Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma

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

doi:10.1002/14651858.CD005533.pub2

. Author manuscript; available in PMC: 2014 Sep 21.

Published in final edited form as: Cochrane Database Syst Rev. 2010 Apr 14;(4):CD005533. doi: 10.1002/14651858.CD005533.pub2

Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma

Francine M Ducharme ¹, Muireann Ni Chroinin ², Ilana Greenstone ³, Toby J Lasserson ⁴

¹Research Centre, CHU Sainte-Justine and the Department of Pediatrics, University of Montreal, Montreal, Canada

²Division of Children’s Services, Cork University Hospital, Cork, Ireland

³Montreal Children’s Hospital, Montreal, Canada

⁴Community Health Sciences, St George’s, University of London, London, UK

^✉

Contact address: Francine M Ducharme, Research Centre, CHU Sainte-Justine and the Department of Pediatrics, University of Montreal, 3175 Cote Sainte-Catherine, Montreal, Québec, H3T 1C5, Canada. francine.m.ducharme@umontreal.ca

Editorial group: Cochrane Airways Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 4, 2010.

Review content assessed as up-to-date: 25 June 2008.

^✉

CONTRIBUTIONS OF AUTHORS Dr Francine Ducharme revised the protocol, supervised the literature search, created the methodology and data extraction forms, reviewed all full-text publications for relevance, reviewed all included trials for methodology and data extraction, corresponded with authors and/or the pharmaceutical companies to identify other possibly relevant trials, to verify methodology and data extraction and request additional information, analysed and interpreted results of the meta-analysis and supervised the writing of the 2010 review.

Dr Ilana Greenstone, under the supervision of Francine Ducharme, conceived the protocol, requested the literature search (1999 to 2001), identified and reviewed the full-text publication of all citations of potential or potentially eligible RCTs, drafted the correspondence to authors and/or the pharmaceutical companies to solicit their collaboration in this review and in the identification of other possibly relevant trials, extracted the methodology and data, entered the description of studies and data entry in RevMan, verified all references, description of studies and data entry. She analysed and interpreted results of the meta-analysis and wrote the 2005 review.

Dr. Muireann Ni Chroinin, under the supervision of Dr. Francine Ducharme, reviewed the searches from 2002 to 2004, identified and reviewed the full-text publication of all citations of potential or potentially eligible RCTs, extracted the methodology and data, entered the description of studies and data in RevMan, interpreted the results and approved the final review.

Toby Lasserson participated in the 2009 update of the review by screening search results, assessing studies, extracting study characteristics and data, entering data in RevMan and writing up the review.

Four research assistants sequentially participated in some aspects of the review, under the supervision of Ilana Greenstone, Muireann Ni Chroinin and Francine Ducharme. From May to July 2001, Helen Magdalinos and from November 2001 to March 2002, Alya Danish, both supported by The Canadian Cochrane Network, entered the references, characteristics of included and excluded studies, revised the table of comparisons and corrected confirmed data from authors. Vincent Masse, medical student supervised by Ilana Greenstone and Muireann Ni Chroinin, participated in verification and organisation of data in RevMan and entered references and reasons for exclusion. Marilyse Julien performed and assisted in the interpretation of the 2009 meta-regression.

PMCID: PMC4169793 EMSID: EMS57456 PMID: 20393943

Abstract

Background

In asthmatic patients inadequately controlled on inhaled corticosteroids and/or those with moderate persistent asthma, two main options are recommended: the combination of a long-acting inhaled ß2 agonist (LABA) with inhaled corticosteroids (ICS) or use of a higher dose of inhaled corticosteroids.

Objectives

To determine the effect of the combination of long-acting ß₂ agonists and inhaled corticosteroids compared to a higher dose of inhaled corticosteroids on the risk of asthma exacerbations, pulmonary function and on other measures of asthma control, and to look for characteristics associated with greater benefit for either treatment option.

Search methods

We identified randomised controlled trials (RCTs) through electronic database searches (MEDLINE, EMBASE and CINAHL), bibliographies of RCTs, clinical trial registries and correspondence with manufacturers until May 2008.

Selection criteria

RCTs that compared the combination of inhaled LABA and ICS to a higher dose of inhaled corticosteroids, in children and adults with asthma.

Data collection and analysis

Two authors independently assessed methodological quality and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was the number of patients experiencing one or more asthma exacerbations requiring oral corticosteroids.

Main results

This review included 48 studies (15,155 participants including 1155 children and 14,000 adults). Participants were inadequately controlled on their current ICS regimen, experiencing ongoing symptoms and with generally moderate (FEV1 60% to 79% of predicted) airway obstruction. The studies tested the combination of salmeterol or formoterol with a median dose of 400 mcg/day of beclomethasone or equivalent (BDP-eq) compared to a median of 1000 mcg/day of BDP-eq, usually for 24 weeks or less. There was a statistically significantly lower risk of exacerbations requiring systemic corticosteroids in patients treated with LABA and ICS (RR 0.88, 95% CI 0.78 to 0.98, 27 studies, N = 10,578) from 11.45% to 10%, with a number needed to treat of 73 (median study duration: 12 weeks). The study results were dominated by adult studies; trial data from three paediatric studies showed a trend towards increased risk of rescue oral steroids (RR 1.24, 95% CI 0.58 to 2.66) and hospital admission (RR 2.21, 95% CI 0.74 to 6.64) associated with combination therapy. Overall, there was no statistically significant difference in the risk ratios for either hospital admission (RR 1.02, 95% CI 0.67 to 1.56) or serious adverse events (RR 1.12, 95% CI 0.91 to 1.37). The combination of LABA and ICS resulted in significantly greater but modest improvement from baseline in lung function, symptoms and rescue medication use than with higher ICS dose. Despite no significant group difference in the risk of overall adverse events (RR 0.99, 95% CI 0.95 to 1.03), there was an increase in the risk of tremor (RR 1.84, 95% CI 1.20 to 2.82) and a lower risk of oral thrush (RR 0.58, 95% CI 0.40 to 0.86)) in the LABA and ICS compared to the higher ICS group. There was no significant difference in hoarseness or headache between the treatment groups. The rate of withdrawals due to poor asthma control favoured the combination of LABA and ICS (RR 0.65, 95% CI 0.51 to 0.83).

Authors’ conclusions

In adolescents and adults with sub-optimal control on low dose ICS monotherapy, the combination of LABA and ICS is modestly more effective in reducing the risk of exacerbations requiring oral corticosteroids than a higher dose of ICS. Combination therapy also led to modestly greater improvement in lung function, symptoms and use of rescue ß₂ agonists and to fewer withdrawals due to poor asthma control than with a higher dose of inhaled corticosteroids. Apart from an increased rate of tremor and less oral candidiasis with combination therapy, the two options appear relatively safe in adults although adverse effects associated with long-term ICS treatment were seldom monitored. In children, combination therapy did not lead to a significant reduction, but rather a trend towards an increased risk, of oral steroid-treated exacerbations and hospital admissions. These trends raised concern about the safety of combination therapy in view of modest improvement in children under the age of 12 years.

Medical Subject Headings (MeSH): Administration, Inhalation; Adrenal Cortex Hormones [*administration & dosage]; Adrenergic beta-Agonists [*administration & dosage]; Anti-Asthmatic Agents [*administration & dosage]; Asthma [*drug therapy]; Drug Therapy, Combination [methods]; Randomized Controlled Trials as Topic

MeSH check words: Adolescent; Adult; Child; Child, Preschool; Humans

BACKGROUND

Beta-2 adrenergic agonists are the major class of medication used for the relief of asthma symptoms. They produce their effects through interaction with specific ß₂ adrenergic receptors located in the plasma membrane of virtually all types of cells, including bronchial wall smooth muscle (Nelson 1995). For several decades, short-acting inhaled ß₂ agonists have been the primary agents used to treat patients with asthma. Their benefits include rapid onset of bronchodilation within five to 15 minutes (D’Alonzo 1997), highly effective protection against exercise-induced asthma and protection against the early asthmatic response to allergen (Sears 1998). Their duration of action is only three to six hours (Nelson 1995). Short-acting ß₂ agonists do not seem to have any effect on overall severity of asthma, nor on inflammation (Sears 1998). Long-acting ß₂ agonists, such as salmeterol and formoterol, have been developed for more prolonged control of symptoms (D’Alonzo 1997). Slightly slower in onset of action than short-acting ß₂ agonists, inhaled salmeterol exerts its bronchodilating effect within ten to 20 minutes (Adkins 1997). This effect then lasts up to 12 hours due to high affinity binding of the molecule’s side chain to a specific site within the ß₂ adrenergic receptor (Adkins 1997; D’Alonzo 1997; Nelson 1995). Formoterol, on the other hand, has an onset of bronchodilation within less than five minutes (Bartow 1998; Moore 1998) and a duration of action similar to that of salmeterol. Due to its ability to enter the cell’s lipid bi-layer, it becomes available over a prolonged period to stimulate the receptor (Nelson 1995). These two long-acting ß₂ agonists have been shown to reduce daytime and nighttime symptoms, improve quality of sleep, reduce requirement for short-acting ß₂ agonists (D’Alonzo 1997; Sears 1998) and protect against methacholine-induced, cold air-induced and exercise-induced bronchoconstriction (D’Alonzo 1997; Nelson 1995; Moore 1998). Long-acting inhaled ß₂ agonists are currently used in the maintenance, rather than in the acute treatment, of children aged six years and older and adults with asthma. At time of publication, these drugs have not yet been marketed for children less than four years old, although such approval may currently be sought in several countries.

The need for frequent use of ß₂ agonists generally indicates a significant inflammatory process that should be controlled with anti-inflammatory drugs (Fireman 1995; Nelson 1995; Kemp 1998). Inhaled corticosteroids are currently the most effective anti-inflammatory drugs used for long-term control of asthma (Adams 2008; Manning 2008).

When asthma control is unsatisfactory despite low doses of inhaled corticosteroids, several options have been proposed: increasing the dose of inhaled corticosteroids or adding other agents such as long-acting ß₂ agonists, leukotriene receptor antagonists or theophylline. Of all add-on therapies, long-acting ß₂ agonists have emerged as the preferred option in terms of efficacy (BTS 2008 (updated June 09); GINA 2008; Lemiere 2004; NIH Publication 2007). Guidelines differ with regards to choosing between increasing the dose of inhaled corticosteroids or adding long-acting ß₂ agonists for adults, children, toddlers and infants/toddlers.

In adults, all but the British guidelines prefer the addition of long-acting ß₂ agonists to inhaled corticosteroids in cases of sub-optimal control on inhaled corticosteroid monotherapy. The Canadian and Australian Consensus statement recommends the addition of long-acting ß₂ agonists if control is unsatisfactory with 400 mcg/day of CFC-beclomethasone dipropionate (BDP) or equivalent (Australia 2006; GINA 2008; Lemiere 2004, ) while doses of 200 to 800 mcg/day are recommended by the British guidelines (BTS 2008 (updated June 09)). In contrast, the American guidelines give equal weight to adding long-acting ß₂ agonists or increasing the dose of inhaled corticosteroids (NIH Publication 2007). In children aged 5 years and older with poor control on 400 mcg/day of BDP-equivalent, it is recommended to first increase the dose of inhaled corticosteroids to a medium dose in the Australian (Australia 2006), Canadian (Lemiere 2004) and International (GINA 2008) statements, before adding long-acting ß₂ agonists, where the paediatric medium dose is 401 to 800 mcg/ day for all but the Gina guidelines where it is 201 to 400 mcg/ day. The American guidelines give equal weight to increasing the inhaled corticosteroid dose of a moderate dose or adding a long-acting ß₂ agonist. In contrast, the British (BTS 2008 (updated June 09)) guidelines recommend the addition of long-acting ß₂ agonists at an inhaled corticosteroid dose of 400 mcg/day before increasing the inhaled corticosteroid dose to 800 mcg/day. In infants and preschool-aged children, the American guidelines (NIH Publication 2007) recommend increasing the dose of ICS to a medium dose as the preferred option. The British Thoracic Society guidelines do not recommend the use of long-acting ß₂ agonists in this age group (BTS 2008 (updated June 09), while other guidelines have made no specific statement. Clearly, uncertainties persist regarding the severity of airway obstruction and the baseline dose of inhaled corticosteroids to which addition of long-acting ß₂ agonists may be preferable to increasing the dose of inhaled corticosteroids. The influence of age for optimising treatment strategies is also unclear.

Two published meta-analyses initially examined the combination of salmeterol with inhaled corticosteroids (Shrewsbury 2000) or with fluticasone specifically (Heyneman 2002) as compared to a double-dose inhaled corticosteroid. Both of these reviews demonstrated clear superiority of combination therapy with regards to lung function, symptoms and use of rescue ß₂ agonists. Shrewsbury 2000 also showed that combination therapy was superior in the prevention of asthma exacerbations. However, these meta-analyses were not systematic reviews in that they:

only included trials sponsored by GlaxoSmithKline;
tested only salmeterol as the long-acting ß₂ agonist; and
were limited to adult trials.

However, the safety of long-acting ß₂ agonists alone or in combination with inhaled corticosteroids has been challenged. There have been clear indications that the use of long-acting ß₂ agonists as monotherapy is worse than use in combination with inhaled corticosteroids (Warner 1998). A recent systematic review combining trials in which long-acting ß₂ agonists were used alone or in combination with inhaled corticosteroids reported an increase in the risk of serious adverse events associated with long-acting ß₂ agonists (Salpeter 2006). The possible protection offered by inhaled corticosteroids has led to recommendations from national and international asthma consensus statements that stipulate the use of long-acting ß₂ agonists only in combination with inhaled corticosteroids (Australia 2006; BTS 2008 (updated June 09); Georgitis 1999; GINA 2008; Lemiere 2004; NIH Publication 2007; Warner 1998). Yet concerns about the safety of long-acting ß₂ agonists must clearly be addressed in adults and particularly in children, in whom few data are available.

We published a Cochrane Review comparing the combination of any long-acting ß₂ agonist preparation and inhaled corticosteroids to increased inhaled corticosteroid dose and documented the beneficial effect of combination therapy on asthma exacerbations requiring systemic corticosteroids, lung function, symptoms and rescue bronchodilators (Greenstone 2005). With the publication of several additional trials since 2005, we believed a systematic review comparing the combination of long-acting ß₂ agonist and inhaled corticosteroids to a higher dose of inhaled corticosteroids in patients with a prior trial of inhaled corticosteroids would provide a more unbiased view of the evidence on safety and efficacy and, perhaps, greater insight as to the patient and treatment characteristics associated with greater benefit or harm from either treatment option. We believed this update would strengthen the evidence supporting the safety of long-acting ß₂ agonists when used in combination therapy (Ernst 2006).

OBJECTIVES

The objective of this review was to compare the relative benefit and safety profile of the combination of long-acting ß₂ agonists (LABAs) and inhaled corticosteroids (ICS) with a higher dose of inhaled corticosteroids in asthmatic patients with or without previous treatment with inhaled corticosteroids. We also wished to examine whether the benefit of either treatment option was influenced by the severity of airway obstruction, age, baseline dose of inhaled corticosteroids to which LABA was added, ICS dose difference between treatment options, use of one or two devices to deliver combination therapy, dose and type of long-acting ß₂ agonist and duration of intervention.

METHODS

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials (RCTs) conducted in adults, adolescents and/or children in whom long-acting ß2 agonists were added to inhaled corticosteroids.

Types of participants

Children aged two years and above, adolescents or adults with recurrent or chronic asthma. We did not include studies where pre-treatment excluded inhaled corticosteroids. The comparison of combination therapy with higher dose steroids in steroid naive patients is covered in Ni Chroinin 2009a.

Types of interventions

Long-acting ß₂ agonist administered twice a day (e.g. salmeterol or formoterol) combined with inhaled corticosteroids compared to a higher dose of inhaled corticosteroids with or without placebo. Delivery of therapy could be either via one or two inhaler devices. Other co-interventions such as xanthines, anticholinergics and non-steroidal anti-inflammatory medications were accepted, provided that the dose remained unchanged throughout the study. The intervention must have been administered for at least 28 days at fixed doses. Inhaled short-acting ß₂ agonists and short courses of oral corticosteroids were permitted rescue interventions.

Types of outcome measures

Primary outcomes

The primary outcome was the proportion of participants with asthma exacerbations requiring a short course of systemic corticosteroids.

Secondary outcomes

Proportion of participants in each group requiring hospital admission for asthma.
Withdrawals.
Serious adverse events.
Pulmonary function tests.
Symptoms (including days and nights without symptoms, and symptom scores.
Quality of life measured with validated scales.
Rescue use of short-acting ß2 agonists.
Measures of inflammation, such as serum eosinophils, serum eosinophil cationic protein and sputum eosinophils.
Clinical and biochemical adverse effects related to treatment were examined for all those that were systematically sought and documented.

Search methods for identification of studies

Electronic searches

A search was carried out in the Cochrane Airways Review Group’s ‘Asthma and Wheez* RCT’ register, which is derived from a comprehensive search of EMBASE (1980 to May 2008), MEDLINE (1966 to May 2008) and CINAHL (1982 to May 2008). In addition, we handsearched 20 of the most productive respiratory care journals and added relevant randomised controlled trials to the register. This register also contains a variety of studies published in foreign languages. We did not exclude trials on the basis of language.

The search of the database used the following terms: (((beta* and agonist*) and long-acting or “long acting”) or ((beta* and adrenergic*) and long-acting or “long acting”) or (bronchodilat* and long-acting or “long acting”) or (salmeterol or formoterol or advair or symbicort)) and (((corticosteroid* or corticosteroid* or corticosteroid*) and inhal*) or (budesonide or beclomethasone or fluticasone or triamcinolone or flunisolide)).

Searching other resources

We searched the clinical trials register of The Cochrane Collaboration (the Central Register of Controlled Trials (CENTRAL)) using the above search strategy. We reviewed reference lists of all included studies and reviews to identify potentially relevant citations.

We also made enquiries regarding other published or unpublished studies known to the authors of the included studies or to the pharmaceutical companies who manufacture the agents (GlaxoSmithKline, Astra Zeneca and Novartis). We searched registers of published and unpublished clinical trial data (http://www.ctr.gsk.co.uk; http://www.clinicalstudyresults.org; http://www.astrazenecaclinicaltrials.com; http://www.novartisclinicaltrials.com).

Data collection and analysis

Selection of studies

From the title, abstract or descriptors, one of the authors (IRG or MNC and FMD or TJL) independently reviewed the literature searches. We excluded all studies that were clearly not randomised controlled trials or that clearly did not fit the inclusion criteria. Two authors (IRG or MNC and FMD or TJL) reviewed all other citations independently in full text, assessing for inclusion based on study design, population, intervention and outcome.

Data extraction and management

Two authors (IRG or MNC and FMD or TJL) independently extracted data for the trials and entered data into the Cochrane Collaboration software program, Review Manager (RevMan) (RevMan 2008). For the 2008 update of the review, one author (TJL) extracted the data.

As a ‘user defined’ item, we recorded the difference in the daily dose of inhaled corticosteroids in the LABA and ICS versus higher ICS groups, reported in chlorofluorocarbon (CFC)-propelled ‘beclomethasone-equivalent’ , where 1 mcg of beclomethasone dipropionate = 1 mcg of budesonide = 0.5 mcg fluticasone propionate (NIH Publication 2007). All doses of inhaled medications are reported based on ex-VALVE, rather than ex-inhaler, values.

Assessment of risk of bias in included studies

We assessed the risk of bias for the allocation, blinding and the handling of missing data from the studies. This is in line with recommendations made in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2008). The method for assessing study quality for previous versions of this review is given in Appendix 2.

Dealing with missing data

We contacted study investigators and/or study sponsors for trials with pharmaceutical company sponsorship to obtain verification of study design and information on missing outcome data. We were particularly interested in obtaining verification and missing data for the two outcomes pertaining to exacerbations: those necessitating systemic corticosteroids and those leading to hospital admission. Where we could not determine whether these outcomes had been collected in the studies we contacted the investigators or study sponsors to ascertain whether this information was available for us to use in our analyses.

We sought additional outcome data (such as FEV1 or PEF) which was incompletely reported from the investigators or from the sponsors.

Assessment of heterogeneity

We assessed statistical heterogeneity with the I² statistic. This gives an estimate of the proportion of heterogeneity between the study results that exceeds what would be expected with the play of chance, expressed as a percentage (Higgins 2003).

Data synthesis

The analysis focused on the following comparison:

Long-acting ß2 agonist (LABA) and inhaled corticosteroids (ICS) versus a higher dose of inhaled corticosteroids as second-line treatment (i.e. in patients who were already taking inhaled corticosteroids at baseline).

Note that given the large size of this review, other comparisons originally stated in the protocol published in 1999 were assessed in two other reviews. This includes comparing the addition of LABA to similar (Ni Chroinin 2005; Ni Chroinin 2009a) and tapering doses of inhaled corticosteroids (Gibson 2005).

If a trial had more than one intervention or control group, we considered additional comparisons, if appropriate. If two comparisons used the same group twice as comparator (e.g. a three-arm study which had two ‘LABA + ICS’ arms but only one ‘higher ICS’ group) (Woolcock 1996a; Woolcock 1996b), we halved the number of participants in the control group (e.g. ICS alone group) to avoid over-representation. For dichotomous outcomes (such as hospitalisation) we halved the control group numerator and denominator.

We calculated treatment effects for dichotomous variables as relative risk (RR) and/or risk difference (RD) with 95% confidence intervals (CI). For continuous outcomes, such as pulmonary function tests, we calculated pooled statistics as mean differences (MD or generic inverse variance) or standardised mean differences (SMD), as indicated, and reported 95% confidence intervals. We tested homogeneity of effect sizes between studies being pooled with the I² statistic and the Dersimonian & Laird method, with values above 25% and a P < 0.05 being used, respectively, as the cut-off level for statistical significance. In the absence of heterogeneity we used a fixed-effect model (Greenland 1985). If heterogeneity was suggested, we applied the Dersimonian & Laird random-effects model (DerSimonian 1986) to the summary estimates. Unless otherwise specified, the pooled estimates are derived from the fixed-effect model.

We assumed equivalence if the relative risk estimate and its confidence interval were between 0.9 and 1.1. We derived numbers needed to treat (NNT) from the pooled relative risks using Visual Rx (Cates 2002).

Subgroup analysis and investigation of heterogeneity

We planned subgroup analyses to explore possible reasons for heterogeneity of the primary outcome and, in the absence of heterogeneity, to identify potential effect modifiers for which the magnitude of benefit may change according to the value of characteristic (e.g. severity of airway obstruction). We examined the following a priori defined subgroups to explore their influence on the magnitude of effect (effect modification).

Magnitude of airway obstruction at baseline as determined by the mean group percent predicted forced expiratory volume in 1 second (FEV1) classified as mild (FEV1: >= 80%), moderate (FEV1 61% to 79%), or severe (FEV1 <= 60%) (GINA 2008).
Dose of inhaled corticosteroids examined as:
1. mean dose (ex-valve) of inhaled corticosteroids in LABA group, reported in CFC-propelled beclomethasone-equivalent (mcg/day);
2. dose difference in dose of inhaled corticosteroids (in CFC-propelled beclomethasone equivalent) between the LABA and the higher ICS groups. When not reported, an estimate of the mean was made based on the provided range.
Long-acting ß2 agonist (salmeterol/formoterol).
Children (< 18 years) versus adults.
Use of one or two devices to deliver the combination of ICS + LABA.
Trial duration (in weeks).

We examined difference in the magnitude of effect attributable to these subgroups with the residual Chi² test from the Peto odds ratios (Deeks 2001). The number of trials allowed us to conduct a multivariate meta-regression to examine the simultaneous impact of, and interaction between the above-named variables on, the heterogeneity of patients with exacerbations requiring systemic corticosteroids. We built backward and forward models using these subgroups as well as using FEV1 (L), dose of inhaled corticosteroids in the LABA group (mcg/day), dose difference in ICS between LABA and control group (mcg/day) and trial duration as continuous variables, using P < 0.10 as entry and exit criteria (Stata, Version 8.2, Stata Corporation, Texas, USA).

Sensitivity analysis

We performed sensitivity analyses to investigate the potential impact of the following variables on the primary outcome:

risk of bias;
publication bias;
funding source.

We used funnel plots to examine the possibility of publication bias (Egger 1997). The fail-safe N test was used to estimate the number of unpublished studies required to reverse the observed group difference (Gleser 1996).

RESULTS

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

For an archive of previous search detail see Table 1. Literature searches conducted between April 2004 and May 2008 yielded 375 citations, from which we included 18 studies. Figure 1 illustrates the handling of literature search results and inclusion of studies in this update.

Table 1.

Search history

Years	Detail
All years to April 2004	Citations identified: 593
	Excluded: 551 for the following reasons
	Duplicate references (N = 209) Not a randomised controlled trial (N = 68) or ongoing trial (N = 14) Subjects were not asthmatics (N = 4) No consistent intervention with inhaled corticosteroids in all subjects (N = 41) Intervention was not regular inhaled long-acting ß2 agonists (N = 19) Control intervention was not inhaled corticosteroids alone (N = 64) Duration of intervention < 30 days (N = 45) Outcomes measures did not reflect asthma control (N = 8) The treatment and intervention groups compared the same medications either in combination or with different delivery devices (N = 30) Co-intervention with non-permitted agent (n = 1) Examination of the combination of long acting beta 2-agonist and inhaled corticosteroid to the same dose of inhaled corticosteroid alone (N = 49)
	Due to the large number of citations considered, the reasons for exclusion are provided only for published randomised controlled trials

Risk status	Median control group risk (%) [range]	Median study duration (weeks) [range]	Mean FEV1 [range]	NNT (benefit)
Low	1.24 [0 to 3.03]	12 [12 to 12]	81.7 [70 to 102]	673
Low to medium	7.89 [2.86 to 9.43]	12 [12 to 24]	83.8 [74 to 92]	106
Medium to high	12.11 [11.11 to 13.78]	18 [12 to 54]	72 [61 to 88]	69
High	18.87 [14.35 to 38.71]	52 [24 to 52]	73.4 [61 to 87]	45

Study	Control group rate	Risk quartile
Li 1999	0.00	Low
SAM104926	0.01	Low
Busse 2003	0.01	Low
SAM40090	0.01	Low
Bateman 2006	0.02	Low
SAS40026	0.03	Low
SAM30022	0.03	Low
Johansson 2001	0.04	Low/medium
Bouros 1999	0.05	Low/medium
LOCCS	0.07	Low/medium
Greening 1994	0.09	Low/medium
SFCF4026	0.09	Low/medium
Wallin 2003	0.11	Low/medium
Van Noord 1999	0.11	Medium/high
Verberne 1998	0.12	Medium/high
Vermetten 1999	0.12	Medium/high
Baraniuk 1999	0.13	Medium/high
SLGA5021	0.13	Medium/high
Murray 1999	0.14	Medium/high
Condemi 1999	0.14	High
Kelsen 1999	0.16	High
O’Byrne 2005	0.18	High
O’Byrne 2001	0.20	High
Pauwels 1997	0.28	High
Kips 2000	0.39	High

Methods	Parallel-group, multicentre study (50 centres). Three groups of which 2 considered here, namely: FP 250 bid; FP 100 + SL 50 bid Jadad quality score = 5
Participants	Symptomatic asthmatic children >= 12 years and adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 454 (FP100 + Salm50: 231; FP250: 223) WITHDRAWALS: FP100 + Salm50: 16; FP250: 13 AGE: mean (range): 41 (12 to 79) GENDER (% male): 40 SEVERITY: Moderate BASELINE % PREDICTED FEV1: 63.1 BASELINE DOSE OF ICS (start of run-in): Not reported ASTHMA DURATION: Not reported ATOPY (%): Not reported ELIGIBILITY CRITERIA: Non-smokers; >= 12 years of age who had asthma defined in accordance with American Thoracic Society criteria; low dose of beclomethasone dipropionate or fluticasone for at least 3 months preceding the study; the daily dosing schedule for the inhaled corticosteroid had to be constant for the 14-day run-in period prior to the study; FEV1 of 40% to 85% of predicted normal values for age, gender and height; reversibility of airway obstruction was demonstrated by >= 15% increase in FEV1 within 30 minutes after 2 puffs of albuterol EXCLUSION CRITERIA: Pregnant/lactating mothers; use of methotrexate, gold, cyclosporine or azathioprine for control of asthma within 30 days prior to study; use of inhaled cromolyn or inhaled nedocromil within weeks prior to the study; use of oral or injectable corticosteroids within 4 weeks prior to the study; significant concomitant illness or concurrent use of any other prescription or over-the-counter medication that might affect the course of asthma or interact with sympathomimetic amines CRITERIA FOR RANDOMISATION DURING RUN-IN: FEV1 between 40% to 65%, if FEV1 65.1% to 85% had to have asthma symptoms; demonstrate compliance and complete diary cards; not to have experienced clinical exacerbation during screening period
Interventions	LABA + ICS versus INCREASED dose of ICS OUTCOMES: Reported at 1, 2, 4, 6, 8 and 12 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: Usual ICS DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: (FP 100 + Salm 50) fluticasone 100 mcg bid + salmeterol 50 mcg bid CONTROL GROUP: (FP 250) fluticasone 250 mcg bid DEVICE: MDI NUMBER OF DEVICES: 2 COMPLIANCE: Assessed CO-TREATMENT: prn SABA and theophylline as needed
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOM SCORES: Symptom scores (score of 0 to 5) FUNCTIONAL STATUS: Rescue medication use; nocturnal awakenings; symptom-free days; physician global assessment INFLAMMATORY MARKERS: Not described ADVERSE EFFECTS: Described WITHDRAWALS: Described Primary outcome measure
Notes	Full-text publication Funded by Glaxo Wellcome Confirmation of methodology and data obtained User-defined number: 1000
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated random numbers
Allocation concealment?	Yes	Numbered coded inhalers supplied by pharmacy
Blinding? All outcomes	Yes	Double-dummy design; use of identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	“Analyses were based on data from the intent-to-treat population, consisting of all patients exposed to the study drug.”
Free of selective reporting?	Yes	Data available for meta-analysis

Methods	Parallel-group, multicentre (37 centres in 6 countries) Jadad quality score = 5
Participants	Patients with asthma >= 18 years % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 92 RANDOMISED: 344 (BUD 200 + Form 6: 168; FP250: 176) WITHDRAWALS: BUD 200 + Form 12: 3; FP250: 8 AGE: mean (range): 42 (17 to 75) GENDER (% male): BUD 200/Form 6: 42; FP250: 44 SEVERITY: Moderate BASELINE % PREDICTED FEV1(mean): 78 BASELINE DOSE OF ICS: Mean mcg/day BDP equivalent: 594 ASTHMA DURATION mean (range) years: 16.3 (0 to 66) ATOPY (%): Not reported SMOKERS (%): 6 ELIGIBILITY CRITERIA: >= 18 years of age with a diagnosis of persistent asthma (minimum duration 6 months) as defined by the Global Initiative for Asthma (GINA) guidelines; using any inhaled glucocorticoid at a constant dose of 200 to 1000 mcg/day for at least 30 days before study entry; FEV1 of 60% to 90% of predicted normal values; reversibility of airway obstruction was demonstrated by >= 12% increase in FEV1 within 30 minutes after bronchodilator EXCLUSION CRITERIA: Female patients of childbearing potential not using adequate contraception; use of oral, parenteral or rectal corticosteroids or respiratory tract infection within 30 days prior to the study; heavy smoking (>= 10 pack years) CRITERIA FOR RANDOMISATION DURING RUN-IN: Required to have diary data for at least 7 of the last 10 days of run-in period
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: Reported at 4, 8 and 12 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: BUD 200 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: (BUD 200 + Fom 6) budesonide 200 mcg bid + formoterol 6 mcg bid CONTROL GROUP: (FP 250) fluticasone 250 mcg bid DEVICE: Diskhaler NUMBER OF DEVICES: 1 COMPLIANCE: Assessed using diary cards CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOM SCORES: Change in symptom score (score of 0 to 3) FUNCTIONAL STATUS: Rescue medication use; % nocturnal awakenings; % of symptom-free days; % asthma-control days INFLAMMATORY MARKERS: Not described ADVERSE EFFECTS: Described WITHDRAWALS: Described Primary outcome measure
Notes	Full-text publication Funded by Astra Zeneca Confirmation of methodology and data: Not obtained User-defined number: 1000
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as randomised; other information not available
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	Yes	Double-dummy; identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	Described as intention-to-treat analysis; explicit details of how missing data were handled not reported
Free of selective reporting?	Yes	Severe exacerbations (including OCS treated exacerbations) extracted as proxy for OCS-treated exacerbations (see Analysis 3.1)

Methods	Parallel-group, multicentre study (37 centres: 36 in USA, 1 in Puerto Rico) Jadad quality score = 4
Participants	Persistent symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 484 (FP/SAL: 246; FP: 238) WITHDRAWALS: FP/SAL: 6; FP: 4 AGE: mean: 41 GENDER: (% male): 41 SEVERITY: Moderate BASELINE % PRED FEV1 (mean): 70 BASELINE DOSE OF ICS: FP500 ASTHMA DURATION: Not reported ATOPY (%): Not reported ELIGIBILITY CRITERIA: > 12 and < 80 years; diagnosis of persistent (non-seasonal) asthma for more than 6 months; treated with short-acting beta-agonists; FEV1 > 60 and < 80% predicted; reversibility to SABA of 15% OR PEF < 85% predicted; achievement of good asthma control in last 4 weeks of open label period; score of >= 2 on combined day and nighttime score on 4 of last 7 days of run-in period EXCLUSION CRITERIA: Treatment with corticosteroids (within 12 weeks) antileukotriene agents, sodium cromoglycate, long-acting beta-agonists, nedocromil sodium, ketotifen, methylxanthines, anti-cholinergic agents (within 4 weeks); participants with acute asthma exacerbation in 6 weeks prior to study; participants with respiratory tract infection within 4 weeks prior to study; significant smoking history
Interventions	LABA/ICS versus INCREASED dose of ICS OUTCOMES: TIMING 12 weeks RUN-IN: 2 weeks on SABA; −12 weeks open label with combination FP/SAL DOSE OF ICS DURING RUN-IN: 250 mcg bid INTERVENTION PERIOD: 12 weeks TEST GROUP: Combination fluticasone 100 mcg and salmeterol 50 mcg bid CONTROL GROUP: Fluticasone 250 mcg bid DEVICE: Diskus NUMBER OF DEVICES: 1 COMPLIANCE: Not assessed CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: am PEF; pm PEF; FEV1 SYMPTOM SCORES: Daytime symptoms; nighttime symptoms; % symptom-free days; % symptom-free nights FUNCTIONAL STATUS: Rescue medication use; exacerbations (moderate: OCS treatment; severe: hospitalisation) INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure
Notes	Full-text article (additional data from available from http://www.ctr.gsk.co.uk) Source of funding: GSK Confirmation of methodology and data: obtained User defined number: 1000
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Identical devices
Incomplete outcome data addressed? All outcomes	Unclear	“The Intent-to-Treat (ITT) population (all subjects who were randomised to treatment and received ≥ 1 dose of double-blind study medication) were used for the safety and efficacy analyses.”
Free of selective reporting?	Yes	OCS-treated exacerbations available on request from study sponsors

Methods	Parallel-group, multicentre study (76 centres) Jadad quality score = 4
Participants	Patients with asthma 18 to 70 years % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 91 RANDOMISED: 365 (FP250/SM 50 bid: 179; FP500 bid: 186) WITHDRAWALS: FP250/SM 50 bid: 13; FP500 bid: 18 AGE mean: 49 GENDER (% male): 47 SEVERITY: Moderate BASELINE % PREDICTED FEV1 mean: 75 BASELINE DOSE OF ICS: Mean mcg/day BDP equivalent: 800 to 1000 of BDP or BUD ASTHMA DURATION (mean (range) years): Not reported ATOPY (%): Not reported SMOKERS: 0 ELIGIBILITY CRITERIA: 18 to 70 years of age with a diagnosis of persistent asthma (minimum duration 6 months) as defined by the German asthma guidelines; asthma of moderate severity (i.e., symptoms < 1/day but no more than 2/week during daytime, or symptoms >= 2/month but less than 1/week at night; FEV1 50% to 80% of predicted; reversibility of airway obstruction was demonstrated by >= 15% increase in FEV1 after 200 mcg salbutamol; non- or ex-smoker; asthma treated with 800 to 1000 mcg/day of BUD or BDP (or 500 FP) per day for at least 3 months prior to study EXCLUSION CRITERIA: Previous therapy with inhaled LABA, oral beta-agonists, oral or parental steroids in preceding 4 weeks; change in asthma medication, treatment with other study medication, respiratory tract infection or hospital stay due to respiratory problems in receding 4 weeks; inability to correctly administer study drugs, known allergy to components of study drugs; severe concomitant illness or other chronic respiratory diseases (such as cystic fibrosis or interstitial fibrosis); in women, inadequate contraception, pregnancy or lactation CRITERIA FOR RANDOMISATION DURING RUN-IN: At least one of the following criteria: use of rescue medication >= 7 of 14 days; total asthma symptoms score >= 10 points (sums of scores from 14 days and nights); excluded if incomplete diary or considered not reliable or respiratory tract infection during run-in
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: Reported at 4, 8 and 12 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: BUD 200 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: (FLUT 200 + SALM50) fluticasone 200 mcg bid + salmeterol 50 mcg bid (1 inhaler) CONTROL GROUP: (FP 500) fluticasone 500 mcg bid DEVICE: Diskus NUMBER OF DEVICES: 1 COMPLIANCE: Assessed using diary cards CO-TREATMENT: Theophylline, cholinergic drugs or leukotrienes if dose was not changed during the trial. Prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOM SCORES: Change in daytime and nighttime symptom score (score of 0 to 4) FUNCTIONAL STATUS: Rescue medication use; % of symptom-free days INFLAMMATORY MARKERS: Not described ADVERSE EFFECTS: Described WITHDRAWALS: Described Primary outcome measure
Notes	Full-text publication Funded by Glaxo Welcome Germany Confirmation of methodology and data: Not obtained User-defined number: 1000
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Identical inhaler devices
Incomplete outcome data addressed? All outcomes	No	“The full analysis set (FAS) consisted of those patients who inhaled at least one dose of study medication and had no critical protocol violation (e.g. a missing diary from the screening period). The last observation carried forward (LOCF) principle was applied to the efficacy variables.”
Free of selective reporting?	Unclear	Unclear whether exacerbations were recorded in the study

Methods	Parallel-group, multicentre study (11 centres) Jadad quality score = 2
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 84 RANDOMISED: 134 (BDP250 + Form 12: 69; BDP500: 65) WITHDRAWALS: BDP250 + Form 12: 4; BDP500: 6 AGE mean: 43 Gender (% male): 35 SEVERITY: Moderate BASELINE % PREDICTED FEV1: 60% to 79% (estimated) BASELINE DOSE OF ICS: BDP 500 mcg/day ASTHMA DURATION: Not described ATOPY (%): Not described SMOKING STATUS: Not described ELIGIBILITY CRITERIA: >= 18 years old; use of inhaled BDP aerosol for at least 1 month prior to enrolment, at a constant daily dose of 500 mg EXCLUSION CRITERIA: Other clinically significant diseases; pregnant or lactating women; patients on B-blocker therapy or hypersensitivity of sympathomimetic amines; received a short course of oral corticosteroid in the 6 weeks prior to enrolment; more then 3 oral corticosteroid short courses during the year prior to enrolment CRITERIA FOR RANDOMISATION DURING RUN-IN: A symptom score of 2 or greater on at least 4 of the 7 days during the second week of the run-in; FEV1 before administration of an inhaler agonist 40% to 85% of the predicted value; a reversibility test with 200 mg salbutamol demonstrating an increase in FEV1 of at least 15% from baseline value
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: Reported at 4, 8 and 12 weeks RUN-IN PERIOD: 2 weeks to document symptoms and beta2 use DOSE OF ICS DURING RUN-IN: BDP 500 mcg/day DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: (BDP500 + Form 12) beclomethasone 250 mcg bid + formoterol fumarate 12 mcg bid CONTROL GROUP: (BDP1000) beclomethasone 500 mcg bid DEVICE: MDI NUMBER OF DEVICES: 2 COMPLIANCE: Not reported CO-TREATMENT: prn SABA (used with a spacer device)
Outcomes	PULMONARY FUNCTION TEST: am PEF; pm PEF; FEV1 SYMPTOM SCORE: Morning and evening score (score of 0 to 4) FUNCTIONAL STATUS: Mean rescue B2-agonist (inhalations per day or night); exacerbations requiring systemic steroids INFLAMMATORY MARKERS: Not described ADVERSE EFFECTS: Described WITHDRAWALS: Reported Primary outcome measure
Notes	Full-text publication Funded by Glaxo Wellcome Confirmation of methodology and data: Not obtained User-defined number: 500 (1000-500)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	No	Open label
Incomplete outcome data addressed? All outcomes	No	Completers analysed
Free of selective reporting?	Yes	OCS-treated exacerbations available

Methods	Parallel-group, multicentre study (90 centres in US). Study had 2 treatment periods: fixed dosing during period 1 (up to week 12), and variable dosing in period 2 (weeks 12 to 24) Jadad quality score = 3
Participants	Stable asthmatic patients 12 years and over % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PATIENTS RANDOMISED: 558/1596 = 35% RANDOMISED: 558 (Salmeterol 50 bid + ICS: 281; ICS + placebo: 277) WITHDRAWALS: S + ICS: 35; ICS: 42 AGE mean (range): 39 (12 to 77) GENDER (% male): 42 BASELINE % PREDICTED FEV1 mean: 80.5 BASELINE DOSE OF ICS (mean): Not reported by treatment groups BDP 400 to 800 mcgs/day; triamcinolone acetate 1200 to 1600 mcgs/day; flunisolide 1000 to 1500 mcgs/day; FP 440 to 660 mcgs/day ASTHMA DURATION: Not reported ATOPY (%): Not described SMOKING STATUS: Not reported ELIGIBILITY CRITERIA: Asthma for at least 6 months and treated with medium dose ICS for at least 30 days before screening; baseline FEV1 of 65% to 95% normal; >= 12% improvement from baseline in lung function following inhaled bronchodilator; best FEV1 within +/− 15% of the best predose FEV1 obtained at screening; no more than 1 nighttime awakening requiring albuterol and fewer than 18 puffs albuterol during the previous week EXCLUSION CRITERIA: Pregnancy and/or lactating; life-threatening asthma; asthma hospitalisation within 3 months of screening; change in asthma regimen 30 days before screening; significant concurrent diseases including recent URTI; systemic corticosteroids in 30 days before screening CRITERIA TO ENTER RUN-IN PERIOD 2: 20% decrease from the screening visit pre-dose FEV1; >= 20% decrease from the mean morning baseline PEF on any one of the 7 days immediately preceding the visit; total symptom score of >= 8 during any week before run-in visit; 2 or more nighttime awakenings due to asthma requiring treatment with albuterol during any week period before run-in visit CRITERIA FOR RANDOMISATION FOLLOWING RUN-IN PERIODS: Patients who regained asthma control following step-up treatment during run-in period 2; best FEV1 >= 65% of predicted and >= 15% of the best predose FEV1 obtained at visit IA
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: Reported at 1, 4, 8 and 12 and 24 weeks (only those at 12 weeks used) DOSEOPTIMISATION PERIOD: 10 weeks; patients commenced on FP 250 mcg bid or equivalent for 2 weeks. Stable patients had their dose dropped to FP 100 bid. Patients who became unstable on this were eligible to continue. FP 250 bid was commenced and patients stable on this were eligible to continue INTERVENTION PERIOD: 12 to 24 weeks (data at 12 weeks used) TEST GROUP: (FP 100 bid + S 50 bid) salmeterol 50 mcg bid + fluticasone propionate 100 bid CONTROL GROUP: Fluticasone propionate 250 bid DEVICE: Diskhaler NUMBER OF DEVICES: 1 COMPLIANCE: Monitored during study CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOMSCORE: Mean change in daily symptom score (score of 0 to 5 Likert scale) FUNCTIONAL STATUS: Exacerbations (defined as any worsening of asthma that required asthma medication beyond blinded study drugs or albuterol); rescue medication use; nocturnal awakening; % rescue-free days; % symptom-free days INFLAMMATORY MARKERS: Not assessed ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure: proportion of patients who remained in study after 12 weeks and who did not withdraw due to lack of efficacy
Notes	Full-text publication. Additional data available from GSK trials register Funded by Glaxo Wellcome Confirmation of methodology and data obtained User-defined number: 600 (1000-400)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Identical inhaler devices
Incomplete outcome data addressed? All outcomes	No	Last observation carried forward: “All analyses for efficacy and safety were conducted through use of the intent-to-treat population (all randomised patients). All data from patients who were withdrawn from the study early were included in the analyses, data available up to the time of study discontinuation being used. No interpolation was used for missing data.”
Free of selective reporting?	Yes	OCS-treated exacerbations available on request from GSK

Methods	Parallel-group, multicentre study (36 research centres) Jadad quality score = 5 Confirmation of methodology obtained
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 85 RANDOMISED: 437 (FP100 + Salm50: 221; FP250: 216) WITHDRAWALS: FP100 + Salm50: 19; F250: 30 AGE mean: 36.9 years GENDER (% male): 39 SEVERITY: Moderate BASELINE % PREDICTED FEV1: 61 BASELINE DOSE OF ICS: Not reported ASTHMA DURATION: < 10 years: 23%; >= 10 years: 87% ATOPY(%): Not reported SMOKERS: None ELIGIBILITY CRITERIA: >= 12 years old; asthma for at least 6 months; increase in FEV1 by 15% or greater after the inhalation of 200 mg of albuterol; FEV1 of 40% to 80% of predicted value; used short-acting bronchodilator on a regular basis for 3 months EXCLUSION CRITERIA: Current tobacco use; hospital admissions for asthma in the past 30 days; upper or lower respiratory infection within 30 days; positive pregnancy test or lactating; excluded during screening if they had an asthma exacerbation CRITERIA FOR RANDOMISATION FOLLOWING RUN-IN: FEV1 40% to 65% of predicted normal; at least one of the following over the 7 days prior to randomisation: an average of >= 4 puffs of albuterol per day; 2 or more days when evening PEF variation was >= 20%; 2 or more nights with awakenings due to asthma; 3 or more days with scores of >= 2 for any of the daytime symptoms of wheeze, chest tightness, shortness of breath or cough
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: Reported at 2,4,8,12,16,20 and 24 weeks RUN-IN: 2 to 4 weeks DOSE OF ICS DURING RUN-IN: FP 100 bid INTERVENTION PERIOD: 24 weeks TEST GROUP: (FP100 + Sal50) fluticasone propionate 100 mg bid + salmeterol 50 mg bid CONTROL GROUP: (FP250) fluticasone propionate 250 mg bid DEVICE: Metered-dose inhalers NUMBER OF DEVICES: 2 COMPLIANCE: Not reported CO-TREATMENT: Albuterol on an as-needed basis
Outcomes	PULMONARY FUNCTION TEST: Change in morning* and evening PEF; change in FEV1(L) SYMPTOM SCORES: Change in daytime symptom scores (scores of 0 to 5) FUNCTIONAL STATUS: Change in mean rescue B2-agonist use ( number of puffs); change in number of nighttime awakenings; change in % nights with no awakenings; exacerbations requiring systemic steroids INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Reported WITHDRAWALS: Described Primary outcome measure*
Notes	Full-text publication Funded by Glaxo Wellcome Confirmation of methodology and data obtained User defined number: 600 (1000-400)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Random computer-generated numbers
Allocation concealment?	Yes	Letter coded inhalers supplied by pharmacy
Blinding? All outcomes	Yes	Double-dummy design; identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	“All statistical analyses were performed on the intent-to-treat (ITT) population consisting of all subjects who were randomised to blinded study drug.”
Free of selective reporting?	Yes	OCS-treated exacerbations available for meta-analysis

Methods	Parallel-group, multicentre 4-arm trial, 2 of which are considered in this review
Participants	% ELIGIBLE OF SCREENED POPULATION: 44 % RUN-IN PARTICIPANTS RANDOMISED: 63 RANDOMISED: 306 (BUD/F: 153; BUD 153) WITHDRAWALS: Not stated AGE mean (range) or mean (SD): 35 (15) SEVERITY: Not stated BASELINE % PREDICTED FEV1: 76% BASELINE DOSE OF ICS: 375 mcg ASTHMA DURATION: Not stated ATOPY (%): Not stated ELIGIBILITY CRITERIA: > 12 years; documented clinical diagnosis of asthma for 6 months prior to screening; stable; maintenance asthma treatment with inhaled corticosteroids (ICS) for at least 4 weeks; FEV1 60% to 90% predicted EXCLUSION CRITERIA: Not stated ELIGIBILITY CRITERIA DURING RUN-IN: Not stated
Interventions	LABA and ICS versus HIGHER dose ICS OUTCOMES 12 weeks RUN-IN PERIOD: 4 to 5 weeks (combination therapy) INTERVENTION PERIOD: 12 weeks TEST GROUP: Combination budesonide and formoterol 200/12 mcg qd CONTROL GROUP: Budesonide 400 mcg qd NUMBER OF DEVICES: 1 COMPLIANCE: Not reported CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOM SCORES: Total symptoms FUNCTIONAL STATUS: Rescue medication use INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Reported WITHDRAWALS: Stated for adverse events only
Notes	Trial report available as download from AZ clinical trials website Funded by AZ Confirmation of methodology and data extraction not obtained User defined: 400
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as randomised; no other information presented
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	Yes	“To maintain blinding with the twice-daily dosing regimen, all subjects randomised to receive once-daily dosing were to take the active treatment in the evening and a matched placebo device (Batch numbers P6492 and P6856) in the morning.”
Incomplete outcome data addressed? All outcomes	Unclear	“The efficacy analysis set (EAS), defined as all randomised subjects who took at least 1 dose of double-blind treatment and for whom the primary efficacy endpoint could be calculated, was used in the primary analysis of efficacy. Sensitivity analyses were performed using the per protocol (PP) analysis set, which excluded subjects with major violations of inclusion or exclusion criteria.”
Free of selective reporting?	Unclear	Not clear whether the study collected information on exacerbations treated with OCS

Methods	Parallel-group, single centre study Jadad quality score = 4 Confirmation of methodology not obtained
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 100 RANDOMISED: 39 (Salm50/FP: 19; HFA BDP: 20) WITHDRAWALS: 0 AGE mean: 44 GENDER (% male): 51 SEVERITY: Moderate-severe BASELINE FEV1% predicted: 69% BASELINE DOSE OF ICS: >= 800 mcg CFC-BDP or equivalent or >= 200 mcg CFC-BDP as second-line therapy ASTHMA DURATION: Not reported ATOPY (%): Not reported SMOKING STATUS: Not reported ELIGIBILITY CRITERIA: FEV1 55% to 85% predicted; >= 15% improvement from baseline in PEF or FEV1 following an inhaled beta2-agonist; PD 20 methacholine < 200 mcg; use of > 2 puffs of rescue medication/ day and symptoms at least 5 days per week; at least 80% compliance with dose prescribed as per dose counters EXCLUSION CRITERIA: Patients receiving oral corticosteroids; asthma exacerbation in the 3 months before study entry CRITERIA FOR RANDOMISATION FOLLOWING RUN-IN: Diary card evidence over the previous month of using at lease 2 puffs per day of rescue medication and having symptoms at least 5 days per week; patients who did not meet these criteria had their treatment tapered in a stepwise fashion at 1 to 2-week intervals until they were taking less than 200 mcg CFC-BDP or equivalent at which point they were withdrawn from the study or their beta-2 agonist use met the above criteria
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: Reported 1, 2 and 4 weeks RUN-IN PERIOD: 4 weeks DOSE OF ICS DURING RUN-IN: BDP 2000 mcg/day TREATMENT DURATION: 4 weeks DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 4 weeks TEST GROUP: (FP 100 mg + SAL50 mg): Fluticasone dipropionate 100 mcg bid + salmeterol 50 mcg bid CONTROLGROUP: (HFA BDP 200 mcg bid) beclomethasone dipropionate 200 mcg bid DEVICE: FP + S via diskhaler; HFA-BDP via metered dose inhaler NUMBER OF DEVICES: 2 COMPLIANCE: Dose counters used to check compliance CO-TREATMENT: Albuterol DPI via clickhaler
Outcomes	PULMONARY FUNCTION TEST: Diurnal variation in PEF (%); FEV1 % predicted; PD 20 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: AQLQ 32 questions with 7-point scale; rescue B2-agonist use INFLAMMATORY MARKERS: Serum ECP; nitric oxide OTHER: Plasma cortisol ADVERSE EFFECTS: Reported WITHDRAWALS: Described Primary outcome: Not reported
Notes	Full-text publication Funded by anonymous research grant and received HFA-BDP and placebo free from 3M healthcare Confirmation of methodology and data not obtained User defined number: 400 (800-400)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as randomised, no other information available
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	Yes	Double-dummy study
Incomplete outcome data addressed? All outcomes	Unclear	Described as intention-to-treat
Free of selective reporting?	Unclear	Not clear whether the study collected information on exacerbations treated with OCS

Methods	Cross-over, single centre study in UK
Participants	% ELIGIBLE OF SCREENED POPULATION: Not specified % RUN-IN PARTICIPANTS RANDOMISED: 74 RANDOMISED: 49 WITHDRAWALS: 10 GENDER: (% male): 51 MEAN AGE: 42 SEVERITY: Not stated BASELINE FEV1 % PREDICTED: 74.8 BASELINE DOSE OF ICS: </−400 BDP ASTHMA DURATION: Not available ATOPIC: 93% SMOKING STATUS: Non or ex-smokers eligible INCLUSION CRITERIA: 18 to 75 years, diagnosed with asthma; receiving treatment with 400 mcg/day beclomethasone dipropionate; one or more of 1) > 15% increase in FEV1 post-SABA; 2) > 20% within-day variability in PEF assessed twice daily over a 2-week period; 3) provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) < 8mg/mL-1; following run-in on 200 mcg day BUD, participants were eligible if they had recorded day or nighttime asthma symptoms on their diary cards on at least 4 days in the third or fourth baseline week EXCLUSION: Current smokers or smoking history of > 10 pack-years, significant comorbidity, treated with oral corticosteroids, long-acting b2-agonists, leukotriene antagonists or theophylline; asthma exacerbation or lower respiratory tract infection within the 4 weeks prior to trial entry
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: 4 weeks RUN-IN PERIOD: 4 weeks DOSE OF ICS DURING RUN-IN: BUD 100 mcg bid TREATMENT DURATION: 4 weeks DOSE OPTIMISATION PERIOD: None TEST GROUP: Budesonide 100 mg bid + formoterol 12 mg bid CONTROL GROUP: Budesonide 400 mg bid DEVICE: Turbohaler NUMBER OF DEVICES: 2 (double-dummy) COMPLIANCE: Not assessed CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TESTS: am PEF; FEV1 SYMPTOM SCORES: VAS; daytime symptoms; nocturnal symptoms FUNCTIONAL STATUS Quality of life (AQLQ); exacerbations (deterioration in PEF or requirement for OCS. Patients who experienced 2 or more exacerbations were withdrawn from the study) INFLAMMATORY MARKERS: Sputum eosinophils; exhaled nitric oxide; PC20 ADVERSE EFFECTS: Not reported WITHDRAWALS: Stated (not by treatment group) Primary outcome measure
Notes	Full-text article Funding source: Not disclosed Methodology and data: TJL emailed 17 April 2008. Response from RG with details of randomisation and data User defined: 800
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	“I believe that this was generated using a computer statistical package generating a random sequence. I don’t know the package that was used and unfortunately the individual has left our organisation but had extensive clinical trials expertise.”
Allocation concealment?	Yes	“…this was indeed generated by a third party, namely the pharmacist responsible for dispensing the double blind medication (…) None of the study investigators were aware of the randomisation schedule until the last patient had completed the cross-over study”
Blinding? All outcomes	Yes	Double-dummy
Incomplete outcome data addressed? All outcomes	No	Completers used for analysis
Free of selective reporting?	Yes	OCS-treated exacerbations reported. Data could not be extracted as only data on events and not number of participants were made available

Methods	Parallel-group, multicentre study Jadad quality score = 5
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 426 (Salm50/BDP: 220; BDP: 206) WITHDRAWALS: Salm50/BDP: 71; BDP: 65 AGE mean: 48 years GENDER (% male): 44 SEVERITY: Moderate BASELINE FEV1: 2.13 Litres/sec Baseline % predicted PEF: 74 BASELINE DOSE OF ICS: Not reported ASTHMA DURATION: 11 years ATOPY (%): Information not available SMOKING STATUS: Current/previous smokers: 50% ELIGIBILITY CRITERIA: FEV1 >= 50% predicted; >= 15% improvement from baseline in PEF or FEV1 following an inhaled beta2-agonist; no courses of oral steroids during the previous 6 weeks or <= 4 short courses during the past year EXCLUSION CRITERIA: Patients receiving regular oral corticosteroids or who had received short course of oral corticosteroids in the 6 weeks prior to start of study or who had received 4 or more short courses in the last year. Patients who had received newly prescribed asthma therapy or who had changed asthma therapy in the 6 weeks prior to entering the study. Patients with FEV1 < 50% or predicted at the start of baseline. Patients who had a medical or physiological condition which in the investigator’s opinion should preclude them from the study, or one or more of the concurrent medical conditions: severe cardiac disease, clinically significant hepatic or renal dysfunction, thyrotoxicosis, uncontrolled diabetes mellitus, history of active neoplastic disease, tuberculosis, acute respiratory infection which required prescribed therapy 2 weeks prior to study, patients receiving beta-blockers, patients currently receiving other long-acting B2-adrenoreceptor agonists, female patients who were pregnant or lactating or were not taking adequate contraceptive precautions, patients whose history over the previous year was not documented, patients who were receiving or had received research medication in the previous month, patients previously enrolled in this study, patients with evidence of alcohol abuse, known hypersensitivity to salbutamol, salmeterol or beclomethasone dipropionate CRITERIA FOR RANDOMISATION DURING RUN-IN: Period variation in PEF over 1 week of >= 15% (highest evening PEF minus lowest morning PEF as a percentage of highest value); symptoms on >= 4 of 7 days during the second baseline week
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: 1, 3, 6 months RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: BDP 200 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 6 months TEST GROUP: Beclomethasone (MDI) 200 mcg bid + salmeterol (Diskhaler) 50 mcg bid CONTROL GROUP: Beclomethasone (MDI) 500 mcg bid + placebo DEVICE: Diskhaler and MDI NUMBER OF DEVICES: 2 COMPLIANCE: Evaluated CO-TREATMENT: prn SABA. Other asthma drugs (xanthines) if already started prior to study
Outcomes	PULMONARY FUNCTION TEST: am PEF; pm PEF SYMPTOM SCORES: Not given FUNCTIONAL STATUS: Nighttime disturbance (% patients with disturbance every night, >= 50% nights , < 50% nights and no night disturbance); daytime symptoms (% patients with symptoms every day, >= 50% of days, < 50% days, and no symptoms); rescue medication use; exacerbations mild (increase in relief medication); moderate (requiring a short course in oral corticosteroids); or severe (requiring hospital admission) INFLAMMATORY MARKERS: Not described ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure*
Notes	Full-text publication Supported by Allen & Hanburys Ltd, Uxbridge, Glaxo Pharmaceuticals Ltd, Uxbridge and Access Ltd, London (data and statistical advice) Confirmation of methodology and data extraction obtained User defined number: 600 (1000-400)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated random numbers
Allocation concealment?	Yes	Numbered coded medication allocated on sequential basis
Blinding? All outcomes	Yes	Use of identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	“All analyses were performed on an intention- to-treat (ITT) basis, i.e. all subjects randomised and who had verifiable data.”
Free of selective reporting?	Yes	OCS-treated exacerbations available for meta-analysis

Methods	Cross-over study, single treatment centre Jadad quality score:4
Participants	Asthmatic children % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 27 WITHDRAWALS: 2 MEAN AGE (RANGE): 9.6 (6.1 to 13.5) GENDER (% male): 52 SEVERITY: Mild to moderate BASELINE FEV1 L (range): Not reported BASELINE PEF L/min (range): 280 l/min BASELINE DOSE OF ICS Mean: BUD 200 bid or equivalent ASTHMA DURATION (range in years): 4.5 (1.4 to 9.5) ATOPY (%): Not reported ELIGIBILITY CRITERIA: Not described EXCLUSION CRITERIA: Not described
Interventions	LABA + ICS versus INCREASED DOSE ICS OUTCOMES: Reported weekly RUN-IN: None DOSE OF ICS DURING RUN-IN: N/A INTERVENTION PERIOD: 12 weeks TEST GROUP: (Form + ICS) formoterol 12 mcg bid + budesonide 100 bid CONTROL GROUP: Placebo + budesonide 200 bid DEVICE: Turbuhaler (ICS); Aerolizer (formoterol) NUMBER OF DEVICES: 2 COMPLIANCE: Turbuhalers weighed and number of formoterol capsules counted CO-TREATMENT: Terbutaline via turbuhaler but no other co-treatments allowed
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOM SCORE: Daytime and nighttime score (score of 0 to 4) FUNCTIONAL STATUS: Exacerbations; rescue medication use; lower leg growth; serum and urinary markers of type I and III collagen turnover INFLAMMATORY MARKERS: Inflammatory markers in serum ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure: Not reported
Notes	Full-text publication Source of funding not stated Confirmation of methodology and data not obtained User-defined number: 200 (400-200)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	“Treatment order was allocated by a computerised randomisation scheme prepared in balanced blocks.”
Allocation concealment?	Unclear	Information on concealment of allocation not provided
Blinding? All outcomes	Yes	Double-blind; double-dummy
Incomplete outcome data addressed? All outcomes	No	Completers used for analysis
Free of selective reporting?	Yes	Data on OCS-treated exacerbations available

Methods	Parallel-group, multicentre study in 100 hospitals and general practices in 6 countries (3 groups of which 2 are considered for this review
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 58%; of 859 recruited 357 not randomised (improved during run-in period) RANDOMISED: 502 (496 with completed case report forms included in intention-to-treat population). 336 for this review: FP/SAL: 171; FP: 165 WITHDRAWALS: FP/SAL: 27; FP: 22 Mean AGE years: 44.4 GENDER (% male): 45 SEVERITY: Moderate to severe BASELINE FEV1: 2.3 L % PREDICTED PEF am: 75 BASELINE DOSE OF ICS (median): 1000 mcg ASTHMA DURATION (range in years): 0.2 to 68 ATOPY (%): Information not available SMOKING STATUS: Not reported ELIGIBILITY CRITERIA: Aged 15 to 75; symptomatic on BDP 500 to 800 mcg bid or equivalent via MDI with good technique; 2 documented exacerbations needing hospitalisation or change in treatment with one occurring in last 6 months; PEF less than 85% of post-bronchodilator PEF at first clinic visit INCLUSION CRITERIA FOR RANDOMISATION DURING RUN-IN: Period variation in PEF over 10 days of >= 15% (highest evening PEF minus lowest morning PEF as a percentage of highest value); PEF not exceeding 90% of the post-bronchodilator PEF at first clinic visit; EXCLUSION CRITERIA: Patients receiving regular oral corticosteroid; patients who had serious uncontrolled systemic disease; participation was deemed unsuitable by their physician from the study
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: 6, 12 18 and 24 weeks RUN-IN PERIOD: 4 weeks DOSE OF ICS DURING RUN-IN: FP 250 mcg bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 6 months TEST GROUP: Combination fluticasone propionate/salmeterol 250/50 mcgs bid (in one device) INCREASED DOSE: FP 500 mcgs bid DEVICE: MDI NUMBER OF DEVICES: 1 COMPLIANCE: Not reported CO-TREATMENT: prn SABA. Other asthma drugs as needed except LABA
Outcomes	PULMONARY FUNCTION TEST: am PEF; pm PEF SYMPTOM SCORES: Nighttime scores 0 to 4; day-time score 0 to 5 FUNCTIONAL STATUS: % symptom-free days and nights; rescue medication use; exacerbations (defined as: mild (requiring increase in relief medication); moderate (requiring the use of additional corticosteroid); severe (requiring emergency hospital treatment) INFLAMMATORY MARKERS: Not described ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure
Notes	Full-text publication Supported by Glaxo Wellcome Research and Development Confirmation of methodology and data extraction not obtained User defined number: 1000 (2000-1000)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	“intent-to-treat population (…) included all patients randomised to treatment with completed case report forms and verifiable data.”
Free of selective reporting?	Yes	Moderate exacerbations extracted as proxy for OCS-treated exacerbations (see Analysis 3.1)

Methods	Parallel-group, multicentre study (44 centres) Jadad quality score = 4
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 353 (FP/SAL: 180; BUD: 173) WITHDRAWALS: FP/SAL: 29; BUD: 30 Mean AGE years: 47 GENDER (% male): 50 SEVERITY: Moderate to severe BASELINE FEV1 % PRED: 70 BASELINE DOSE OF ICS median mcg/day prior to randomisation (n): FP500 (85); BUD 800 (168); BDP 1000 (101) *One patient was receiving both FP and BDP prior to study entry ASTHMA DURATION: < 1 year: 6%; 1 to 5 =18%; 5 to 10 = 16%; > 10: 60% ATOPY (%): Information unavailable SMOKING STATUS: Not reported ELIGIBILITY CRITERIA: > 12 years; documented reversible airways obstruction receiving ICS (BUD or BDP 800 to 1600 mcg/day or FP 400 to 600 mcg/day for > 4 weeks); baseline FEV1 or PEF 50% to 85% of normal; 15% increase in FEV1 or PEF 85% of maximum after bronchodilator; using rescue bronchodilator more than twice per day or total symptom score > 2 on > 4 of 7 days EXCLUSION CRITERIA: Acute exacerbation requiring hospitalisation, systemic corticosteroids, lower respiratory tract infection or change in asthma medication in 4 weeks prior to recruitment; LABA treatment or slow release bronchodilator in 2 weeks before recruitment; smoking history > 10 pack-years; pregnant or lactating females; regular oral corticosteroid treatment; serious uncontrolled systemic disease CRITERIA FOR RANDOMISATION DURING RUN-IN: No other additional criteria
Interventions	LABA + ICS versus INCREASED dose of ICS OUTCOMES: 4, 12 and 24 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: Usual ICS DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 24 weeks TEST GROUP: (FP/SAL) Combination fluticasone and salmeterol 250/50 mcg bid in single device, plus placebo turbuhaler INCREASED dose: BUD (DPI): Budesonide 800 mcg bid by turbuhaler + placebo Diskus DEVICE: Diskus (FP/SAL) and Turbuhaler (BUD) NUMBER OF DEVICES: 1 COMPLIANCE: Not reported CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: am PEF; pm PEF; FEV1 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Symptom-free days and nights; % salbutamol-free days in each group; % symptom-free days in each group; exacerbations severe (requiring emergency hospital treatment); moderate (requiring additional inhaled corticosteroids); mild (requiring increase in use of relief medication which physician considered to be clinically relevant) INFLAMMATORY MARKERS: Not described ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure
Notes	Full-text publication Supported by Glaxo Wellcome Research and Development Confirmation of methodology and data extraction not obtained User defined number: 600 (1600-1000)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Double-dummy design
Incomplete outcome data addressed? All outcomes	Unclear	“The Intent-to-Treat (ITT) population was defined as all patients who entered the study, were randomised, and received at least one dose of study treatment, was used for assessment of safety data as well as for all efficacy analyses.”
Free of selective reporting?	Yes	Moderate exacerbations extracted as proxy for OCS-treated exacerbations (see Analysis 3.1)

Methods	Parallel-group, multicentre study (39 centres in North America, Europe and South Africa) Jadad quality score = 5
Participants	Symptomatic asthmatic patients % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 80 RANDOMISED: 349 (FP/SAL: 176; BUD: 173) WITHDRAWALS: FP/SAL: 23; BUD: 15 AGE mean (years): 36 GENDER (% male): 43 SEVERITY: moderate BASELINE % PREDICTED FEV1: 77 BASELINE DOSE OF ICS: mean in mcg (note: 19% of Sal FP group and 40% of BUD group on no corticosteroids before randomisation): FP 375; BUD 400; BDP 500 ASTHMA DURATION: Not reported ATOPY (%): Not reported SMOKING STATUS: Not reported ELIGIBILITY CRITERIA (including run-in criteria for randomisation): Mild to moderate asthma; symptomatic patients determined either by use of rescue salbutamol (on more than 2 occasions per 24 hours) or symptoms (total daytime and nighttime diary card symptom score of >= 2) on at least 4 of the last 7 days of the run-in period EXCLUSION CRITERIA: If patients had changed their regular asthma medication or received any long-acting or slow-release bronchodilators within the previous 2 weeks, had had a lower respiratory tract infection within the previous 4 weeks, or were smokers with a history of 10 pack years or more; if in the previous 4 weeks patients had had an asthma exacerbation requiring hospitalisation and/or treatment with oral, parenteral or depot corticosteroids; patients with serious uncontrolled diseases likely to interfere with the study or who showed evidence of alcohol or drug abuse; pregnant or lactating females, or those likely to become pregnant
Interventions	LABA + ICS versus INCREASED dose of ICS OUTCOMES: Reported at 12 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: Usual ICS DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: Combination fluticasone/salmeterol 100/50 mcg bid CONTROL GROUP: Budesonide 400 mcg bid DEVICE: FP/SAL: Diskus, BUD: Turbuhaler NUMBER OF DEVICES: 1 COMPLIANCE: Not reported CO-TREATMENT: prn SABA (use of stable asthma medications permitted)
Outcomes	PULMONARY FUNCTION TEST: am PEF; pm PEF; diurnal variation in PEF post-treatment in each group SYMPTOM SCORES: % days and nights when symptom score < 2 (daytime 0 to 5; nighttime 0 to 4) FUNCTIONAL STATUS: Rescue medication use; symptom-free days/nights INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure
Notes	Full-text publication Funded by GlaxoSmithKline Confirmation of methodology and data extraction: Not obtained User defined number: 400 (800-400)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Use of identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	“The Intent-to-Treat (ITT) population was defined as all patients who entered the study, were randomised, and received at least one dose of study treatment: it was used for assessment of safety data as well as for all efficacy analyses.”
Free of selective reporting?	Yes	OCS-treated exacerbations available on request from study sponsor

Methods	Parallel-group study. Other details not available. Jadad quality score = 2
Participants	Unclear severity % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 115 (FP/SAL: 59; FP: 56) WITHDRAWALS: Not stated AGE mean: Not reported GENDER (% male): Not reported SEVERITY: Not reported BASELINE % PREDICTED FEV1 (mean): Not reported BASELINE DOSE OF ICS: Not reported ASTHMA DURATION: Not reported ATOPY (%): Not reported ELIGIBILITY CRITERIA: >= 18 years of age EXCLUSION CRITERIA: Not stated
Interventions	LABA + ICS versus INCREASED dose ICS OUTCOME TIMING: 12 weeks RUN-IN: 4 weeks DOSE OF ICS DURING RUN-IN: Not stated INTERVENTION PERIOD: 12 weeks TEST GROUP: Combination fluticasone and salmeterol 100/50 mcg bid CONTROL GROUP: Fluticasone 200 mcg bid DEVICE: Rotahaler NUMBER OF DEVICES: 1 COMPLIANCE: Not reported CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: am PEF; FEV1 SYMPTOM SCORES: Daily symptom scores; nighttime symptom scores FUNCTIONAL STATUS: Rescue-free days INFLAMMATORY MARKERS: Not stated ADVERSE EFFECTS: Not stated WITHDRAWALS: Not stated Primary outcome measure*
Notes	Conference abstract publication Source of funding: Not stated Confirmation of methodology and data: Not obtained User defined number: 800
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as randomised; other information not available
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	Yes	Identical inhaler devices used
Incomplete outcome data addressed? All outcomes	Unclear	Information not available
Free of selective reporting?	Unclear	Unclear whether exacerbations were recorded in the study

Methods	Parallel-group, multicentre study (34 centres) Jadad quality score: 5
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 483/639 = 76% RANDOMISED: 483 (BDP + Sal: 239; BDP: 244) WITHDRAWALS: BDP + Sal: 48; BDP: 49 AGE mean (years): 42 GENDER (% male): 39 SEVERITY: Moderate BASELINE % PREDICTED FEV1: 64.5 BASELINE DOSE OF ICS: at least 400 mcg BDP or 800 mcg triamcinolone acetonide ASTHMA DURATION: Not reported ATOPY(%): Not reported SMOKING STATUS: No smokers ELIGIBILITY CRITERIA: Non-smokers; >= 18 years and up; baseline FEV1 of 45% to 80% of predicted value; FEV1 of >= 12 % after inhalation of 2 puffs of albuterol; using inhaled corticosteroids regularly for at least 3 months prior to enrolment; 14 days prior to enrolment must have taken 400 mg of beclomethasone daily or 800 mg of triamcinolone EXCLUSION CRITERIA: Not described CRITERIA FOR RANDOMISATION DURING RUN-IN: Must have symptomatic asthma defined as: >= 3 nights with nighttime awakening; >= 3 days with daytime symptoms; >= 3 days with albuterol used as a rescue medication occurring during the 7 days prior to randomisation
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES: Reported at 4, 12 and 24 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: BDP 200 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 24 weeks TEST GROUP: (BDP 200 + Salm50) beclomethasone 200 mcg + salmeterol 50 mcg bid CONTROL GROUP: (BDP 400) beclomethasone 400 mcg bid DEVICE: Inhalation aerosol NUMBER OF DEVICES: 2 COMPLIANCE: Recorded in diary cards CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOM SCORES: Mean symptom score (score of 0 to 4) FUNCTIONAL STATUS: Rescue medication use; symptom-free days; nocturnal disturbance; severe exacerbation (requiring systemic steroids) INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure
Notes	Full-text publication Funded by Glaxo Wellcome Confirmation of methodology and data: obtained User-defined number: 400 (800-400)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Use of identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	Analysis population described as all participants randomised to double-blind treatment
Free of selective reporting?	Yes	OCS-treated exacerbations available for meta-analysis (from GSK; study data included non-OCS exacerbations)

Methods	Parallel-group, multicentre study (3 centres) Jadad quality score = 4
Participants	Well-controlled asthmatic adults (acute ICS reduction): considered as SYMPTOMATIC % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 86 RANDOMISED: 60 BUD + F: 29; BUD: 31 WITHDRAWALS: Not described AGE mean years (range): 36 (19 to 69) GENDER (% male): 40 SEVERITY: Mild BASELINE % PREDICTED FEV1 mean: 79 BASELINE DOSE OF ICS (start of run-in) mean (range): 691 (50 to 1500) mcg ASTHMA DURATION: Not described ATOPY (%): Not described SMOKING STATUS: Not described ELIGIBILITY CRITERIA: Established diagnosis of asthma for 6 months; treated with inhaled corticosteroids (ICS) for at least 3 months; baseline FEV1 > 50% of predicted; >= 15% increase in FEV1 or >= 9% in % predicted FEV1 after 1 mg of inhaled terbutaline EXCLUSION CRITERIA: Treated daily with >= 2000 mg of beclomethasone, >= 1600 mg of budesonide via pressure metered dose inhaler, >= 800 mg of budesonide via Turbuhaler, >= 800 mg of fluticasone; 3 courses of oral steroids in < 6 months; hospital admission due to asthma < 6 months CRITERIA FOR RANDOMISATION DURING RUN-IN: Compliance between 75% and 125% of recommended doses stable asthma for the last 10 days of run-in period; unstable asthma defined as: diurnal variation in PEF exceeded 20% on 2 consecutive days; B2 agonist use exceeded 4 inhalations per day; awakenings due to asthma occurred on 2 consecutive nights; patient needed oral corticosteroids
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES reported at 6, 12, 24 and 52 weeks RUN-IN PERIOD: 4 weeks with budesonide 800 mcg bid to monitor compliance and document asthma stability DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 months TEST GROUP: (BUD200 + F) budesonide 100 mcg + formoterol 12 mcg bid CONTROL GROUP: (BUD800) budesonide 400 mcg + placebo bid DEVICE: Turbuhaler NUMBER OF DEVICES: 2 COMPLIANCE: Measured by means of hidden counter in inhaler CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1 predicted; PEF SYMPTOM SCORES: Change in symptom score (score of 0 to 3) FUNCTIONAL STATUS: Rescue medication use; nocturnal awakenings in each group; severe exacerbation (requiring systemic steroids); episode-free days INFLAMMATORY MARKERS: sputum eosinophils; sputum EG2 + cells; sputum eosinophil cationic protein; sputum differential cell count ADVERSE EFFECTS: Not described WITHDRAWALS: Not described Primary outcome measure
Notes	Full-text publication Funded by Astra Draco Confirmation of methodology and data obtained User-defined number: 600 (800-200)
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated random numbers
Allocation concealment?	Yes	Opaque consecutive numbered envelopes containing assignment
Blinding? All outcomes	Yes	Identical placebo used
Incomplete outcome data addressed? All outcomes	No	“The analysis is based on a “per protocol” approach. Data from patients violating the protocol were included up to the violation time.”
Free of selective reporting?	Yes	OCS-treated exacerbations available for meta-analysis

PERMALINK

Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma

Francine M Ducharme

Muireann Ni Chroinin

Ilana Greenstone

Toby J Lasserson

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors’ conclusions

BACKGROUND

OBJECTIVES

METHODS

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Dealing with missing data

Assessment of heterogeneity

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

RESULTS

Description of studies

Results of the search

Table 1.

Figure 1.

Included studies

Participants

Type of long-acting ß2 agonist, delivery device, inhaled steroid and co-treatment

Study duration

Funding source

Excluded studies

Risk of bias in included studies

Figure 2.

Allocation

Blinding

Incomplete outcome data

Other potential sources of bias

Effects of interventions

Primary outcome: oral steroid-treated exacerbations

Figure 3.

Table 2.

Figure 4.

Figure 5.

Secondary outcomes

Hospital admission and withdrawal

Lung function - end of treatment values

Lung function - change from baseline

Symptoms

Rescue medication use

Quality of life

Inflammatory markers

Adverse events

DISCUSSION

AUTHORS’ CONCLUSIONS

Implications for practice

Implications for research

PLAIN LANGUAGE SUMMARY.

The addition of long-acting beta2-agonists to inhaled steroids compared to higher doses of inhaled steroids alone as maintenance treatment for chronic asthma

ACKNOWLEDGEMENTS

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

DATA AND ANALYSES

Comparison 1.

Type of long-acting ß₂ agonist, delivery device, inhaled steroid and co-treatment

Methods	Parallel-group, multicentre study (51 centres in 7 countries) Jadad quality score: 3
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 94 RANDOMISED: 467 (BDP + F: 230; BDP: 237) WITHDRAWALS: BDP + F: 15; BUD: 22 Mean AGE years (range): 41 (18 to 78) GENDER (% male): 43 SEVERITY: Mild to moderate BASELINE FEV1 % predicted (range): 81 (38 to 157) BASELINE DOSE OF ICS mean (range): 387 (200 to 500) ASTHMA DURATION (range in years): 0 to 53 years ATOPY (%): Information not available ELIGIBILITY CRITERIA: Aged >= 18; diagnosis of asthma minimum 6 months; FEV1 60% to 90% predicted normal; 12% reversibility post-bronchodilator; ICS at constant dose 200 to 500 mcgs /day for at least 1 month prior to study entry EXCLUSION CRITERIA: Patients receiving systemic corticosteroids within 30 days of study entry; respiratory infection within previous 4 weeks; known hypersensitivity to study medication or inhaled lactose; patients with severe cardiovascular disorders or other serious diseases; current or previous smokers with a history of smoking > or = 10 pack years; all female patients were required to be postmenopausal, sterile or using contraception CRITERIA FOR RANDOMISATION DURING RUN-IN: No other additional criteria
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES reported at 4, 8 and 12 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: BDP 100 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: Combination budesonide and formoterol 100/6 mcg bid in a single inhaler CONTROL GROUP: Budesonide 200 mcg bid DEVICE: Turbuhaler NUMBER OF DEVICES: 1 COMPLIANCE: Not reported CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1 predicted; am PEF; pm PEF SYMPTOM SCORES: Score of 0 to 3 FUNCTIONAL STATUS: Rescue medication use; % symptom-free days; nighttime awakening; asthma control days; exacerbations (defined as requirement for OCS or fall in PEF of > 30%) INFLAMMATORY MARKERS: None ADVERSE EFFECTS: Reported WITHDRAWALS: Described Primary outcome measure: Not described
Notes	Full-text publication Funded by Astra Zeneca Confirmation of methodology and data: Not obtained User-defined number: 200
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as randomised; other information not available
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	Yes	Identical inhaler devices
Incomplete outcome data addressed? All outcomes	Unclear	“Efficacy analyses were carried out on all randomised patients (intention-to-treat approach).”
Free of selective reporting?	Yes	Severe exacerbations included OCS exacerbations; added as additional study to sensitivity analysis

Methods	Parallel-group study. Three treatment arms, 2 of which are considered for this review Jadad quality score = 5
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 70 RANDOMISED: 32 Sal + usual ICS: 16; FP + usual ICS: 16 WITHDRAWALS: Sal + usual ICS: 3; FP + usual ICS: 0 AGE mean years: 40 GENDER (% male): 66 SEVERITY: Mild to moderate BASELINE FEV1 % predicted median (range): 82 BASELINE DOSE OF ICS: Mean (range): 400 (200 to 500) ASTHMA DURATION (range in years): Not reported ATOPY (%): 83 ELIGIBILITY CRITERIA: Aged 20 to 70 years; diagnosis of asthma; FEV1 >= 60 % predicted normal; treated with ICS for minimum 12 months in dose up to 500 mcg / day of BDP or BUD EXCLUSION CRITERIA: Respiratory infection within previous 4 weeks; any change in asthma medication in previous 4 weeks; hospital admission with airway disease in previous 4 weeks CRITERIA FOR RANDOMISATION DURING RUN-IN: At least one of the following: symptom score >= 2 on 7 of last 14 days; prn SABA >= 7 of 14 last days variation > 15% in PEF over a 24 hour period on >= 7 of last 14 days with some degrees of symptoms and rescue medication use during that time
Interventions	LABA + ICS vs INCREASED dose ICS OUTCOMES: measured at 12 weeks RUN-IN PERIOD: 2 to 6 weeks DOSE OF ICS DURING RUN-IN: Same as baseline dose of ICS DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: (Salm50 + ICS) Salmeterol 50 mg bid + usual ICS CONTROL GROUP: (FP100 + usual ICS) fluticasone 100 mcg bid + usual ICS (‘double dose’) DEVICE: Dry powder diskhaler NUMBER OF DEVICES: 2 COMPLIANCE: Not reported CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: am PEF; FEV1 SYMPTOM SCORES: score of 0 to 4 (mean/day) FUNCTIONAL STATUS: Rescue medication use; nocturnal awakenings; exacerbations requiring OCS OTHER: Methacholine challenge PD 20 methacholine before and after treatment INFLAMMATORY MARKERS: on BAL and bronchial biopsy; mast cells in BAL; eosinophils in BAL; lymphocytes in BAL; macrophages in BAL and bronchial biopsies ADVERSE EFFECTS: Not reported WITHDRAWALS: Reported PRIMARY OUTCOME: Not specified
Notes	Full-text publication Funded by Glaxo Wellcome, Alfred Foundation and the NH&MRC of Australia Confirmation of methodology and data obtained User-defined number: 400
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated numbers in balanced blocks
Allocation concealment?	Yes	Opaque consecutive numbered envelopes containing assignment
Blinding? All outcomes	Unclear	Identical inhaler devices
Incomplete outcome data addressed? All outcomes	No	Completers analysed
Free of selective reporting?	Yes	OCS-treated exacerbations available for meta-analysis

Methods	Parallel-group, multicentre 3-arm study conducted in USA
Participants	% ELIGIBLE OF SCREENED POPULATION: 60 % RUN-IN PARTICIPANTS RANDOMISED: 63 RANDOMISED: 334 (FP 169; FP/SAL:165) WITHDRAWALS: 29 (FP 13; FP/SAL 16) AGE mean (range) or mean (SD): 30 (14) SEVERITY: Mild BASELINE % PRED FEV1: 92 BASELINE DOSE OF ICS: 400 mcg BDP equivalent ASTHMA DURATION: Not reported ATOPY (%): Not reported ELIGIBILITY CRITERIA: physician-diagnosed asthma; > 6 years; FEV1 predicted 60% or more; > 12% reversibility to SABA or a pc20 of 8 mg per millilitre or less within previous 2 years EXCLUSION CRITERIA: hospitalisation, urgent medical care, oral corticosteroid use, or use of additional asthma medication during run-in; presence of temperature exceeding 38.0 °C, or 100.4 °F) within previous 24 hours ELIGIBILITY CRITERIA DURING RUN-IN: adequate adherence with diary card; FEV1 > 80% predicted; Asthma Control Questionnaire score < 1.5; < 16 puffs of a rescue beta-agonist per week during final 2 weeks of run-in
Interventions	LABA + ICS versus HIGHER dose ICS OUTCOMES: 16 weeks RUN-IN PERIOD: 4 to 6 weeks DOSE OPTIMISATION PERIOD: NA TEST GROUP: Combination fluticasone and salmeterol 100/50 mcg (once daily, evening) CONTROL GROUP: Fluticasone 100 mcg bid NUMBER OF DEVICES: 1 (double-dummy design as combination given twice daily) COMPLIANCE: Assessed by counters on inhalers and counts of pills CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1 predicted; FVC predicted; PEF predicted SYMPTOM SCORES: Daytime symptoms FUNCTIONAL STATUS: Treatment failure*; oral steroid use; quality of life (AQLQ); rescue medication use INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Stated
Notes	Full-text publication Funding source: GSK Confirmation of data and methodology: Not obtained. TJL contacted for separate OCS requirement between adults and children User defined: 400
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	“The randomization schedule was a permuted block design stratified by clinic and pediatric status”
Allocation concealment?	Yes	Central randomisation
Blinding? All outcomes	Yes	Treble dummy: “At randomization each participant was instructed to use two Diskus inhalers each day, one in the morning and the other in the evening. The inhalers either were two containing fluticasone for the fluticasone group, one containing fluticasone and salmeterol and one placebo inhaler for the fluticasone/salmeterol group, or two placebo inhalers for the montelukast group. Inhalers were labelled AM or PM and had yellow or blue dots, respectively, to ensure compliance to the protocol. Each participant also took a capsule (or chewable tablet for 5 mg dose) containing montelukast or placebo once a day in the evening.”
Incomplete outcome data addressed? All outcomes	Unclear	“Analyses were performed on the basis of the intention-to-treat principle; all available data from all patients were included in all analyses.”
Free of selective reporting?	Yes	OCS-treated exacerbations available for meta-analysis

Methods	Parallel-group, multicentre trial (16 centres) Jadad quality score: 4
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 203/274 (74%) RANDOMISED: 203 (BDP/F: 102; BDP: 101) WITHDRAWALS: BDP/F: 7; BDP: 12 AGE mean: 43.9 GENDER (% males): 44.6 SEVERITY: Moderate to severe BASELINE % PREDICTED FEV1 mean: 72 BASELINE DOSE OF ICS: Not reported ASTHMA DURATION mean: 27 years ATOPY (%): Not reported SMOKING STATUS: Current smokers: 8%; previous smokers: 40 ELIGIBILITY CRITERIA: Aged 18 years or more; moderate to severe asthma; FEV1 >= of predicted and increased by 15% or more within 30 minutes after beta2 agonists or historical evidence of reversibility; had to have received Rx with ICS (metered dose inhaler) at a constant daily dose of 1000 mcg beclomethasone dipropionate or 800 mcg budesonide for at least 1 month before screening EXCLUSION CRITERIA: Change in daily dose of ICS in the previous month; use of a LABA or having received a course of oral corticosteroid in the month before the screening; problems using the Aeroliser (R) despite proper instruction CRITERIA FOR RANDOMISATION DURING RUN-IN: Presence of at least 2 of the following on at least 2 of the last 7 days of the run-in period: waking at least once/night because of asthma; asthma interfering with daily activities on at least 1 day; at least 4 puffs of salbutamol rescue medication a day; diurnal variation in PEF of at least 15%
Interventions	LABA + ICS vs INCREASED dose ICS OUTCOMES: measured at 4, 8 and 12 weeks RUN-IN PERIOD: 2 to 4 weeks DOSE OF ICS DURING RUN-IN: 500 BDP bid DOSE OPTIMISATION PERIOD: Not reported INTERVENTION PERIOD: 12 weeks TEST GROUP: (BDP/F) beclomethasone 500 mcg bid and formoterol 12 mcg bid CONTROL GROUP: (BDP) beclomethasone 1000 mcg bid and placebo INHALER DEVICE: Formoterol: Aerolizer; BDP: dry powder inhaler NUMBER OF DEVICES: 2 COMPLIANCE: Not reported CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: am PEF; FEV1 SYMPTOM SCORES: Score of 0 to 4 (day and night ) FUNCTIONAL STATUS: Rescue medication use; exacerbations INFLAMMATORY MARKERS: None ADVERSE EFFECTS: Reported WITHDRAWALS: Described Primary outcome measure
Notes	Full-text publication Funded by Novartis Pharmaceutical Australia Pty Ltd Confirmation of methodology and data: not obtained User-defined number: 1000
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as randomised; no other information available
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	Yes	Double-dummy design
Incomplete outcome data addressed? All outcomes	Unclear	“The analysis of efficacy was carried out in the intention-to-treat analysis and, in addition, a confirmatory analysis was carried out on the mean morning pre-medication PEF measured during the last 7 days of treatment in the patients who had completed the whole treatment period.”
Free of selective reporting?	Unclear	Moderate exacerbations included OCS exacerbations; added as additional study to sensitivity analysis (see Analysis 3.1)

Methods	Parallel-group, multicentre study (35 centres) Jadad quality score: 5
Participants	Symptomatic asthmatic patients % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 514 (BDP + Sal: 260; BDP: 254) WITHDRAWAL: BDP + Sal: 50; BDP: 57 AGE: mean (range): 42 (18 to 82) GENDER (% males): 43 SEVERITY: Moderate BASELINE % PREDICTED FEV1 mean: 65 BASELINE DOSE OF ICS: BDP 400 mcg daily or triamcinolone 800 mcg daily at study entry ASTHMA DURATION: Not reported ATOPY (%): Not reported ELIGIBILITY CRITERIA: FEV1 of 45% to 80% of the predicted value based on Capro standards adjusted for race; increase in FEV1 of at least 12% following the inhalation of 200 mg of albuterol; symptomatic while taking 400 mg of inhaled beclomethasone dipropionate or 800 mg triamcinolone acetonide daily EXCLUSION CRITERIA: Pregnant females or those planning a pregnancy; concurrent use of any medication affecting the course of asthma; interacting with sympathomimetic amines or corticosteroids; immunotherapy allowed if patient had received a constant dose for at least 12 weeks before enrolment with a continuation of the same regimen during the study CRITERIA FOR RANDOMISATION DURING RUN-IN: >= 3 nocturnal awakenings due to asthma symptoms during the 7 days before randomisation; >= 3 days with daytime symptoms during the 7 days before randomisation; >= 3 days with albuterol used as a relief medication during the 7 days before randomisation
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES reported at 4, 12 and 24 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: BDP 200 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 24 weeks TEST GROUP: Beclomethasone 200 mg plus salmeterol 50 mg twice daily CONTROL GROUP: Beclomethasone 400 mg twice daily DEVICE: MDI NUMBER OF DEVICES: 2 COMPLIANCE: Evaluated CO-TREATMENT: prn SABA; maintenance theophylline
Outcomes	PULMONARY FUNCTION TEST: FEV1 predicted; am PEF*; pm PEF SYMPTOM SCORES: Change in symptom score (score of 0 to 4) FUNCTIONAL STATUS: Rescue medication use; nocturnal awakening; exacerbation (defined as events requiring treatment with any asthma medication excluded during study participation); mean % symptom-free days INFLAMMATORY MARKERS: No laboratory analysis was performed ADVERSE EFFECTS: Reported WITHDRAWALS: Reported
Notes	Full-text publication Funded by Glaxo Welcome Confirmation of methodology and data obtained User-defined number: 400
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated random numbers
Allocation concealment?	Yes	Number coded inhalers supplied by pharmacy
Blinding? All outcomes	Yes	Identical placebos used
Incomplete outcome data addressed? All outcomes	Unclear	“All efficacy and safety analyses were performed on the intent-to-treat (ITT) population consisting of all subjects randomised to blinded study medication.”
Free of selective reporting?	Yes	OCS-treated exacerbations available on request from GSK

Methods	Parallel-group, multicentre study. Four treatment groups of which 2 considered for this review, namely: BUD 200 + F12 bid and BUD 400 bid Jadad quality score: 4
Participants	Symptomatic asthmatic teenagers >= 12 years and adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 634 (BUD200 + F: 323; BUD400: 312) WITHDRAWALS: Not reported by subgroup AGE mean: 37 GENDER (% male): 43.6 SEVERITY: Mild BASELINE % PREDICTED FEV1: 87 BASELINE DOSE OF ICS : <= 400 mcg/d BUD ASTHMA DURATION: Not reported ATOPY(%): Not reported ELIGIBILITY CRITERIA: >= 12 years of age with mild asthma; taking <= 400 mcg/daily of inhaled budesonide or its equivalent for >= 3 months; FEV1 >= 70% predicted normal after terbutaline EXCLUSION CRITERIA: Experience 3 severe exacerbations during the initial 6 months or 5 exacerbations in total; 2 poorly controlled asthma days, defined as days with morning PEF values >= 2 above baseline, or with asthma awakening CRITERIA FOR RANDOMISATION DURING RUN-IN: Randomised patients demonstrated a need for 2 or more inhalations per week of rescue medication during the last 2 weeks of run-in, a >= 15% variability in peak expiratory flows, or a >= 12% increase in FEV1 after terbutaline
Interventions	LABA + ICS vs INCREASED dose ICS OUTCOMES reported at 52 weeks RUN-IN PERIOD: 4 weeks DOSE OF ICS DURING RUN-IN: BUD 100 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 52 weeks TEST GROUP: Budesonide 100 mcg bid + formoterol 12 mcg bid CONTROL GROUP: Budesonide 200 mcg bid DEVICE: Turbuhaler NUMBER OF DEVICES: 2 COMPLIANCE: Not reported CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: am PEF; FEV1 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Asthma symptom days; nocturnal awakenings; rescue medication use; exacerbations INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Not reported WITHDRAWAL: Not reported *Primary outcome: time to the first severe asthma exacerbation defined as need for treatment with oral corticosteroids or hospital admission or emergency treatment for worsening asthma or a decrease in morning PEF > 25% from baseline
Notes	Full-text publication Funded by AstraZeneca Confirmation of methodology obtained User-defined number: 200
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated random numbers
Allocation concealment?	Yes	Opaque consecutive numbered envelopes containing assignment
Blinding? All outcomes	Yes	Use of identical placebo
Incomplete outcome data addressed? All outcomes	Unclear	Intention-to-treat analysis stated, but explicit description of its composition not available
Free of selective reporting?	Yes	Primary outcome data available from study publication

Methods	Parallel-group, multicentre study (246 centres in 22 countries). Three treatment groups: BUD; BUD/F and BUD/F (with BUD/F also as reliever) Jadad quality score: 4
Participants	Symptomatic asthmatic adults and children % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 85 RANDOMISED: 1835 (BUD: 926; BUD/F: 909) WITHDRAWALS: BUD/F: 148; BUD: 142 AGE mean (range): 35 (4 to 79) GENDER (% male): 44 SEVERITY: Moderate BASELINE % PREDICTED FEV1 (mean): 73 BASELINE DOSE OF ICS: 615 mcg/d ASTHMA DURATION: 9 years ATOPY (%): Not reported ELIGIBILITY CRITERIA: 4 to 80 years; treatment with 400 to 1000 mcg/d ICS (200 to 500 mcg/d for participants aged 4 to 11 years) for 3 or more months; FEV1 predicted 60% to 100%; 12 or more inhalations during last 10 days of run-in (8 for participants aged 4 to 11 years) EXCLUSION CRITERIA: Participants using 10 or more inhalations on one day during run-in (7 or more for participants aged 4 to 11 years); participants experiencing an exacerbation of asthma during run-in period
Interventions	LABA + ICS versus INCREASED dose ICS OUTCOMES: TIMING 12 months RUN-IN: 14 to 18 days DOSE OF ICS DURING RUN-IN: Same as pre-study ICS dose (+ terbutaline) INTERVENTION PERIOD: 12 months TEST GROUP: Combination budesonide and formoterol (100/6 mcg) bid CONTROL GROUP: Budesonide 400 mcg bid (plus as needed terbutaline) DEVICE: Turbohaler NUMBER OF DEVICES: 1 COMPLIANCE: Self-reported compliance on 84% of days; self-reported non-compliance on 3% of days; incomplete records on 13% of days CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1; am PEF; pm PEF SYMPTOM SCORES: Daytime scores; nighttime scores; % symptom-free days FUNCTIONAL STATUS: Exacerbations (treated with oral steroids, hospitalisation or ED visit); rescue medication use; night awakenings INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Reported WITHDRAWALS: Reported Primary outcome measure
Notes	Full-text publication Source of funding Astra Zeneca Confirmation of methodology and data: Requested, obtained for adults. Data on children were requested directly from the study sponsors concurrently. The data for OCS-treated exacerbations for children were not available User defined number: 800
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated randomisation scheme
Allocation concealment?	Unclear	Eligible patients were randomised in balanced blocks by allocating patient numbers in consecutive order
Blinding? All outcomes	Yes	Double-blind; identical inhaler devices used
Incomplete outcome data addressed? All outcomes	Unclear	“All analyses were performed on an intention-to-treat basis.” Additional information on the composition of the ITT population was not provided
Free of selective reporting?	Yes	Data on OCS-treated exacerbations reported as composite with ED visits/hospitalisations, PEF falls and requirement for medical intervention. Separate data for OCS-treated exacerbations and hospital admission received. Data on adults were received from study sponsors directly. We requested data for children from the study sponsors concurrently but these were not available

Methods	Parallel-group study Jadad quality score: 1
Participants	Symptomatic asthmatic children % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 20 (BDP/Sal: 10; BDP: 10) WITHDRAWALS: Not described AGE range: 6 to 19 years GENDER (% male): Not described SEVERITY: Moderate BASELINE % PREDICTED FEV1: Not described ASTHMA DURATION: Not reported ATOPY(%): Not reported ELIGIBILITY CRITERIA: Still symptomatic despite maintenance treatment with 200 mcg bid of BDP EXCLUSION CRITERIA: Not described
Interventions	LABA + ICS vs INCREASED dose ICS OUTCOMES: reported at 8,12 weeks RUN-IN PERIOD: 2 weeks DOSE OF ICS DURING RUN-IN: BDP 200 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 weeks TEST GROUP: Salmeterol 50 mcg bid + beclomethasone 200 mcg bid CONTROL GROUP: Beclomethasone 400 bid DEVICE: Not specified NUMBER OF DEVICES: 2 COMPLIANCE: Not reported CO-TREATMENT: Not specified
Outcomes	PULMONARY FUNCTION TEST: FEV1; PEF; FEF 25% to 75% SYMPTOM SCORES: Daily symptoms (no data for control group) FUNCTIONAL STATUS: Not reported INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Not reported WITHDRAWAL: Not reported
Notes	Abstract Funding not reported Confirmation of methodology and data extraction: Not obtained User-defined order: 400
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as randomised; no other information presented
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	No	Open label
Incomplete outcome data addressed? All outcomes	Unclear	No information provided
Free of selective reporting?	Unclear	Unclear whether data on OCS-treated exacerbations were collected in the study

Methods	Parallel-group, multicentre study (71 centres). Four treatment groups of which 2 considered here, namely: F12 + BUD 100 bid and BUD 400 + placebo bid Jadad quality score: 5
Participants	Symptomatic asthmatic adults % ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: 77 RANDOMISED: 424 (F12 bid + BUD 100 bid: 210; BUD 400 mcg bid: 214) WITHDRAWAL: BUD/F: 39; BUD: 37 AGE: mean (range): 42 (18 to 70) GENDER (% male): 49 ASTHMA SEVERITY: Moderate BASELINE % PREDICTED FEV1 mean: 75.6 BASELINE DOSE OF ICS (start of run-in): 820 (100 to 2000) ASTHMA DURATION: Not reported ATOPY(%): Not reported ELIGIBILITY CRITERIA: Asthma for at least 6 months; treated with an inhaled corticosteroid for at least 3 months; baseline FEV1 >= 50% predicted; >= 15% improvement following inhalation of 1 mg of terbutaline EXCLUSION CRITERIA: Use of beclomethasone > 2000 mcg/day or budesonide by MDI > 1600 mcg/day or budesonide by turbuhaler > 800 mcg/day or fluticasone > 800 mcg/day; >= 3 courses of oral steroids in past 6 months; hospitalisation for asthma in past 6 months CRITERIA FOR RANDOMISATION DURING RUN-IN: Compliance with 75% to 125% of the recommended dose of budesonide; stable asthma over the preceding 10 days as defined by the absence of the following criteria: diurnal variation of more than 20% in PEF on 2 consecutive days; use of 4 or more inhalations of rescue medication per day on 2 consecutive days; awakening due to asthma on 2 consecutive nights or the need to use oral glucocorticoids
Interventions	LABA + ICS vs INCREASED dose of ICS OUTCOMES reported at 1, 2, 3, 6, 9 and 12 months RUN-IN PERIOD: 4 weeks to document stability and compliance DOSE OF ICS DURING RUN-IN: BUD 800 bid DOSE OPTIMISATION PERIOD: None INTERVENTION PERIOD: 12 months TEST GROUP: (BUD/F) formoterol 12 mcg bid + budesonide 100 mcg bid CONTROL GROUP: (BUD) budesonide 400 mcg bid + placebo DEVICE: Turbuhaler NUMBER OF DEVICES: 2 COMPLIANCE: Yes - hidden mechanical counter built into inhaler which could only be seen by investigators CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: FEV1 predicted; am PEF; pm PEF SYMPTOM SCORES: Mean daytime and nighttime symptom scores at end of study (4-point scale: averaged over 10 days) FUNCTIONAL STATUS: Rescue medication use; nocturnal awakening (number per night); severe exacerbation (requiring systemic steroids); episode free days (mean % of year) INFLAMMATORY MARKERS: Not reported ADVERSE EFFECTS: Reported WITHDRAWAL: Reported *Primary outcome: rates of severe and mild exacerbations of asthma per patient per year
Notes	Full-text publication Funded by Astra Draco, Lund, Sweden Confirmation of methodology and data obtained User-defined order: 600
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer-generated random numbers list
Allocation concealment?	Unclear	Information not available
Blinding? All outcomes	Yes	Identical inhaler devices
Incomplete outcome data addressed? All outcomes	No	Last observation carried forward: “The analysis included all randomised patients (intention-to-treat approach). Data for patients who withdrew or discontinued therapy were included up to the time of their withdrawal.”
Free of selective reporting?	Yes	OCS-treated exacerbations available from study report

Methods	Parallel-group, multicentre study
Participants	% ELIGIBLE OF SCREENED POPULATION: Not reported % RUN-IN PARTICIPANTS RANDOMISED: Not reported RANDOMISED: 321 (FP/SAL: 160; FP: 161) WITHDRAWALS: FP/SAL: 3; FP: 6 AGE mean: 8 SEVERITY: Not reported BASELINE % PREDICTED FEV1: 102 BASELINE DOSE OF ICS: Not stated ASTHMA DURATION: Not stated ATOPY (%): Not stated ELIGIBILITY CRITERIA: 4 to 1 years; diagnosis of asthma for aminimum of 6 months; airway reversibility of = 15% based either on FEV1 or PEF; treatment with medium dose ICS (beclomethasone dipropionate (BDP) equivalent 400 to 500 mcg/day for 3 months prior to Visit 1 EXCLUSION CRITERIA: Respiratory tract infection in previous 4 weeks; acute asthma exacerbation requiring emergency room treatment within the last 4 weeks/hospitalisation within last 12 weeks; use of systemic corticosteroid within the last 12 weeks, or use of LABA, oral ß2-agonists, leukotriene antagonists or theophyllines during 4 weeks prior to screening visit; ineligible for randomisation if, during the run-in period, change in asthma medication including use of systemic corticosteroids, or respiratory tract infection or asthma exacerbation ELIGIBILITY CRITERIA DURING RUN-IN: Asthma assessed as not “well-controlled” for at least 2 of 4 weeks of run-in; FEV1 > 60% during run-in
Interventions	LABA + ICS versus INCREASED dose ICS OUTCOMES: 12 weeks RUN-IN PERIOD: 4 weeks DOSE OPTIMISATION PERIOD: N/A INTERVENTION PERIOD: 12 weeks TEST GROUP: Combination fluticasone and salmeterol 100/50 mcg bid CONTROL GROUP: Fluticasone 200 mcg bid INHALER DEVICE: Dry powder inhaler NUMBER OF DEVICES: 1 COMPLIANCE: Not assessed CO-TREATMENT: prn SABA
Outcomes	PULMONARY FUNCTION TEST: am PEF SYMPTOM SCORES: NA FUNCTIONAL STATUS: N achieving well-controlled asthma INFLAMMATORY MARKERS: NA ADVERSE EFFECTS: Reported WITHDRAWALS: Reported
Notes	Unpublished study Funding source: GSK Confirmation of methodology and data: obtained for methods User defined: 800
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	See Appendix 3
Allocation concealment?	Yes	See Appendix 3
Blinding? All outcomes	Yes	Double-blind; double-dummy
Incomplete outcome data addressed? All outcomes	Unclear	No detailed information on how intention-to-treat population was composed
Free of selective reporting?	Yes	OCS-exacerbations available on request from study sponsor