term treatment of asthma. European Respiratory Journal. ;121998:434S.

Harrison 1999 Harrison TW, Wisniewski J, Honour JW, Tattersfield AE. Systemic activity of inhaled fluticasone propionate and budesonide in subjects with and without asthma. European Respiratory Journal. ;141999:466S. Lipworth 1997 *Lipworth BJ, Clark DJ, McFarlane LC. Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to asthmatic school children. Thorax 1997;52:686−9. Lipworth BJ, Wilson DJ, Clark DJ. Adrenal activity with chronic dosing of fluticasone propionate (FP) and budesonide (BUD) in asthmatic children. American Journal of Respiratory & Critical Care Medicine. ;1551997:A267. Lofdahl 1999 Lofdahl CG, Thorsson L. Systemic availability of inhaled fluticasone propionate and budesonide in asthmatic patients and healthy subjects. European Respiratory Journal. ;141999:466S. Medici 1998 Medici TG, Grebski E, Hacki M, Ruegsegger P, maden C, Efthimiou J. One−year treatment with inhaled fluticasone propionate or beclomethasone dipropionate does not affect bone density and bone metabolism. A randomised, parallel group study in adult asthmatics. American Journal of Respiratory & Critical Care Medicine. ;1571998:A407. O'Reilly 1998 O'Reilly JF, Weir DC, Banham S, Basran GS, Boyd G, Patel KR. Is high−dose fluticasone propionate via a metered−dose inhaler and Volumatic as efficacious as nebulized budesonide in adult asthmatics?. Respiratory Medicine 1998;92(1):111−7. Price 1998 Price DB, Appleby JL. Fluticasone propionate: an audit of outcomes and cost−effectiveness in primary care. Respiratory Medicine 1998;92:351−3. Primhak 1999 Primhak RA, Smith CM, Powell CVE. A comparison of the systemic effects of high dose inhaled steroids in asthmatic children. American Journal of Respiratory & Critical Care Medicine. ;1591999:A909. Spelman 1999 Spelman R, Hughes J, Price M. The cost effectiveness of inhaled fluticasone propionate comapred with budesonide in adults and children with asthma in Ireland. American Journal of Respiratory & Critical Care Medicine. ;1591999:A762. Stempel 1999 Stempel D, Stanford R, Thwaites R, Price M. The costs and effectiveness of inhaled fluticasone propionate and budesonide in the mamnagement of asthma. American Journal of Respiratory & Critical Care Medicine. ;1591999:A630. Thorsson 1999 Thorsson l, Edsbacker S. Lung uptake of budesonide via dry powder inhaler was greater than that of fluticasone propionate via dry powder inhaler or PMDI. European Respiratory Journal. ;141999:62S. Thwaites 1997 Thwaites RMA, Kane K, Price MJ. The cost−effectiveness of inhaled fluticasone propionate and budesonide in the treatment of asthma in adults and children. European Respiratory Journal. ;101997:105S. Tsoi 1998 Tsoi A, Gafurov M, Shor O. The maintainance treatment of asthmatic patients with comparable doses of different inhaled corticosteroids (IC). European Respiratory Journal. ;121998:63S. Wilson 1998 Wilson AM, Clark DJ, Devlin MM, McFarlane LC, Lipworth BJ. Adrenocortical activity with repeated administration of one−daily inhaled fluticasone propionate and budesonide in asthmatic adults. European Journal of Clinical Pharmacology 1998;53(5):317−20.

References to studies awaiting assessment

Aubier 2001 Aubier M, Wettenger R, Gans SJ. Efficacy of HFA−beclomethasone dipropionate extra−fine aerosol (800 microg day(−1)) versus HFA−fluticasone propionate (1000 microg day(−1)) in patients with asthma. Respiratory Medicine 2001;95(3):212−20. Chlumsky 1998 Chlumsky J. Comparison of the clinical effect of fluticasone propionate and beclomethasone dipropionate in patients with bronchial asthma [Srovnani klinickeho ucinku flutikazon propionatu s beklometazon dipropionatem u pacientu s bronchialnim astmatem]. Prakticky Lekar 1998;78(4):186−9. Derom 1999 Derom E, Van Schoor J, Verhaeghe W, Vincken W, Pauwels R. Systemic effects of inhaled fluticasone propionate and budesonide in adult patients with asthma. American Journal of Respiratory & Critical Care Medicine 1999;160(1):157−61. Dong 1999 Dong Kyu Yang, Young Sam Kim, Chul Min Ahn, Won Ki Ko, Chang J, Sung Kyu Kim, Won Young Lee. Fluticasone propionate and beclomethasone dipropionate in asthmatic patients. [Korean]. Tuberculosis & Respiratory Diseases 1999;47(5):629−41. Fairfax 2001 Fairfax A, Hall I, Spelman R. A randomized, double−blind comparison of beclomethasone dipropionate extrafine aerosol and fluticasone propionate. Annals of Allergy, Asthma, & Immunology 2001;86(5):575−82. Heinig 1999 Heinig JH, Boulet LP, Croonenborghs L, Mollers MJ. The effect of high−dose fluticasone propionate and budesonide on lung function and asthma exacerbations in patients with severe asthma. Respiratory Medicine 1999;93(9):613−20. Kannisto 2000 Kannisto S, Korppi M, Remes K, Voutilainen R. Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. Journal of Clinical Endocrinology & Metabolism 2000;85(2):652−7. Karakoc 2001 Karakoc F, Karadag B, Kut A, Ersu R, Bakac S, Cebeci D, Dagli E. A comparison of the efficacy and safety of a half dose of fluticasone propionate with beclamethasone dipropionate and budesonide in childhood asthma. Journal of Asthma 2001;38(3):229−37. Nong 2001 Nong BR, Huang YF, Hsieh KS, Huang YY, Huang CF, Chuang SL, Liu CC. A comparison of clinical use of fluticasone propionate and beclomethasone dipropionate in pediatric asthma. Kao−Hsiung i Hsueh Ko Hsueh Tsa Chih [Kaohsiung Journal of Medical Sciences] 2001;17(6):302−11.

Additional references Adams 2001a Adams NP, Bestall JB, Jones PW. Inhaled beclomethasone at different doses for long−term asthma (Cochrane Review). In: The Cochrane Library, 4, 2001. Oxford: Update Software. Adams 2001b Adams NP, Bestall JB, Jones PW. Budesonide at different doses for chronic asthma (Cochrane Review). In: Cochrane Library, 4, 2001. Oxford: Update Software. Adams 2002 Adams NP, Bestall JB, Jones PW. Inhaled fluticasone at different doses for chronic asthma (Cochrane review). In: Cochrane Library, 1, 2002. Oxford: Update Software. Barnes 1998 Barnes NC, Hallett C, Harris TAJ. Clinical experience with fluticasone propionate in asthma: a meta−analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less. Respiratory Medicine 1998;92:95−104. BTS 1997

British Thoracic Society. The British guidelines on asthma management 1995 review and position statement. Thorax 1997;52(Suppl 1):S1−20. GINA 1995 National Asthma Education and Prevention Program. Global initiative for asthma management and prevention NHBLI/WHO workshop report. National Institute of Health, Bethseda, MD. 1995;(NIH Publication No. 95−3659) Jadad 1996 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17(1):1−12. Kelly 1998 Kelly HW. Establishing a therapeutic index for the inhaled corticosteroids: part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids. Journal of Allergy & Clinical Immunology 1998;102:S36−S51. Lipworth 1999 Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy . A systematic review and meta−analysis. Archives of Internal Medicine 1999;159:941−955. Lonnebo 1996 Lonnebo A, Grahnen A, Jansson B, Bruden RM Ling−Andersson A. An assessment of the systemic effects of single repeated doses of inhaled fluticasone propionate, and inhaled budesonide in healthy volunteers. European Journal of Clinical Pharmacology 1996;49:459−463. NHLBI 1997 National Asthma Education and Prevention Program. Guidelines for the Diagnosis and Managment of Asthma, Expert Panel Report No. 2. Bethesda MD: NIH/National Heart, Lung and Blood Institute. 1997;(NIH Publication No. 97−4051) Phillipps 1990 Phillipps GH. Structure−activity relationships of topically active steroids: the selection of fluticasone propionate. Respiratory Medicine 1990;84(Suppl A):19−23. Stellato 1999 Stellato C, Atsuta J, Bickel CA, Schleimer RP. An in vitro comparsion of commonly used topical glucocorticoid preparations. Journal of Allergy & Clinical Immunology 1999;104:623−629. Thorsson 1997 Thorsson L, Dahlstrom K, Edsbacker S, Kallen A, Paulson J, Wiren JE. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. British Journal of Clinical Pharmacology 1997;43(2):155−61. * Indicates the major publication for the study

GRAPHS 01 FP v BDP or BUD, parallel group studies: dose ratio 1:2 Outcome title 01 FEV1 (% predicted) 02 FEV1 (litres) 03 Change in FEV1 (litres) compared to No. of No. of Statistical studies participants method 2 3 2 266 1107 399 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] Effect size −1.928 [−7.414, 3.558] 0.108 [0.014, 0.202] 0.139 [0.046,

baseline 04 Change in FVC (litres) compared to baseline 05 Morning PEFR (L/min) 06 Change in morning PEFR (L/min) compared to baseline 07 Evening PEFR (L/min) 08 Change in evening PEFR (L/min) compared to baseline 09 Daily PEFR (% predicted) 10 Clinic PEFR (L/min) 11 Change in FEF 25−75 (L/second) compared to baseline 12 Change in daily asthma symptom score compared to baseline 13 Change in percentage of symptom free days compared to baseline 14 Percentage of symptom free days 15 Change in daily use of rescue beta2 agonist (puffs/day) compared to baseline 16 Change in percentage of days with no rescue beta2 agonist requirement compared to baseline 17 No change or reduction in daytime rescue beta2 agonist use (% of patients) 18 Withdrawal due to asthma exacerbation (No. of patients) 19 One or more exacerbations (No. of patients) 20 Sore throat/pharyngitis (No. of patients) 21 Hoarseness (No. of patients) 22 Oropharyngeal Candidiasis (No. of patients) 2 7 4 5 2 1 2 2 2 2 2 2 2 399 2087 831 1698 399 518 675 399 399 399 699 399 399

[95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI]

0.232] 0.127 [0.005, 0.249] 13.288 [4.881, 21.695] 12.360 [7.441, 17.280] 10.519 [0.657, 20.381] 4.988 [−2.994, 12.969] 3.400 [0.184, 6.616] 17.608 [0.807, 34.409] 0.160 [0.033, 0.287] −0.160 [−0.263, −0.058] 6.431 [0.473, 12.388] 4.904 [−0.736, 10.544] −0.556 [−0.949, −0.164] 6.890 [0.318, 13.461] 1.53 [0.87, 2.69] 0.77 [0.54, 1.10] 0.70 [0.45, 1.09] 2.16 [1.42, 3.28] 0.92 [0.38, 2.22] 1.11 [0.63, 1.96]

1 11 2 6 5 10

387 2824 851 1859 1524 2748

23 Morning plasma cortisol (nmol/L)

143

WMD [Fixed] [95% CI]

11.729 [−38.374, 61.833]

02 FP v BDP or BUD, crossover studies: dose ratio 1:2 Outcome title 01 FEV1 (% predicted) 02 FEV1 (litres) 03 FVC (% predicted) 04 Morning PEFR (L/min) 05 Evening PEFR (L/min) 06 Daytime breathlessness score 07 Night−time breathlessness score 08 Percentage of symptom free days 09 Percentage of symptom free nights 10 One or more night−time awaking due to asthma symptoms (No. of patients) 11 Symptoms on wakening in the morning (No. of patients) 12 Percentage of rescue beta2 agonist free days (No. of patients) 13 Morning plasma cortisol (nmol/L) 14 Plasma cortisol 30 min post 25U cosyntropin (nmol/L) 15 24 hour urinary free cortisol (nmol/L) 03 FP v BDP or BUD, parallel studies: dose ratio 1:1 Outcome title 01 FEV1 (% predicted) No. of No. of Statistical studies participants method 1 242 WMD [Fixed] Effect size 0.900 [−4.896, No. of No. of Statistical studies participants method 1 2 1 2 2 1 1 2 2 1 1 1 3 1 1 138 76 138 76 76 42 42 618 618 138 138 584 782 138 138 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Effect size −0.100 [−5.941, 5.741] 0.017 [−0.229, 0.263] −0.300 [−4.773, 4.173] 3.019 [−28.277, 34.315] 5.864 [−23.584, 35.312] 0.900 [−4.641, 6.441] −0.300 [−6.143, 5.543] −1.325 [−7.623, 4.973] 1.395 [−3.590, 6.379] 1.69 [0.41, 7.03] 1.47 [0.73, 2.99] 0.800 [−5.657, 7.257] −0.341 [−27.699, 27.016] 60.000 [−33.839, 153.839] −4.000 [−28.174, 20.174]

[95% CI] 02 FEV1 (litres) 03 FVC (litres) 04 Morning PEFR (L/min) 05 Evening PEFR (L/min) 06 Change in morning PEFR compared to baseline (L/min) 07 Change in evening PEFR compared to baseline (L/min) 08 Clinic PEFR (L/min) 09 Daytime asthma symptom score 10 Night−time asthma symptom score 11 Percentage of symptom free days 12 Percentage of symptom free days (No. of patients) 13 Percentage of symptom free nights (No. of patients) 14 Daytime rescue beta2 agonist use (puffs/daytime) 15 Night−time rescue beta2 agonist use (puffs/night) 16 Percentage of rescue beta2 agonist free days (No. of patients) 17 Withdrawal due to asthma exacerbation (No. of patients) 18 Requirement for one or more courses of oral steroid for asthma exacerbation (No. of patients) 19 Sore throat (No. of patients) 20 Hoarseness (No. of patients) 1 1 2 2 1 1 1 1 1 1 1 1 1 1 1 4 2 116 116 429 427 134 134 116 116 116 239 274 274 116 116 274 947 408 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] SMD [Fixed] [95% CI] SMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI]

6.696] 0.070 [−0.265, 0.405] 0.010 [−0.394, 0.414] 14.928 [−6.168, 36.024] 14.340 [−6.632, 35.312] −12.900 [−43.273, 17.473] −4.100 [−39.173, 30.973] 9.100 [−47.863, 66.063] −0.257 [−0.625, 0.111] −0.049 [−0.416, 0.318] 4.000 [−5.733, 13.733] 1.13 [0.69, 1.83] 1.07 [0.66, 1.74] −0.110 [−0.789, 0.569] 0.220 [−0.106, 0.546] 0.58 [0.33, 1.01] 0.68 [0.36, 1.28] 0.28 [0.13, 0.60]

3 3

637 676

1.81 [0.99, 3.32] 2.43 [1.10, 5.39]

21 Oropharyngeal Candidiasis (No. of patients) 22 Change in morning plasma cortisol (nmol/L) compared to baseline

4 1

1122 134

Peto OR [95% CI] WMD [Fixed] [95% CI]

0.85 [0.51, 1.39] −173.900 [−247.949, −99.851]

04 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by drug Outcome title 01 FEV1 (litres) 02 Morning PEFR (L/min) 03 Change in morning PEFR (L/min) compared to baseline 04 Evening PEFR (L/min) 05 Withdrawal due to asthma exacerbation (No. of patients) 06 Sore throat/pharyngitis (No. of patients) 07 Hoarseness (No. of patients) 08 Oropharyngeal Candidiasis (No. of patients) No. of No. of Statistical studies participants method 3 7 4 5 11 6 5 10 1107 2087 831 1698 2824 1859 1524 2748 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Effect size 0.108 [0.014, 0.202] 13.288 [4.881, 21.695] 12.360 [7.441, 17.280] 10.519 [0.657, 20.381] 0.77 [0.54, 1.10] 2.16 [1.42, 3.28] 0.92 [0.38, 2.22] 1.11 [0.63, 1.96]

05 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by age Outcome title 01 FEV1 (litres) 02 Morning PEFR (L/min) 03 Change in morning PEFR (L/min) compared to baseline 04 Evening PEFR (L/min) 05 Withdrawal due to asthma exacerbation (No. of patients) 06 Sore throat/pharyngitis (No. of patients) No. of No. of Statistical studies participants method 3 7 4 5 11 6 1107 2087 831 1698 2824 1859 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] Effect size 0.108 [0.014, 0.202] 13.288 [4.881, 21.695] 12.360 [7.441, 17.280] 10.519 [0.657, 20.381] 0.77 [0.54, 1.10] 2.16 [1.42, 3.28]

07 Hoarseness (No. of patients) 08 Oropharyngeal Candidiasis (No. of patients)

5 10

1524 2748

Peto OR [95% CI] Peto OR [95% CI]

0.92 [0.38, 2.22] 1.11 [0.63, 1.96]

06 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by dose range Outcome title 01 FEV1 (litres) 02 Morning PEFR (L/min) 03 Change in morning PEFR (L/min) compared to baseline 04 Evening PEFR (L/min) 05 Withdrawal due to asthma exacerbation (No. of patients) 06 Sore throat/pharyngitis (No. of patients) 07 Oropharyngeal Candidiasis (No. of patients) 08 Hoarseness (No. of patients) No. of No. of Statistical studies participants method 3 5 4 5 11 6 10 5 1107 1709 831 1698 2824 1859 2748 1524 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Effect size 0.108 [0.014, 0.202] 16.434 [7.281, 25.587] 12.360 [7.441, 17.280] 10.519 [0.657, 20.381] 0.77 [0.54, 1.10] 2.16 [1.42, 3.28] 1.11 [0.63, 1.96] 0.92 [0.38, 2.22]

07 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by asthma severity Outcome title 01 FEV1 (litres) 02 Morning PEFR (L/min) 03 Change in morning PEFR (L/min) compared to baseline 04 Evening PEFR (L/min) 05 Withdrawal due to asthma exacerbation (No. of patients) 06 Sore throat/pharyngitis (No. of patients) 07 Hoarseness (No. of patients) No. of No. of Statistical studies participants method 3 5 4 5 11 6 5 1107 1709 831 1698 2824 1859 1524 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% Effect size 0.108 [0.014, 0.202] 16.434 [7.281, 25.587] 12.360 [7.441, 17.280] 10.519 [0.657, 20.381] 0.77 [0.54, 1.10] 2.16 [1.42, 3.28] 0.92 [0.38, 2.22]

CI] 08 Oropharyngeal Candidiasis (No. of patients) 10 2748 Peto OR [95% CI] 1.11 [0.63, 1.96]

08 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by delivery device Outcome title 01 FEV1 (litres) 02 Morning PEFR (L/min) 03 Change in morning PEFR (L/min) compared to baseline 04 Evening PEFR (L/min) 05 Withdrawal due to asthma exacerbation (No. of patients) 06 Sore throat/pharyngitis (No. of patients) 07 Hoarseness (No. of patients) 08 Oropharyngeal Candidiasis (No. of patients) No. of No. of Statistical studies participants method 3 7 4 5 11 6 5 10 1107 2087 831 1698 2824 1859 1524 2748 WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] WMD [Fixed] [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Peto OR [95% CI] Effect size 0.108 [0.014, 0.202] 13.288 [4.881, 21.695] 12.360 [7.441, 17.280] 10.519 [0.657, 20.381] 0.77 [0.54, 1.10] 2.16 [1.42, 3.28] 0.92 [0.38, 2.22] 1.11 [0.63, 1.96]

COVER SHEET Title Reviewer(s) Contribution of reviewer(s) Fluticasone versus beclomethasone or budesonide for chronic asthma Adams N, Bestall JM, Jones PW Nick Adams retrieved papers identified by electronic search, handsearched addtional sources for relevent studies, 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 clarificiation or trial details and/or request missing data. Paul Jones provided editiorial support . Information not available

Issue protocol first published Issue review first published

Information not available

Date of most 15 November 2001 recent amendment Date of most recent SUBSTANTIVE amendment Most recent changes Date new studies sought but none found Date new studies found but not yet included/excluded Date new studies found and included/excluded Date reviewers' conclusions section amended Contact address 22 February 2000

Information not supplied by reviewer

Dr Nick Adams 14 Dewinter House, Granville Road, Sevenoaks TN13 1DZ Kent UK Telephone: +44 0207 352 8121 E−mail: nadams2001@btinternet.com CD002310

Cochrane Library number Editorial group Editorial group code

Cochrane Airways Group HM−AIRWAYS

SOURCES OF SUPPORT Extramural sources of support • No sources of support supplied Intramural sources of support • NHS Research and Development UK

SYNOPSIS

Inhaled fluticasone is at least as effective as beclomethasone and budesonide in the treatment of chronic asthma at half the daily dose. When given at the same doses, however, fluticasone may cause more sore throat than the other two treatments. Further research is required. This review compares the effectiveness of three inhaled steroids. Fluticasone (FP) was compared with either beclomethasone (BDP) or budesonide (BUD) for treating people with chronic asthma. When FP was given to children or adults at approximately half the daily dose of either BDP or BUD, it appeared to be at least as effective as the other two drugs in improving airway opening. There was not enough information available to draw conclusions concerning the effect of these drugs on symptoms, or the risk of an acute asthma exacerbation. However, when given at the same dose as BDP or BUD, FP was associated with increased side effects, such as a sore throat. Further research should consider using quality of life questionnaires to assess whether FP improves quality of life in people with asthma, when compared with BDP or BUD.

GRAPHS AND OTHER TABLES

Fig. 01 FP v BDP or BUD, parallel group studies: dose ratio 1:2

01.01 FEV1 (% predicted)

01.02 FEV1 (litres)

01.03 Change in FEV1 (litres) compared to baseline

01.04 Change in FVC (litres) compared to baseline

01.05 Morning PEFR (L/min)

01.06 Change in morning PEFR (L/min) compared to baseline

01.07 Evening PEFR (L/min)

01.08 Change in evening PEFR (L/min) compared to baseline

01.09 Daily PEFR (% predicted)

01.10 Clinic PEFR (L/min)

01.11 Change in FEF 25−75 (L/second) compared to baseline

01.12 Change in daily asthma symptom score compared to baseline

01.13 Change in percentage of symptom free days compared to baseline

01.14 Percentage of symptom free days

01.15 Change in daily use of rescue beta2 agonist (puffs/day) compared to baseline

01.16 Change in percentage of days with no rescue beta2 agonist requirement compared to baseline

01.17 No change or reduction in daytime rescue beta2 agonist use (% of patients)

01.18 Withdrawal due to asthma exacerbation (No. of patients)

01.19 One or more exacerbations (No. of patients)

01.20 Sore throat/pharyngitis (No. of patients)

01.21 Hoarseness (No. of patients)

01.22 Oropharyngeal Candidiasis (No. of patients)

01.23 Morning plasma cortisol (nmol/L)

Fig. 02 FP v BDP or BUD, crossover studies: dose ratio 1:2

02.01 FEV1 (% predicted)

02.02 FEV1 (litres)

02.03 FVC (% predicted)

02.04 Morning PEFR (L/min)

02.05 Evening PEFR (L/min)

02.06 Daytime breathlessness score

02.07 Night−time breathlessness score

02.08 Percentage of symptom free days

02.09 Percentage of symptom free nights

02.10 One or more night−time awaking due to asthma symptoms (No. of patients)

02.11 Symptoms on wakening in the morning (No. of patients)

02.12 Percentage of rescue beta2 agonist free days (No. of patients)

02.13 Morning plasma cortisol (nmol/L)

02.14 Plasma cortisol 30 min post 25U cosyntropin (nmol/L)

02.15 24 hour urinary free cortisol (nmol/L)

Fig. 03 FP v BDP or BUD, parallel studies: dose ratio 1:1

03.01 FEV1 (% predicted)

03.02 FEV1 (litres)

03.03 FVC (litres)

03.04 Morning PEFR (L/min)

03.05 Evening PEFR (L/min)

03.06 Change in morning PEFR compared to baseline (L/min)

03.07 Change in evening PEFR compared to baseline (L/min)

03.08 Clinic PEFR (L/min)

03.09 Daytime asthma symptom score

03.10 Night−time asthma symptom score

03.11 Percentage of symptom free days

03.12 Percentage of symptom free days (No. of patients)

03.13 Percentage of symptom free nights (No. of patients)

03.14 Daytime rescue beta2 agonist use (puffs/daytime)

03.15 Night−time rescue beta2 agonist use (puffs/night)

03.16 Percentage of rescue beta2 agonist free days (No. of patients)

03.17 Withdrawal due to asthma exacerbation (No. of patients)

03.18 Requirement for one or more courses of oral steroid for asthma exacerbation (No. of patients)

03.19 Sore throat (No. of patients)

03.20 Hoarseness (No. of patients)

03.21 Oropharyngeal Candidiasis (No. of patients)

03.22 Change in morning plasma cortisol (nmol/L) compared to baseline

Fig. 04 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by drug

04.01 FEV1 (litres)

04.02 Morning PEFR (L/min)

04.03 Change in morning PEFR (L/min) compared to baseline

04.04 Evening PEFR (L/min)

04.05 Withdrawal due to asthma exacerbation (No. of patients)

04.06 Sore throat/pharyngitis (No. of patients)

04.07 Hoarseness (No. of patients)

04.08 Oropharyngeal Candidiasis (No. of patients)

Fig. 05 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by age

05.01 FEV1 (litres)

05.02 Morning PEFR (L/min)

05.03 Change in morning PEFR (L/min) compared to baseline

05.04 Evening PEFR (L/min)

05.05 Withdrawal due to asthma exacerbation (No. of patients)

05.06 Sore throat/pharyngitis (No. of patients)

05.07 Hoarseness (No. of patients)

05.08 Oropharyngeal Candidiasis (No. of patients)

Fig. 06 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by dose range

06.01 FEV1 (litres)

06.02 Morning PEFR (L/min)

06.03 Change in morning PEFR (L/min) compared to baseline

06.04 Evening PEFR (L/min)

06.05 Withdrawal due to asthma exacerbation (No. of patients)

06.06 Sore throat/pharyngitis (No. of patients)

06.07 Oropharyngeal Candidiasis (No. of patients)

06.08 Hoarseness (No. of patients)

Fig. 07 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by asthma severity

07.01 FEV1 (litres)

07.02 Morning PEFR (L/min)

07.03 Change in morning PEFR (L/min) compared to baseline

07.04 Evening PEFR (L/min)

07.05 Withdrawal due to asthma exacerbation (No. of patients)

07.06 Sore throat/pharyngitis (No. of patients)

07.07 Hoarseness (No. of patients)

07.08 Oropharyngeal Candidiasis (No. of patients)

Fig. 08 FP v BDP or BUD, parallel group studies: dose ratio 1:2 subgroup by delivery device

08.01 FEV1 (litres)

08.02 Morning PEFR (L/min)

08.03 Change in morning PEFR (L/min) compared to baseline

08.04 Evening PEFR (L/min)

08.05 Withdrawal due to asthma exacerbation (No. of patients)

08.06 Sore throat/pharyngitis (No. of patients)

08.07 Hoarseness (No. of patients)

08.08 Oropharyngeal Candidiasis (No. of patients)

Metadata

Title

Cochrane Chronic Asthma Review

Abstract

Background Beclomethasone dipropionate (BDP) and budesonide (BUD) are commonly prescribed inhaled corticosteroids for the treatment of asthma, Fluticasone propionate (FP) is newer agent with greater potency in in−vitro assays. Objectives: To compare the efficacy and safety of Fluticasone to Beclomethasone or Budesonide in the treatment of chronic asthma.

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