Anti‐leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children

Abstract

Background

Anti‐leukotrienes (5‐lipoxygenase inhibitors and leukotriene receptors antagonists) serve as alternative monotherapy to inhaled corticosteroids (ICS) in the management of recurrent and/or chronic asthma in adults and children.

Objectives

To determine the safety and efficacy of anti‐leukotrienes compared to inhaled corticosteroids as monotherapy in adults and children with asthma and to provide better insight into the influence of patient and treatment characteristics on the magnitude of effects.

Search methods

We searched MEDLINE (1966 to Dec 2010), EMBASE (1980 to Dec 2010), CINAHL (1982 to Dec 2010), the Cochrane Airways Group trials register, and the Cochrane Central Register of Controlled Trials (Dec 2010), abstract books, and reference lists of review articles and trials. We contacted colleagues and the international headquarters of anti‐leukotrienes producers.

Selection criteria

We included randomised trials that compared anti‐leukotrienes with inhaled corticosteroids as monotherapy for a minimum period of four weeks in patients with asthma aged two years and older.

Data collection and analysis

Two review authors independently assessed the methodological quality of trials and extracted data. The primary outcome was the number of patients with at least one exacerbation requiring systemic corticosteroids. Secondary outcomes included patients with at least one exacerbation requiring hospital admission, lung function tests, indices of chronic asthma control, adverse effects, withdrawal rates and biological inflammatory markers.

Main results

Sixty‐five trials met the inclusion criteria for this review. Fifty‐six trials (19 paediatric trials) contributed data (representing total of 10,005 adults and 3,333 children); 21 trials were of high methodological quality; 44 were published in full‐text. All trials pertained to patients with mild or moderate persistent asthma. Trial durations varied from four to 52 weeks. The median dose of inhaled corticosteroids was quite homogeneous at 200 µg/day of microfine hydrofluoroalkane‐propelled beclomethasone or equivalent (HFA‐BDP eq). Patients treated with anti‐leukotrienes were more likely to suffer an exacerbation requiring systemic corticosteroids (N = 6077 participants; risk ratio (RR) 1.51, 95% confidence interval (CI) 1.17, 1.96). For every 28 (95% CI 15 to 82) patients treated with anti‐leukotrienes instead of inhaled corticosteroids, there was one additional patient with an exacerbation requiring rescue systemic corticosteroids. The magnitude of effect was significantly greater in patients with moderate compared with those with mild airway obstruction (RR 2.03, 95% CI 1.41, 2.91 versus RR 1.25, 95% CI 0.97, 1.61), but was not significantly influenced by age group (children representing 23% of the weight versus adults), anti‐leukotriene used, duration of intervention, methodological quality, and funding source. Significant group differences favouring inhaled corticosteroids were noted in most secondary outcomes including patients with at least one exacerbation requiring hospital admission (N = 2715 participants; RR 3.33; 95% CI 1.02 to 10.94), the change from baseline FEV₁ (N = 7128 participants; mean group difference (MD) 110 mL, 95% CI 140 to 80) as well as other lung function parameters, asthma symptoms, nocturnal awakenings, rescue medication use, symptom‐free days, the quality of life, parents' and physicians' satisfaction. Anti‐leukotriene therapy was associated with increased risk of withdrawals due to poor asthma control (N = 7669 participants; RR 2.56; 95% CI 2.01 to 3.27). For every thirty one (95% CI 22 to 47) patients treated with anti‐leukotrienes instead of inhaled corticosteroids, there was one additional withdrawal due to poor control. Risk of side effects was not significantly different between both groups.

Authors' conclusions

As monotherapy, inhaled corticosteroids display superior efficacy to anti‐leukotrienes in adults and children with persistent asthma; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines' recommendation that inhaled corticosteroids remain the preferred monotherapy. 

Plain language summary

Anti‐leukotriene agents compared to inhaled corticosteroids for people with asthma

In an asthma attack, the airways (passages to the lungs) narrow because of muscle spasms (bronchospasm), inflammation (swelling) and mucus secretion phlegm. The airway passage narrowing results in breathing problems, wheezing and coughing. Inhaled corticosteroids are considered the gold standard to reduce the airway inflammation in adults and children with asthma. Anti‐leukotrienes (5‐lipoxygenase inhibitors and leukotriene receptors antagonists) are anti‐inflammatory drugs that may have fewer adverse effects than inhaled corticosteroids. The review suggests that anti‐leukotrienes are safe, but less effective than a low dose of inhaled corticosteroids.

Background

Asthma is a condition that affects the airways, it is characterised by bronchoconstriction and underlying inflammation. Infiltration of bronchial airways with eosinophils and neutrophils with release of inflammatory mediators is characteristic of asthma (Murphy 1993). The cysteinyl leukotrienes are considered as the most potent inflammatory mediators in asthma. They are produced by the 5‐lipoxygenase pathway of the arachidonic acid metabolism. These mediators stimulate the production of airway secretions, cause micro vascular leakage and enhance eosinophilic migration in the airways; thus, leukotrienes are believed to play a pivotal role in mediating bronchoconstriction and inflammatory changes in the pathophysiology of asthma (Peters‐Golden 2007).

All recent consensus statements on asthma advocate aggressive treatment of airway inflammation (Australia 2006; NAEPP 2007; Lougheed 2010; GINA 2010; BTS 2011). Although several drugs such as ketotifen, sodium cromoglycate and sodium nedocromil have anti‐inflammatory properties, inhaled glucocorticoids remain the cornerstone of asthma management because of their efficacy, tolerability and rapid onset of action (Spahn 1996). Prolonged low dose administration of inhaled corticosteroids is generally considered safe, although there is considerable concern about the long‐term effects of steroids among some consumers (Elwyn 2010). However, when moderate or high doses are required to control symptoms, adverse effects such as growth stunting in children (Sharek 2000; Richard 2006), suppression of the adrenal axis (Bisgaard 1988; Phillip 1992; Padfield 1993; Zöllner 2007), and osteopenia (Todd 1996; Heuck 1997) may be observed.

Anti‐leukotrienes form a class of anti‐inflammatory drugs that interfere with leukotriene production (5‐lipoxygenase inhibitors) or with leukotriene receptors (leukotriene receptors antagonists, LTRAs). Anti‐leukotrienes have the advantage of being administered orally in a single or twice daily dose and importantly, seem to lack the adverse effects on growth, bone mineralization and adrenal axis, associated with long‐term or high‐dose systemic glucocorticoid therapy.

Why it is important to do this review

The previous version of this review (Ducharme 2004) summarised the accumulating evidence derived from 25 randomised controlled trials (three paediatric and 22 adult) and concluded that low doses of inhaled corticosteroids were superior in efficacy than anti‐leukotrienes. With the publications of several new randomised controlled trials especially in children, an update of the systematic review was deemed useful to review the safety and efficacy of anti‐leukotrienes as monotherapy as compared to inhaled corticosteroids and to provide better insight into the influence of patient and treatment characteristics on the magnitude of effects.

In addition, several national guidelines currently advocate their use as second choice monotherapy after inhaled corticosteroids in patients with mild asthma and as adjunct therapy with inhaled corticosteroids as an alternative of combination of long acting β₂‐agonist and inhaled corticosteroids in patients with moderate asthma (Australia 2006; NAEPP 2007; Lougheed 2010; GINA 2010; BTS 2011).

Objectives

The aims of this systematic review were:

1. to compare the safety and efficacy of daily oral anti‐leukotrienes with that of inhaled corticosteroids;

2. to determine the dose of inhaled corticosteroids equivalent to the effect of anti‐leukotrienes in the management of asthma in adults and children; and

3. to explore different factors such as patients' age group, disease severity, anti‐leukotriene used, intervention duration, hydrofluoroalkane‐propelled beclomethasone or equivalent (HFA‐BDP eq) dose of inhaled corticosteroids, methodological quality, publication status and funding that could influence the magnitude of effect.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) conducted in adults and children, or both, in which anti‐leukotrienes were compared with inhaled corticosteroids.

Types of participants

We included children (aged two to 17 years) and adults (aged over 18 years) with chronic persistent asthma. We included participants who were either corticosteroid‐naive or had been taking maintenance inhaled corticosteroid therapy prior to randomisation.

Types of interventions

We included trials with interventions consisting of daily oral anti‐leukotrienes at usual licensed doses (see under 'Unit of analysis issues') compared to any type of daily inhaled corticosteroids. Interventions had to be administered for at least four weeks. We excluded trials that administered concomitant anti‐inflammatory or anti‐asthmatic drug such as sodium cromoglycate or theophylline. Only rescue medications, such as inhaled short‐acting β₂‐agonists and short courses of oral corticosteroids were permitted and recorded.

Types of outcome measures

Primary outcomes

The primary outcome was the number of patients with at least one exacerbation requiring systemic corticosteroids.

Secondary outcomes

1. Other clinical outcomes reflecting the severity of asthma exacerbations (e.g. hospital admissions, acute care visits)

2. Clinical or physiologic outcomes reflecting chronic asthma control (e.g. pulmonary function tests, symptom score, β₂‐agonist use, measures of functional status, quality of life, patient's and physician's satisfaction, etc.)

3. Biological markers of inflammation (e.g. eosinophil count in blood and sputum, leukotriene C₄ in biological samples, expired nitric oxide, etc);

4. Clinical and biochemical adverse effects (e.g., elevation of liver enzymes, growth)

5. Withdrawal rates (overall withdrawals, withdrawals due to poor asthma control and withdrawals due to adverse effects)

In studies designed to identify the minimum effective dose of inhaled corticosteroids needed to achieve asthma control, and in which the control obtained with inhaled corticosteroids was similar to that obtained with anti‐leukotrienes, we aimed to report the median effective dose of inhaled corticosteroids; this dose may be taken to be equivalent in effect to that of the anti‐leukotrienes. We excluded trials that only documented compliance.

Search methods for identification of studies

Electronic searches

Trials were identified using the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts (please see Appendix 1 for further details). All records in the CAGR coded as 'asthma' were searched using the following terms:

(leukotriene* OR anti‐leukotriene* OR leukotriene* antagonist* OR lukast*) AND [inhaled corticosteroids* OR steroid* OR corticosteroid* OR cortico‐steroid* OR beclomethasone* OR fluticasone* OR budesonide* OR triamcinolone* OR flunisolide* OR bronalide* OR becotide* OR azmacort* OR aerobid* OR flixotide* OR aerobec* OR flovent* OR becloforte* OR pulmicort* OR aerobid* OR beclovent* OR azmacort* OR vanceril* OR ciclesonide OR alvesco).

Searching other resources

Reference lists of all identified RCTs were checked to identify potentially relevant citations. In addition, between 1998 and 2003, we searched abstract books of the American Thoracic Society and the European Respiratory Society Meetings; we contacted the international headquarters of pharmaceutical companies producing anti‐leukotrienes; and enquiries regarding other published or unpublished studies known and/or supported by these companies or their subsidiaries were made so that these results could be included in our 2003 review. In 2010, we searched the websites of pharmaceutical companies that are producers or distributors of inhaled corticosteroids or anti‐leukotrienes for any posted report of potential relevant trials.

Data collection and analysis

Selection of studies

One review author (BFC) reviewed and annotated each title and abstract returned from the search as either 1) RCT; 2) clearly not an RCT; or 3) unclear. The full text publications of references annotated as clearly, or potentially, relevant RCTs were obtained and reviewed by BFC.

Data extraction and management

Both review authors extracted data independently (BFC and FMD) and we dealt with disagreement by consensus. We consulted authors and the funding pharmaceutical companies for confirmation of data extraction for all included trials where necessary.

Assessment of risk of bias in included studies

We assessed the methodological quality of the eligible studies using the Cochrane Collaboration's 'Risk of bias' tool (Higgins 2008). This instrument evaluates the reported quality of randomisation, allocation concealment, blinding, incomplete outcome data, selective reporting and other bias.

We previously used the five‐point scoring instrument proposed by with the Cochrane Classification 'Risk of bias' tool to assess study quality. Based on revised recommendations from the Cochrane Handbook for Systematic Reviews of Interventions, we assessed the risk of bias for each eligible study according to six pre‐specified domains (Higgins 2008). Both review authors performed this quality assessment independently. We resolved disagreement by consensus. We sought confirmation of methodology for included trials directly from the authors or the funding pharmaceutical companies. We assessed risk of bias against the following domains.

1. Allocation generation. The method used to allocate participants to treatment group (e.g. computer‐generated random number sequences).

2. Allocation concealment. The method used to conceal the sequence of treatment group assignment from study investigators and participants (e.g. assignment by date of birth, opaque sealed envelopes).

3. Blinding. The method by which knowledge of treatment group assignment was concealed from study investigators and participants after the study began (double‐blind, single‐blind).

4. Completeness of outcome data. The method for handling data from participants who withdrew from the study (e.g. intention‐to‐treat analysis, available case).

5. Selective reporting. Whether there was evidence that outcomes measured in the study were unreported (e.g. unreported harms, relevant efficacy data that were not available due for reporting and not statistical reasons).

6. Other sources of bias. Any other aspect of the study design which may be a source of bias.

We collected and reported information for each domain of bias and provided a judgment based on this information as high, low or unclear risk of bias. We considered reported data with low risk in bias for the three main parameters (randomisation, blinding and low withdrawal rate in both groups) as high quality data for sensitivity analysis (see below).

Measures of treatment effect

We summarised differences between groups in event rates, such as number of exacerbations in a specific period, using either a ratio of rates or relative risk when pertaining to "one or more" events per patient. In continuous outcomes, such as pulmonary function tests or symptom scores, we used the mean difference (MD) or standard mean difference (SMD) method as indicated to estimate the individual and pooled effect sizes. We reported all estimates with their 95% confidence interval and performed meta‐analysis using Reference Manager 5.1 (RevMan).

Studies designed to test equivalence in treatment efficacy require a different analytical approach to that used for trials in which the hypothesis under test is that one treatment has greater efficacy than its comparator. This is because small trials may favour the conclusion that there was no difference between treatments, since the confidence intervals for the two treatments will be wide and therefore more likely to include the line of no difference between the two treatments. We set limits of treatment efficacy at +/‐ 0.10 on either side of the no‐difference line for the number of patients with at least one exacerbation requiring systemic corticosteroids. The null hypothesis tested whether the confidence interval for the difference between the two treatments included one of these limits.

Unit of analysis issues

We referred to usual licensed doses of leukotriene receptor antagonists as: montelukast 4, 5, or 10 mg daily (patients aged two to five, six to 14 and > 15 years respectively); pranlukast 450 mg daily (children aged ≥ 12 years and adults), and zafirlukast 20 mg twice daily (children aged ≥ 12 years and adults). Doses of inhaled corticosteroids were converted to microfine HFA‐BDP eq based on 1 μg of fluticasone = 1 μg of microfine HFA‐propelled beclomethasone = 1 μg of ciclesonide = 1 μg of mometasone = 2 μg of budesonide = 2 μg of chlorofluorocarbon (CFC)‐propelled beclomethasone = 4 μg triamcinolone = 4 μg of flunisolide (NAEPP 2007). All doses of inhaled medications are reported based on ex‐valve, rather than ex‐inhaler, value.

Assessment of heterogeneity

We tested homogeneity of effect sizes between pooled studies using the DerSimonian and Laird method or the I², which estimates the amount of statistical variation between the studies above what would be expected with the play of chance (Cochrane Handbook). We set values of P greater than 0.05 or I² greater than 25% as providing an indication of significant heterogeneity. If heterogeneity was suggested by one or both statistical methods, we applied the DerSimonian and Laird random‐effects model to the summary estimates (available in RevMan). Unless specified otherwise we employed the fixed‐effect model.

Assessment of reporting biases

We used funnel plots to test for the presence of possible publication bias (Egger 1997).

Data synthesis

Meta‐analyses were performed using Reference Manager 5.1 (RevMan). We derived the number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) from the pooled Odds Ratio using Visual Rx (www.nntonline.net). We used this method because the resulting NNTB or NNTH is independent of the way that the data are entered, which is not the case for relative risk (Cates 2002).

Subgroup analysis and investigation of heterogeneity

We performed subgroup analysis to explore possible reasons for heterogeneity of the primary outcome. All outcomes were stratified in children versus adults for the specific purpose of providing estimates particularly for these age groups and to explore a possible modifying effect of age. Additional a priori defined subgroups included:

1. anti‐leukotriene used (montelukast versus zafirlukast);

2. doses of inhaled corticosteroids in HFA‐BDP eq (100 to ‐150 µgversus 200 to ‐250 µg versus 400 to 500 µg HFA‐BDP eq);

3. intervention duration (four to eight weeks versus 12 to 16 weeks versus 24 to 26 weeks versus 36 to 52 weeks);

4. baseline severity of airway obstruction (moderate = FEV₁ 60 to 79% versus mild = FEV₁ ≥80%);

5. publication status;

6. funding source.

We examined the difference in the magnitude of effect attributable to these subgroups with the residual Chi² test from the Peto odds ratios (Deeks 2001).

Sensitivity analysis

For the primary outcome, we performed sensitivity analyses were performed to investigate the effect of methodological quality based on the reported quality of randomisation, concealment of allocation, blind assessment of outcomes, and description of withdrawals and dropouts. The fail‐safe N test will be used to assess the robustness of the results (Gleser 1996).

Results

Description of studies

Results of the search

The search strategy updated up to December 2010 yielded a total of 401 additional citations which combined to 658 previously identified citations lead to a total of 1053 citations. The data hereafter are presented as total exclusions (exclusions from latest search + exclusions from previous search). Of these 652 (319 + 333) citations were excluded for the following non‐mutually exclusive reasons: (1) duplicate references (31 + 162 = 193), (2) not a randomised controlled trial (31 + 253 = 284) or ongoing trials (23 + 1 = 24), (3) subjects were not asthmatics (3 + 17 = 20), (4) the tested intervention was not anti‐leukotrienes (82 + 17 = 99), (5) the control intervention was not inhaled corticosteroids (65 + 124 = 189), (6) use of higher than licensed doses of anti‐leukotrienes (from previous review = 1) (Korenblat 1998), (7) use of non permitted drugs (106 + 28 = 134), (8) the tested intervention was administered for less than 4 weeks (14 + 19 = 33), (9) acute care setting (3 + 1 = 4). Due to the large number of citations considered, the references and reasons for exclusion were provided only for full‐text randomised controlled trials in the last review up to October 2003, while reasons for exclusion for all references were included for 2003 to 2010. Some trials were excluded with more than one reason.

Included studies

Sixty‐five trials met the inclusion criteria for this review. There were nine (237 children and 241 adults) eligible clinical trials that did not contribute data to the review due to different format of presenting data than specified in the protocol or incomplete reports (Riccioni 2003; Basyigit 2004; Abadoglu 2005; Zeiger 2006; Lazarus 2007; Kanazawa 2007; Stelmach 2008; Khan 2008; Zedan 2009). The data presented hereafter pertains to only the 56 eligible trials representing total of 10,005 adults and 3,333 children with mild or moderate asthma that contributed data to meta‐analyses. Of these, most (N = 44) trials were published in full text; three were published as abstracts with additional unpublished report provided by the authors (Laitinen 1997; Hughes 1999 (FP); Hughes 1999 (BDP)) and the remaining nine citations were available only in abstract form (FLTA4031; FLTA4030; FMS40012; Dempsey 2002a; Sheth 2001; FPD40013; Jayaram 2002; NCT00442559; MK0479‐332). We described below the characteristics of the 56 trials that contributed to data analysis for this review.

Design: Sixteen paediatric and 33 adult trials had a parallel‐group design while three paediatric (Szefler 2005; Caffey 2005; Ng 2007) and four adult trials (Dempsey 2002a; Kanniess 2002; Jenkins 2005; Lu 2009) had a cross‐over design.

Participants: Thirteen trials involved children (Maspero 2001; FPD40013; Garcia Garcia 2005; Ostrom 2005; Peroni 2005; Caffey 2005; Ng 2007; Szefler 2007; Kumar 2007; Sorkness 2007; NCT00442559; Kooi 2008; Zielen 2010); five trials involved children and adolescents (Stelmach 2004; Stelmach 2005; Szefler 2005; Zeiger 2005; Stelmach 2007); one trial did not report the age of children (Peroni 2005); 19 trials involved adolescents and adults (FLTA4031; FLTA4030; Malmstrom 1999; Laviolette 1999; Bleecker 2000; Kim 2000; Nathan 2001; Busse 2001a; Busse 2001b; Meltzer 2002; Israel 2002; Brabson 2002; Baumgartner 2003; Jenkins 2005; Bousquet 2005; Koenig 2008; Lu 2009; Sheth 2001; Sheth 2001b); 10 trials involved adults (FMS40012; Riccioni 2001; Dempsey 2002a; Riccioni 2002b; Kanniess 2002; Yurdakul 2003; Overbeek 2004; Boushey 2005; Tamaoki 2008; MK0479‐332); and one trial involved adults and children (Peters 2007). Most trials described a gender ratio of 45% to 50% (range 18% to 81%) males. Almost half of the trials (N = 27) focused on asthmatics with mild airway obstruction, as defined as a baseline FEV₁ ≥ 80% of predicted, 25 trials (Laitinen 1997; FLTA4031; FLTA4030; Malmstrom 1999; Laviolette 1999; Bleecker 2000; Nathan 2001; Busse 2001a; Busse 2001b; Meltzer 2002; FPD40013; Stelmach 2002a; Stelmach 2002b; Israel 2002; Kanniess 2002; Baumgartner 2003; Stelmach 2004; Stelmach 2005; Ostrom 2005; Jenkins 2005; Jayaram 2005; Kumar 2007; Koenig 2008; Lu 2009) focused on asthmatics with moderate airway obstruction, as defined as a baseline FEV₁ 60 to 79% of predicted; one trial reported mild to moderate airway obstruction (NCT00442559), while three trials (Jayaram 2002; Kooi 2008; MK0479‐332) did not reported the severity of airway obstruction at baseline. Asthma triggers were seldom reported, when atopy was reported.
 
 Intervention duration: Most paediatric and adult trials varied in the duration of intervention from four to eight weeks. Five paediatric trials (FPD40013; Ostrom 2005; Kumar 2007; NCT00442559; Kooi 2008) and 13 adult trials (FLTA4031; FLTA4030; Malmstrom 1999; Laviolette 1999; Bleecker 2000; Busse 2001a; Sheth 2001; Riccioni 2002a; Riccioni 2002b; Yurdakul 2003; Zeiger 2005; Peters 2007; Koenig 2008) were of 12 to 16 weeks; two paediatric trials (Maspero 2001; Stelmach 2005) and three adult trials (Busse 2001b; Meltzer 2002; MK0479‐332) were of 24 to 26 weeks; while three paediatric trials (Garcia Garcia 2005; Szefler 2007; Sorkness 2007) and two adult trials (Boushey 2005; Bousquet 2005) were of 36 to 52 weeks duration.

Intervention drugs were: montelukast 4, 5 or 10 mg per day, depending on age, for the 19 paediatric trials, montelukast 10 mg per day in 23 adult studies; pranlukast 450 mg per day in two trials (Yamauchi 2001; Tamaoki 2008), and zafirlukast 20 mg twice a day in 12 adult trials (Laitinen 1997; FLTA4031; FLTA4030; Bleecker 2000; Kim 2000; FMS40012; Nathan 2001; Riccioni 2001; Busse 2001b; Sheth 2001; Brabson 2002; Boushey 2005). One study tested two doses of anti‐leukotrienes, including a higher than licensed doses of zafirlukast (i.e. 80 mg per day) (Laitinen 1997).

The daily dose of inhaled corticosteroids (control intervention) in μg HFA‐BDP eq was relatively uniform across the 56 trial: eight trials tested a daily dose of 100 μg HFA‐BDP eq (FPD40013; Stelmach 2002a; Stelmach 2002b; Stelmach 2004; Ostrom 2005; Caffey 2005; Stelmach 2007; Tamaoki 2008); two trials tested a daily dose of 150 μg HFA‐BDP eq (Maspero 2001; Dempsey 2002a); 37 trials tested a daily dose of 200 μg HFA‐BDP eq.; two trials tested a daily dose of 250 μg HFA‐BDP eq (Jenkins 2005; Szefler 2007); three trials tested a daily dose of 400 μg HFA‐BDP eq (Riccioni 2001; Riccioni 2002a; Riccioni 2002b); two trials tested a daily dose of 500 μg HFA‐BDP eq (Jenkins 2005; MK0479‐332); and two trials did not mentioned the dose of inhaled corticosteroids (Jayaram 2002; NCT00442559). In all trials, the dose of inhaled corticosteroids was maintained throughout the intervention period; no trial tapered the dose of inhaled corticosteroids to the minimum effective dose.

Co‐intervention. No trials reported the use of additional anti‐asthmatic drugs other than rescue β₂‐agonists and systemic corticosteroids.

Outcomes

Whenever possible, we considered outcomes measured at four to eight weeks, 12 to 16 weeks, 24 to 26 weeks and 36 to 52 weeks. The primary outcome, patients with at least one exacerbation requiring systemic corticosteroids, was documented in six (32%) paediatric and 15 (41%) adult trials; children contributed 23% of the weight of the main outcome. Other reported outcomes included patients with at least one exacerbation requiring admission, change from baseline FEV₁ (forced expiratory volume in one second) (L), change from baseline FEV₁ (%), change in FEV₁ % of predicted, change in morning PEFR (peak expiratory flow rate) (L/min), change from baseline in daytime symptom scores, change from baseline in night‐time awakenings, change from baseline in mean daily use of β₂‐agonists (puffs/day), change in proportion of symptom‐free days, change in rescue‐free days, change from baseline in quality of life, days with use of β₂‐agonists, change from baseline in blood eosinophils, change in sputum eosinophils, leukotriene C₄ concentration in nasal wash, % asthma control days during intervention period, change in PC₂₀, % rescue‐free days, days off work or school, days with symptoms, days with β₂‐agonist use (%), change in growth (cm), patient's satisfaction, physician's satisfaction, overall withdrawals, withdrawal due to poor asthma control/exacerbations, withdrawal due to adverse effects, overall adverse effects, elevated liver enzymes, upper respiratory tract infections, headache, nausea, oral candidiasis, hoarseness and death.

Risk of bias in included studies

Full details of the risk of bias for all 65 eligible trials can be found in the Characteristics of included studies tables with a graphical summary of in Figure 1.The following information pertains only to the 56 trials contributing data to the meta‐analysis.

1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Although all trials were described as randomised, only 32 trials (10 paediatric and 22 adult trials) reported the method of randomisation. Therefore, we judged 32 trials to be at low risk of bias and 24 rest were unclear. Fifty‐two trials did not describe the method of concealment of treatment and were therefore judged at unclear risk of bias, while four trials reported the way the concealment was performed and were judged to be of low risk of bias.

Blinding

Forty‐one trials (13 paediatric and 28 adult trials) reported double‐blinding with convincing details, while nine trials used open label and six trials did not report sufficient information to ascertain blinding.

Incomplete outcome data

Forty‐two trials (14 paediatric and 28 adult trials) reported all data with balanced numbers in both groups, while seven trials failed to do so and seven trials were unclear.

Selective reporting

This bias refers to an outcome measured as part of the protocol but not reported in the publication. Judging from the reported methodology in the publication, most (N = 52) trials reported data without any apparent biasness, two trials were assessed as being at high risk of bias while the remaining two trials failed to report sufficient details for this assessment. With the similar proportion of paediatric (N = 6, 32%) and adult (N = 15, 41%) trials reporting the main outcome, there is no suspicion of a differential under reporting of this outcome in paediatric versus adult studies.

Other potential sources of bias

We did not encounter any other significant sources of bias in the included trials.

Effects of interventions

Primary outcome: people with at least one exacerbation requiring a course of oral corticosteroids

Twenty‐one (33%) trials on 6077 participants contributed to the primary end point; people with at least one exacerbation requiring systemic corticosteroids. Compared with inhaled corticosteroids, patients treated with anti‐leukotrienes had a 51% increased risk of experiencing one or more exacerbation requiring systemic corticosteroids (Risk ratio (RR) = 1.51, 95% confidence interval (CI) 1.17, 1.96; random‐effects model), that is, from 7% to 11% (Figure 2).

2.

Forest plot of comparison: 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), outcome: 1.1 Patients with at least one exacerbation requiring systemic steroids.

The number need to treat to prevent one more exacerbation requiring corticosteroid (NNT) is 28 (95% CI 15 to 82; Figure 3). There was no evidence of systematic bias identified by the test for funnel plot asymmetry (intercept 0.33, 95% CI ‐0.10 to 0.75; Figure 4). The fail‐safe N (the number of unpublished studies with null results needed to negate the current finding) was 180 trials. Selecting only one inhaled corticosteroid group (BDP or FP) as comparator in the three‐group Hughes trial fail to affect the overall estimate due to the absence of events in this study. There was heterogeneity between and within anti‐leukotrienes, the following subgroup and sensitivity analyses were performed on the main outcome to explore possible effect modifiers.

3.

In the control group (on ICS) 7 people out of 100 had at least one exacerbation requiring systemic steroids over 4 to 52 weeks, compared to 10 (95% CI 8 to 13) out of 100 for the active treatment group given LRTA.

4.

Funnel plot of comparison: 1 Anti‐leukotriene (AL) versus. Inhaled glucocorticoids (in HFC‐BDP equivalent), outcome: Patients with at least 1 exacerbation requiring systemic corticosteroids.

Subgroup analysis: Age group of subjects

Six (32%) paediatric trials on 1662 children and 15 (41%) adult trials on 4415 adults reported the primary outcome, number of patients with at least one exacerbation requiring systemic corticosteroids; children contributed 23% of the weight of the summary estimate. There was no significant group difference between paediatric (N = 6 trials, 1662 participants; RR 1.35; 95% CI 0.99 to 1.86) compared with adult, (N = 15 trials, 4415 participants; RR 1.61;95% CI 1.12 to 2.31) trials (Chi² = 1.95 (1 df), P = 0.16; Analysis 1.1).

1.1. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 1 Patients with at least one exacerbation requiring systemic steroids.

Subgroup analysis: Anti‐leukotrienes

There was no significant difference in the risk of patients with at least one exacerbation requiring systemic corticosteroids according to the anti‐leukotriene used (montelukast versus zafirlukast) (Chi² = 0.12 (1 df), P = 0.73); montelukast [N = 15 trials, 4352 participants: RR = 1.55 (95% CI: 1.14 to 2.12; Analysis 1.67)versus zafirlukast (N = 6 trials, 1725 participants; RR 1.92;95% CI 0.88 to 4.20).

1.67. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 67 Primary outcome ‐ stratified by anti‐leukotrienes.

Subgroup analysis: Duration of intervention

The duration of intervention was not a determinant of the magnitude of effect (Chi² = 5.42 (3 df), P = 0.14): four to eight weeks (N = 9 trials, 2346 participants; RR 1.74; 95% CI 0.78 to 3.87; Analysis 1.68), 12 to 16 weeks (N = 7 trials, 1541 participants; RR 2.06; 95% CI 1.43 to 2.96), 24 to 26 weeks (N = 2 trials, 657 participants; RR 1.17; 95% CI 0.55 to 2.45), and 36 to 52 weeks (N = 3 trials, 1533 participants; RR = 1.29; 95% CI 0.87 to 1.91).

1.68. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 68 Primary outcome ‐ stratified by duration of intervention.

Subgroup analysis: Severity of airway obstruction

Baseline severity of airway obstruction played a significant role in the magnitude of the risk of exacerbation requiring systemic corticosteroid (Test for subgroup differences: Chi² = 4.59, (df = 1), P = 0.03, I² = 78.2%); baseline FEV₁ between 60 to 79% of predicted (N = 11 trials, 3922 participants; RR = 2.03; 95% CI 1.41 to 2.91; Analysis 1.69) versus baseline FEV₁ ≥ 80% of predicted (N = 10 trials, 2155; RR = 1.25; 95% CI 0.97 to 1.61).

1.69. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 69 Main outcome ‐stratified by severity of airway obstruction.

Subgroup analysis: Methodological quality

There was no significant group difference among the trials with high reported methodological quality (N = 11 trials, 4366 participants; RR = 1.62; 95% CI 1.29 to 2.03; Analysis 1.70) compared with hose with poor quality (N = 10 trials, 1695 participants; RR = 1.34; 95% CI 0.74 to 2.43) (Chi² = 0.22 (1 df), P = 0.64).

1.70. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 70 Primary outcome ‐ stratified by methodological quality.

Subgroup analysis: Funding source

The source of funding did not significantly influence results (Chi² = 3.61 (2 df), P = 0.16): funding from producers of inhaled corticosteroids (N = 9 trials, 2638 participants; RR = 1.71; 95% CI 1.05 to 2.80; Analysis 1.71), funding from producers of anti‐leukotrienes (N = 5 trials, 2797 participants; RR = 1.52; 95% CI 0.99 to 2.35) and no industry funding or not reported funding (N =7 trials, 642 participants; RR =1.22; 95% CI 0.90 to 1.66).

1.71. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 71 Primary outcome‐ stratified by funding source.

Subgroup analysis: HFC‐BDP equivalent

The comparative dose of inhaled corticosteroids did not significantly influence the magnitude of the risk of exacerbation requiring systemic corticosteroids (Chi² = 1.97 (1 df), P = 0.16): 100 to 150 μg HFC‐BDP equivalent (N = 3 trials, 216 participants; RR = 0.74; 95% CI 0.26 to 2.08; Analysis 1.72), 200 to 250 μg HFC‐BDP equivalent (N = 15 trials, 5767 participants; RR = 1.75; 95% CI 1.29 to 2.38), and 400 to 500 μg HFC‐BDP equivalent (N = 3 trials, 94 participants; RR = 0.54; 95% CI 0.11 to 2.78).

1.72. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 72 Primary outcome ‐ stratified by HFC‐BDP equivalent.

Secondary outcomes reflecting the severity of asthma exacerbations

There was a three‐fold increase in the number of patients experiencing an exacerbation requiring hospital admission in the group treated with anti‐leukotrienes (N = 12 trials, 2715 participants; RR = 3.33; 95% CI: 1.02 to 10.94; Analysis 1.2) with no significant difference across the paediatric trials (N = 4 trials, 558 participants; RR = 3.04; 95% CI 0.12 to 73.93) and adult (N = 8 trials, 2157 participants; RR = 3.38; 95% CI 0.94 to 12.17) trials (Chi² = 0.00 (1 df), P = 0.95).

1.2. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 2 Patients with at least one exacerbation requiring hospital admission.

Secondary outcomes reflecting asthma control

Lung function

Compared with inhaled corticosteroids, a significant group difference in the improvement from baseline in FEV₁ (L) was observed at all points in time in disfavour of anti‐leukotrienes: at four to eight weeks (N = 12 trials, 3020 participants; mean difference (MD) ‐0.12 L; 95% CI ‐0.15 to ‐0.08, random‐effects model; Analysis 1.3), at 12 to 16 weeks (N = 9 trials, 1890 participants; MD ‐0.12 L; 95% CI ‐0.20 to ‐0.04, random‐effects model; Analysis 1.4), and at 24 to 26 weeks (N = 3 trials, 1178 participants; MD ‐0.13 L; 95% CI ‐0.22 to ‐0.04; random‐effects model; Analysis 1.5), at 36 to 52 weeks (N = 2 paediatric trials, 1040 participants; MD ‐0.03 L; 95% CI ‐0.07 to 0.00; model; Analysis 1.6). Similarly, a significant group difference in the per cent change from baseline FEV₁ was observed in time in disfavour of anti‐leukotrienes: at 12 to 16 weeks (N = 2 adults trials, 603 participants; MD ‐5.70, 95% CI ‐9.81 to ‐1.59; Analysis 1.10) and at 24 to 26 weeks (N = 2 adult trials, 838 participants; MD ‐8.20%; 95% CI ‐10.85 to ‐5.55; Analysis 1.11), and only one trial reporting data at four to eight weeks and at 36 to 52 weeks each, precluding aggregation.

1.3. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 3 Change from baseline FEV₁ (L) at 4 ‐ 8 weeks.

1.4. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 4 Change from baseline FEV₁( L) 12 ‐ 16 weeks.

1.5. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 5 Change from baseline FEV₁ (L) at 24 ‐ 26 weeks.

1.6. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 6 Change from baseline FEV₁ (L) at 36 ‐ 52 weeks.

1.10. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 10 Change from baseline FEV₁ (%) 12 ‐ 16 weeks.

1.11. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 11 Change from baseline FEV₁ (%) at 24 ‐ 26 weeks.

No significant group difference was observed with regards to the change from baseline FEV₁ % predicted at four to eight weeks (N = 2 trials, 219 participants; MD ‐2.58%; 95% CI ‐6.56 to 1.40; random‐effects model; Analysis 1.12), but a significant group difference was observed in disfavour of anti‐leukotrienes at 12 to 16 weeks (N = 3 trials, 948 participants; MD ‐3.76%; 95% CI ‐5.01 to ‐2.50; Analysis 1.13) and at 36 to 52 weeks (N = 3 paediatric trials, 1229 participants; MD ‐3.51%; 95% CI ‐7.14 to 0.12; random‐effects model; Analysis 1.14).

1.12. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 12 Change from baseline FEV₁ % of predicted at 4 ‐ 8 weeks.

1.13. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 13 Change from baseline FEV₁ % of predicated at 12 ‐ 16 weeks.

1.14. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 14 Change from baseline FEV₁ % of predicated at 36 ‐ 52 weeks.

A significant group difference in the change from baseline morning PEFR in disfavour of anti‐leukotrienes was observed at four to eight weeks (N = 8 trials, 1926 participants; MD ‐15.12 L; 95% CI ‐20.80 to ‐9.44; random‐effects model; Analysis 1.15), at 12 to 16 weeks (N = 10 trials, 2713 participants; MD ‐19.07 L; 95% CI ‐25.86 to ‐12.27; random‐effects model; Analysis 1.16), 24 to 26 weeks (N = 3 trials, 1718 participants; MD ‐21.62 L; 95% CI ‐40.19 to ‐3.05; random‐effects model; Analysis 1.17) and at 36 to 52 weeks (N = 4 trials, 1652 participants; MD ‐5.34 L; 95% CI ‐9.35 to ‐1.34; random‐effects model; Analysis 1.18).

1.15. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 15 Change from baseline AM PEFR (L/min) at 4 ‐ 8 weeks.

1.16. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 16 Change from baseline AM PEFR (L/min) at 12 ‐ 16 weeks.

1.17. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 17 Change from baseline AM PEFR (L/min) at 24 ‐ 26 weeks.

1.18. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 18 Change from baseline AM PEFR (L/min) at 36 ‐ 52 weeks.

Symptom scores

A significant group difference in the improvement from baseline daytime symptom scores in favour of inhaled corticosteroids were observed at four to eight weeks (N = 6 trials, 1925 participants; standard mean difference (SMD) 0.20; 95% CI 0.08 to 0.32; random‐effects model; Analysis 1.19), at 24 to 26 weeks (N = 3 adult trials, 1719 participants; (SMD 0.22; 95% CI 0.02 to 0.42)SMD 0.25; 95% CI 0.18 to 0.33; random‐effects model; Analysis 1.21), but not at 12 to 16 weeks (N = 9 trials, 2650 participants; (SMD 0.25; 95% CI 0.18 to 0.33); random‐effects model; Analysis 1.20) or 36 to 52 weeks (N = 2 paediatric trials, 582 participants; SMD 0.16 95% CI ‐0.02 to 0.34; random‐effects model; Analysis 1.22).

1.19. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 19 Change from baseline daytime symptom scores at 4 ‐ 8 weeks.

1.21. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 21 Change from baseline daytime symptom scores at 24 ‐ 26 weeks.

1.20. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 20 Change from baseline daytime symptom scores at 12 ‐ 16 weeks.

1.22. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 22 Change from baseline daytime symptom scores at 36 ‐ 52 weeks.

Nightime awakening

A significant group difference in favour of inhaled corticosteroids was observed for change from baseline night‐time awakenings at 12 to 16 weeks (N = 9 adult trials, 2916 participants; SMD 0.18, 95% CI 0.11 to 0.26; Analysis 1.24), at 24 to 26 weeks (N = 2 trials, 1055 participants; SMD 0.23; 95% CI 0.11 to 0.35; Analysis 1.25), but not at four to eight weeks (N = 3 adult trials, 798 participants; SMD = 0.22; 95% CI ‐0.02 to 0.46; random‐effects model; Analysis 1.23); only one trial reported at 36 to 52 weeks, precluding aggregation.

1.24. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 24 Change from baseline night‐time awakenings at 12 ‐ 16 weeks.

1.25. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 25 Change from baseline night‐time awakenings at 24 ‐ 26 weeks.

1.23. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 23 Change from baseline night‐time awakenings at 4 ‐ 8 week.

Rescue medication use

A significant group difference in the reduction from baseline mean daily use of β₂‐agonists in favour of inhaled corticosteroids as observed at four to eight weeks (N = 10 trials, 3264 participants; SMD 0.20; 95% CI 0.07 to 0.34; random‐effects model; Analysis 1.26), at 12 to 16 weeks (N = 12 trials, 3479 participants; SMD 0.23; 95% CI 0.17 to 0.30; Analysis 1.27), at 24 to 26 weeks (N = 2 adult trials, 1055 participants; SMD 0.31; 95% CI 0.19 to 0.43; Analysis 1.28), only one paediatric trial reporting data at 36 to 52 weeks, precluding aggregation.

1.26. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 26 Change from baseline mean daily use of β₂‐agonists at 4 ‐ 8 weeks.

1.27. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 27 Change from baseline mean daily use of β₂‐agonists at 12 ‐ 16 weeks.

1.28. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 28 Change from baseline mean daily use of β₂‐agonists at 24 ‐ 26 weeks.

No significant difference was observed in change from baseline rescue‐free days (%) at four to eight weeks (N = 5 trials, 1315 participants; MD ‐6.83 %; 95% CI ‐17.73 to 4.07; random‐effects model; Analysis 1.30), but a significant group difference was observed in disfavour of anti‐leukotrienes: at 12 to 16 weeks (N = 7 trials, 2304 participants; MD ‐9.64 %; 95% CI ‐13.71 to ‐5.56; random‐effects model; Analysis 1.31) and at 36 to 52 weeks (N = 3 trials, 1949 participants; MD ‐3.38 %; 95% CI ‐5.49 to ‐1.27; Analysis 1.33). Only one trial reported data at 24 to 26 weeks, precluding aggregation.

1.30. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 30 Change in rescue‐free days (%) at 4 ‐ 8 weeks.

1.31. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 31 Change in rescue‐free days (%) at 12 ‐ 16 weeks.

1.33. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 33 Change in rescue‐free days (%) at 36 ‐ 52 weeks.

Symptom‐free days

A significant group difference was observed in change in proportion of symptom‐free days (%) at all points in time in disfavour of anti‐leukotrienes at four to eight weeks (N = 3 adult trials, 1154 participants; MD ‐10.46%; 95% CI ‐14.56 to ‐6.36; Analysis 1.34), at 12 to 16 weeks (N = 9 trials, 2535 participants; MD ‐8.89%; 95% CI ‐11.92 to ‐5.87; Analysis 1.35), and at 36 to 52 weeks (N = 4 trials, 1805 participants; MD ‐5.71%; 95% CI ‐8.68 to ‐2.74; Analysis 1.36). Only one trial reported data at 24 to 26 weeks, precluding aggregation.

1.34. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 34 Change in proportion of symptom‐free days (%) at 4 ‐ 8 weeks.

1.35. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 35 Change in proportion of symptom‐free days (%) at 12 ‐ 16 weeks.

1.36. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 36 Change in proportion of symptom‐free days (%) at 24 ‐ 26 weeks.

Quality of life

A significant group difference was observed in the change in quality of life at all points in time in disfavour of anti‐leukotrienes: at 12 to 16 weeks (N = 2 adult trials, 1065 participants; MD ‐0.21; 95% CI ‐0.34 to ‐0.09; Analysis 1.39), at 24 to 26 weeks (N = 2 adult trials, 1028 participants; MD ‐0.38; 95% CI ‐0.54 to ‐0.21; Analysis 1.40), at 36 to 52 weeks (N = 2 trials, 1034; MD ‐0.19; 95% CI ‐0.31 to ‐0.07; Analysis 1.41). Only one trial reported data at four to eight weeks, precluding aggregation. Only one trial reported data on days with use of β₂‐agonists at 36 to 52 weeks; Analysis 1.56, precluding aggregation.

1.39. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 39 Change from baseline quality of life (QOL) at 12 ‐ 16 weeks.

1.40. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 40 Change from baseline quality of life (QOL) at 24 ‐ 26 weeks.

1.41. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 41 Change from baseline quality of life (QOL) at 36 ‐ 52 weeks.

Airway inflammation

Although few trials examined indices of airway inflammation, there was a significant group difference in the reduction in blood eosinophils in favour of inhaled corticosteroids at four to eight weeks (N = 4 trials, 1294 participants; MD 0.06 x 10⁹, 95% CI 0.02 to 0.10; random‐effects model; Analysis 1.43) but not at 12 to 16 weeks (N = 2 trials, 1013 participants; MD ‐0.0 x 10⁹, 95% CI ‐0.03 to 0.02; Analysis 1.44) and only one trial reported at 36 to 52 weeks. However, no significant group difference was observed in sputum eosinophils at four to eight weeks (N = 2 trials, 117 participants; MD 0.71 x 10⁹; 95% CI ‐2.06 to 3.47; random‐effects model; Analysis 1.45) and only one trial reported at 36 to 52 weeks. One paediatric trial examined the change in LTC₄ concentration in nasal washes with no group difference observed at 12 to 24 weeks; Analysis 1.47.

1.43. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 43 Change from baseline blood eosinophils at 4 ‐ 8 weeks.

1.44. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 44 Change from baseline blood eosinophils at 12 ‐ 16 weeks.

1.45. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 45 % Change in sputum eosinophils at 4 ‐ 8 weeks.

1.47. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 47 LTC₄ concentration (ng/mL) in nasal wash at 24 ‐ 26 weeks.

Asthma control days

Few trials evaluated the percentage of asthma control days during the intervention period; it was in disfavour of anti‐leukotrienes at four to eight weeks (N = 2 trials, 1293 participants; MD ‐5.72%; 95% CI ‐10.86 to ‐0.59; Analysis 1.48) and at 24 to 26 weeks (N = 2 trials, 1185 participants; MD ‐8.19%; 95% CI ‐19.46 to 3.07; random‐effects model; Analysis 1.49).

1.48. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 48 % Asthma control days during intervention period at 4 ‐ 8 weeks.

1.49. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 49 % Asthma control days during intervention period at 24 ‐ 26 weeks.

Bronchial challenge (PC₂₀)

Only one trial reported PC₂₀ at four to eight weeks, Analysis 1.50, precluding aggregation.

1.50. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 50 Change in PC₂₀ at 4 ‐ 8 weeks.

There was no significant group difference in days off work or school at 24 to 26 weeks (N = 2 trials, 606 participants; MD 0.12; 95% CI ‐0.01 to 0.26; Analysis 1.52). Only one trial reported patient and physician's level of satisfaction, precluding aggregation.

1.52. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 52 Days off work or school at 24 ‐ 26 weeks.

Only one study (Sorkness 2007) reported change in height in paediatric patients at 48 weeks (Analysis 1.53).

1.53. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 53 Change in height (cm).

Withdrawals

Anti‐leukotriene therapy was associated with a 24% increased risk of overall withdrawals (N = 43 trials, 11,317 participants; RR 1.22; 95% CI 1.09 to 1.37; random‐effects model; Analysis 1.56) (Chi² = 3.07 (1 df), P = 0.08).The withdrawals appeared to be attributable to an increased risk of withdrawals due to poor asthma control (N = 26 trials, 7669 participants; RR 2.56; 95% CI 2.01 to 3.27; P < 0.00001; Analysis 1.57) and with no statistically significant group difference due to adverse effects (N = 25 trials, 8518 participants, RR 1.24; 95% CI 0.95 to 1.63; P = 0.12; Analysis 1.58). Of note, there was no significant effect of age group on these withdrawal rates. The number needed to treat to harm (NNTH), that is, to observe one withdrawal due to poor asthma control is 31 (95% CI 22 to 47); in other words, 31 patients need to be treated with anti‐leukotrienes rather than inhaled corticosteroids to observe one more withdrawal due to poor asthma control (Figure 5).

1.56. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 56 Overall Withdrawals.

1.57. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 57 Withdrawal due to poor asthma control/exacerbations.

1.58. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 58 Withdrawals due to adverse effects.

5.

In the control group (on ICS) 2 people out of 100 had withdrawal due to poor control over 4 to 52 weeks, compared to 6 (95% CI 4 to 7) out of 100 for the active treatment group (given LRTA).

Adverse effects

There was no significant group difference in the number of patients who experienced "any adverse effects", (N = 22 trials, 7818 participants; RR 1.00; 95% CI 0.95 to 1.05; P = 0.90; Analysis 1.59), which met our definition of equivalence. There was also no significant group difference in elevation of liver enzymes (N = 7 trials, 1716 participants; RR 1.13; 95% CI 0.58 to 2.19; Analysis 1.60), upper respiratory infections (N = 8 trial, 2729 participants; RR 1.04; 95% CI 0.84 to 1.29; Analysis 1.61), headache (N = 24 trials, 8872 participants; RR 0.99; 95% CI 0.89 to 1.11; Analysis 1.62), nausea (N= 17 trials, 5563 participants; RR 0.83; 95% CI 0.64 to 1.08; Analysis 1.63), oral candidiasis (N = 3 trials, 865 participants; RR 0.25; 95% CI 0.05 to 1.19; Analysis 1.64), or death (N= 13 trials, 5489 participants; RR 3.05; 95% CI 0.32 to 29.26; Analysis 1.66) which was reported in only two trials both in anti‐leukotriene group. Only one trial reported growth in paediatric patients and the change in height between two groups could not achieve a statistical significant level Analysis 1.53; Sorkness 2007).

1.59. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 59 Overall Adverse effects.

1.60. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 60 Elevated liver enzymes.

1.61. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 61 Upper respiratory tract infections.

1.62. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 62 Headache.

1.63. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 63 Nausea.

1.64. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 64 Oral candidiasis.

1.66. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 66 Death.

Discussion

In adults and children with mild to moderate airway obstruction due to persistent asthma, four to 52 weeks of treatment with daily oral anti‐leukotrienes carries a 51% increased risk (from 7% to 11%) of an asthma exacerbation requiring systemic corticosteroids than treatment with inhaled corticosteroids at a median dose of 200 HFA‐BDP eq. Twenty‐eight people need to be treated with inhaled corticosteroids rather than anti‐leukotriene to prevent one person from experiencing an exacerbation requiring corticosteroid i.e. the NNT is 28. These data appear robust as 180 new trials with no group difference would be needed to reverse these findings.

The baseline severity of asthma obstruction significantly influenced the magnitude of response; indeed, the risk of exacerbation requiring rescue systemic steroids was increased by 'two‐fold' in patients with moderate airway obstruction treated with anti‐leukotrienes rather than inhaled corticosteroids, while the risk was increased by 25% in patients with mild asthma obstruction. The magnitude of the risk was not significantly influenced by age, choice of anti‐leukotrienes, duration of intervention, publication status, methodological quality, funding source and dose of inhaled corticosteroids in HFA‐BDP eq.

Secondary outcomes clearly favoured the use of inhaled corticosteroids over anti‐leukotriene agents in adults and children. There was a three‐fold increase in the risk of patients experiencing an exacerbation requiring hospital admission when treated with anti‐leukotriene agents compared with inhaled corticosteroids. With regards to other indicators of asthma control, inhaled corticosteroids were more effective than anti‐leukotrienes in improving lung function (FEV₁ and PEFR), the percentage of symptom‐free and rescue‐free days, as well as in reducing symptoms, night‐time awakenings and rescue β₂‐agonist use. These group differences were generally present at all points in time over four to 52 weeks of treatment.

The risk of overall adverse effects was similar in both treatment groups, meeting our a priori definition of equivalence. There was also no group difference in the following specific adverse effects, namely liver enzyme elevation, headaches, upper respiratory infections, oral candidiasis, nausea, and death. Anti‐leukotriene use was not associated with an increased risk of withdrawals due to adverse effects. However, adverse effects typically associated with inhaled corticosteroids such as growth suppression (in children), osteopenia and adrenal suppression were seldom measured except in one trial (Sorkness 2007, in which growth was measured), thus preventing a fair comparison of the safety of long‐term use of inhaled corticosteroids versus anti‐leukotrienes.

The increased risk of all‐cause withdrawals was significantly higher among patients treated with anti‐leukotriene agents as compared to inhaled corticosteroids. Most of the increased risk seems attributable to increased withdrawals due to poor asthma control with the use of anti‐leukotrienes which indirectly supports the superiority of inhaled corticosteroids over anti‐leukotrienes.

The results of this review pertain to asthmatic adults and children with a mild or moderate persistent asthma. The results can apply to school‐aged children; 19 trials with paediatric and adolescents contributed data to the review of which six trials (23% of the weight of the summary estimate) contributed to the primary outcome. The relatively modest number of trials could fall in the priori defined category of high methodological quality indicates either poor designing of trials or inadequate reporting of methodology. More long‐term trials are needed to compare the safety of anti‐leukotrienes versus inhaled corticosteroids as monotherapy in the treatment of paediatric asthma, as only one trial reported growth or effect of long‐term administration of inhaled corticosteroids in paediatrics.

This review summarises the best evidence available until December 2010. With a total of 56 trials (37 adult and 19 paediatric), it represents a significant update from the previous update in August 2003 which was based on 25 trials (22 adult and three paediatric). With 16 more paediatric trials than in the prior review, the current data more adequately represents children; paediatric trials represent now 23% of weight of the primary outcome compared with 6.7% in the prior review. While the results remain admittedly notably influenced by adults, the absence of a significant group difference between adults and children would support that the conclusion apply to both age groups. Twenty‐one (38%) of 56 trials contributing data to the meta‐analysis were of high reported methodological quality as per our predefined criteria using the Cochrane Classification 'Risk of bias' tool (29% of paediatric and 71% of adult trials); the impact of the large proportion of lower reported methodological quality on study results is unclear but could have led to an overestimation of the true effect. On the other hand, the robustness of the study results is supported by the fail‐safe N of 180 trials indicating the number of unpublished/future studies with no group difference in rescue oral corticosteroids needed to change the direction of the current findings. Consequently, in line with the previous version, the present review confirms the greater efficacy of inhaled corticosteroids administered at a median dose of 200 HFA‐BDP eq over anti‐leukotrienes in children and adult with mild and moderate persistent asthma.

Authors' conclusions

Implications for practice.

In symptomatic adults and children with mild or moderate asthma, anti‐leukotrienes are less effective than inhaled corticosteroids at a median dose of 200 HFA‐BDP eq for preventing exacerbations and achieving asthma control; the superiority of ICS is particularly marked in patients with moderateversus mild airway obstruction but does not appear influenced by age, duration of intervention, or anti‐leukotriene used. The use of anti‐leukotrienes is associated with a 51% increased risk of experiencing an exacerbation requiring systemic corticosteroids, a three‐fold increased hospital admission rate and more than a two‐fold increased risk of withdrawals due to poor asthma control compared to inhaled corticosteroids. The superiority of inhaled corticosteroids was also observed in lung function, symptoms, use of rescue β₂‐agonists, quality of life, inflammatory markers and withdrawals including withdrawals due to poor asthma control. Although anti‐leukotrienes have a similar safety profile to that of inhaled corticosteroids, one must note that adverse effects typically associated with inhaled corticosteroids such as growth suppression (in children), osteopenia and adrenal suppression have not been measured in these trials. On the basis of efficacy, the results support the current guidelines' recommendation that inhaled corticosteroids remain the preferred monotherapy in adults and children with persistent asthma.

Implications for research.

There is little need for additional efficacy studies in this area, other perhaps than to determine the exact dose‐equivalence of anti‐leukotrienes, which is clearly less than 200 μg/day of HFA‐BDP eq or to compare the safety profile (on growth) in children. Acknowledging the low and potential differential adherence rate to daily controller therapies, one area of interest is certainly examining the real‐life effectiveness of low‐dose daily inhaled corticosteroids compared to anti‐leukotrienes,

Long‐term high methodological quality trials with adequate documentation of adverse effects associated with inhaled corticosteroids are needed to provide a fair comparison of the safety of both treatment options. Future trials should aim for the following design characteristics:

• pragmatic effectiveness trials;

• double blinding, adequate randomisation and complete reporting of withdrawals and drop outs with intention‐to‐treat analysis;

• parallel‐group;

• have a minimal intervention period of 24 to 52 weeks to assess the long‐term side effects of both interventions (anti‐leukotrienes and inhaled corticosteroids);

• complete reporting of continuous (denominators, mean change and mean standard deviation of change) and dichotomous (denominators and rate) data;

• specific reporting of exacerbations requiring systemic corticosteroids;

• systematic documentation of reasons for withdrawals and adverse effects, including those associated with inhaled corticosteroids such as oral candidiasis, osteopenia, adrenal suppression, growth suppression, etc; and

• compare different anti‐leukotriene agents (synthesis inhibitor and receptor antagonists).

Feedback

Data entry error

Summary

I believe there may be an error in Table 1.13. The numbers for Ostrom 2005 are exactly the same as in Table 1.10.

Reply

Response from Cochrane Airways editorial base: Thank you for bringing this error to our attention. The duplicate data has been removed from analysis 1.10.1 and the text updated in the results section to reflect this change. The impact on the results of this analysis is negligible.

Contributors

Stephanie Weinreich

Academic Medical Center, Amsterdam, The Netherlands

What's new

Date	Event	Description
8 December 2014	Feedback has been incorporated	Feedback incorporated and typos corrected

History

Protocol first published: Issue 2, 1999
 Review first published: Issue 3, 2000

Date	Event	Description
31 December 2010	New search has been performed	New literature search run.
31 December 2010	New citation required but conclusions have not changed	29 new studies included. Risk of bias has been updated across all studies.
30 June 2008	New search has been performed	Converted to new review format with added information.
17 October 2003	New citation required and conclusions have changed	Substantive amendment

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database	Frequency of search
MEDLINE (Ovid)	Weekly
EMBASE (Ovid)	Weekly
CENTRAL (the Cochrane Library)	Quarterly
PsycINFO (Ovid)	Monthly
CINAHL (EBSCO)	Monthly
AMED (EBSCO)	Monthly

 

Hand‐searches: core respiratory conference abstracts

Conference	Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)	2001 onwards
American Thoracic Society (ATS)	2001 onwards
Asia Pacific Society of Respirology (APSR)	2004 onwards
British Thoracic Society Winter Meeting (BTS)	2000 onwards
Chest Meeting	2003 onwards
European Respiratory Society (ERS)	1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)	2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)	1999 onwards

 

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti‐asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1‐15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1‐7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

Data and analyses

Comparison 1. Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Patients with at least one exacerbation requiring systemic steroids	21	6077	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.17, 1.96]
1.1 Paediatrics	6	1662	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.99, 1.86]
1.2 Adults	15	4415	Risk Ratio (M‐H, Random, 95% CI)	1.61 [1.12, 2.31]
2 Patients with at least one exacerbation requiring hospital admission	12	2715	Risk Ratio (M‐H, Fixed, 95% CI)	3.33 [1.02, 10.94]
2.1 Paediatrics	4	558	Risk Ratio (M‐H, Fixed, 95% CI)	3.04 [0.12, 73.98]
2.2 Adults	8	2157	Risk Ratio (M‐H, Fixed, 95% CI)	3.38 [0.94, 12.17]
3 Change from baseline FEV1 (L) at 4 ‐ 8 weeks	12	3020	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.15, ‐0.08]
3.1 Paediatrics	1	56	Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.69, 0.13]
3.2 Adults	11	2964	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.15, ‐0.08]
4 Change from baseline FEV1( L) 12 ‐ 16 weeks	8	1778	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.20, ‐0.04]
4.1 Paediatrics	2	179	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.13, 0.09]
4.2 Adults	6	1599	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.24, ‐0.05]
5 Change from baseline FEV1 (L) at 24 ‐ 26 weeks	3	1178	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.22, ‐0.04]
5.1 Paediatrics	1	123	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.14, 0.12]
5.2 Adults	2	1055	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.23, ‐0.11]
6 Change from baseline FEV1 (L) at 36 ‐ 52 weeks	2	1040	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.07, 0.00]
6.1 Paediatrics	2	1040	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.07, 0.00]
7 FEV1 irrespective of time of treatment	23	7016	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.14, ‐0.08]
7.1 Paediatrics	4	1398	Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.07, 0.00]
7.2 Adults	19	5618	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.16, ‐0.09]
8 Responders (defined as change from baseline in FEV1 >= 7.5%	1		Odds Ratio (Fixed, 95% CI)	Totals not selected
9 Change from baseline FEV1 (%) at 4 ‐ 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Change from baseline FEV1 (%) 12 ‐ 16 weeks	2	603	Mean Difference (IV, Fixed, 95% CI)	‐5.70 [‐9.81, ‐1.59]
10.1 Adults	2	603	Mean Difference (IV, Fixed, 95% CI)	‐5.70 [‐9.81, ‐1.59]
11 Change from baseline FEV1 (%) at 24 ‐ 26 weeks	2	838	Mean Difference (IV, Fixed, 95% CI)	‐8.20 [‐10.85, ‐5.55]
11.1 Adults	2	838	Mean Difference (IV, Fixed, 95% CI)	‐8.20 [‐10.85, ‐5.55]
12 Change from baseline FEV1 % of predicted at 4 ‐ 8 weeks	2	219	Mean Difference (IV, Random, 95% CI)	‐2.58 [‐6.56, 1.40]
12.1 Paediatrics	1	183	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐4.82, 3.74]
12.2 Adults	1	36	Mean Difference (IV, Random, 95% CI)	‐4.6 [‐8.86, ‐0.34]
13 Change from baseline FEV1 % of predicated at 12 ‐ 16 weeks	3	948	Mean Difference (IV, Fixed, 95% CI)	‐3.76 [‐5.01, ‐2.50]
13.1 Paediatrics	1	335	Mean Difference (IV, Fixed, 95% CI)	‐6.02 [‐9.45, ‐2.59]
13.2 Adults	2	613	Mean Difference (IV, Fixed, 95% CI)	‐3.41 [‐4.76, ‐2.06]
14 Change from baseline FEV1 % of predicated at 36 ‐ 52 weeks	3	1229	Mean Difference (IV, Random, 95% CI)	‐3.51 [‐7.14, 0.12]
14.1 Paediatrics	3	1229	Mean Difference (IV, Random, 95% CI)	‐3.51 [‐7.14, 0.12]
15 Change from baseline AM PEFR (L/min) at 4 ‐ 8 weeks	8	1926	Mean Difference (IV, Random, 95% CI)	‐15.12 [‐20.80, ‐9.44]
15.1 Paediatrics	1	332	Mean Difference (IV, Random, 95% CI)	‐7.76 [‐13.43, ‐2.09]
15.2 Adults	7	1594	Mean Difference (IV, Random, 95% CI)	‐17.63 [‐22.56, ‐12.69]
16 Change from baseline AM PEFR (L/min) at 12 ‐ 16 weeks	9	2601	Mean Difference (IV, Random, 95% CI)	‐19.07 [‐25.86, ‐12.27]
16.1 Paediatrics	1	335	Mean Difference (IV, Random, 95% CI)	‐16.9 [‐28.54, ‐5.26]
16.2 Adults	8	2266	Mean Difference (IV, Random, 95% CI)	‐19.57 [‐27.27, ‐11.87]
17 Change from baseline AM PEFR (L/min) at 24 ‐ 26 weeks	3	1718	Mean Difference (IV, Random, 95% CI)	‐21.62 [‐40.19, ‐3.05]
17.1 Adults	3	1718	Mean Difference (IV, Random, 95% CI)	‐21.62 [‐40.19, ‐3.05]
18 Change from baseline AM PEFR (L/min) at 36 ‐ 52 weeks	3	1028	Mean Difference (IV, Random, 95% CI)	‐5.06 [‐10.58, 0.45]
18.1 Adults	3	1028	Mean Difference (IV, Random, 95% CI)	‐5.06 [‐10.58, 0.45]
19 Change from baseline daytime symptom scores at 4 ‐ 8 weeks	6	1925	Std. Mean Difference (IV, Random, 95% CI)	0.20 [0.08, 0.32]
19.1 Paediatrics	1	393	Std. Mean Difference (IV, Random, 95% CI)	0.06 [‐0.14, 0.26]
19.2 Adults	5	1532	Std. Mean Difference (IV, Random, 95% CI)	0.23 [0.11, 0.36]
20 Change from baseline daytime symptom scores at 12 ‐ 16 weeks	9	2650	Std. Mean Difference (IV, Fixed, 95% CI)	0.25 [0.18, 0.33]
20.1 Paediatrics	2	388	Std. Mean Difference (IV, Fixed, 95% CI)	0.28 [0.08, 0.48]
20.2 Adults	7	2262	Std. Mean Difference (IV, Fixed, 95% CI)	0.25 [0.16, 0.33]
21 Change from baseline daytime symptom scores at 24 ‐ 26 weeks	3	1719	Std. Mean Difference (IV, Random, 95% CI)	0.22 [0.02, 0.42]
21.1 Adults	3	1719	Std. Mean Difference (IV, Random, 95% CI)	0.22 [0.02, 0.42]
22 Change from baseline daytime symptom scores at 36 ‐ 52 weeks	2	582	Std. Mean Difference (IV, Random, 95% CI)	0.16 [‐0.02, 0.34]
22.1 Paediatrics	2	582	Std. Mean Difference (IV, Random, 95% CI)	0.16 [‐0.02, 0.34]
23 Change from baseline night‐time awakenings at 4 ‐ 8 week	3	798	Std. Mean Difference (IV, Random, 95% CI)	0.22 [‐0.02, 0.46]
23.1 Adults	3	798	Std. Mean Difference (IV, Random, 95% CI)	0.22 [‐0.02, 0.46]
24 Change from baseline night‐time awakenings at 12 ‐ 16 weeks	9	2916	Std. Mean Difference (IV, Fixed, 95% CI)	0.18 [0.11, 0.26]
24.1 Adults	9	2916	Std. Mean Difference (IV, Fixed, 95% CI)	0.18 [0.11, 0.26]
25 Change from baseline night‐time awakenings at 24 ‐ 26 weeks	2	1055	Std. Mean Difference (IV, Fixed, 95% CI)	0.23 [0.11, 0.35]
25.1 Adults	2	1055	Std. Mean Difference (IV, Fixed, 95% CI)	0.23 [0.11, 0.35]
26 Change from baseline mean daily use of β2‐agonists at 4 ‐ 8 weeks	10	3264	Std. Mean Difference (IV, Random, 95% CI)	0.20 [0.07, 0.34]
26.1 Paediatrics	1	393	Std. Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.22, 0.17]
26.2 Adults	9	2871	Std. Mean Difference (IV, Random, 95% CI)	0.24 [0.10, 0.38]
27 Change from baseline mean daily use of β2‐agonists at 12 ‐ 16 weeks	11	3367	Std. Mean Difference (IV, Fixed, 95% CI)	0.23 [0.17, 0.30]
27.1 Paediatrics	1	335	Std. Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.20, 0.23]
27.2 Adults	10	3032	Std. Mean Difference (IV, Fixed, 95% CI)	0.26 [0.19, 0.33]
28 Change from baseline mean daily use of β2‐agonists at 24 ‐ 26 weeks	2	1055	Std. Mean Difference (IV, Fixed, 95% CI)	0.31 [0.19, 0.43]
28.1 Adults	2	1055	Std. Mean Difference (IV, Fixed, 95% CI)	0.31 [0.19, 0.43]
29 Change from baseline mean daily use of β2‐agonists at 36 ‐ 52 weeks	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
29.1 Paediatrics	1		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
30 Change in rescue‐free days (%) at 4 ‐ 8 weeks	5	1315	Mean Difference (IV, Random, 95% CI)	‐6.83 [‐17.73, 4.07]
30.1 Paediatrics	1	393	Mean Difference (IV, Random, 95% CI)	2.72 [‐3.11, 8.55]
30.2 Adults	4	922	Mean Difference (IV, Random, 95% CI)	‐13.25 [‐18.11, ‐8.39]
31 Change in rescue‐free days (%) at 12 ‐ 16 weeks	7	2304	Mean Difference (IV, Random, 95% CI)	‐9.64 [‐13.71, ‐5.56]
31.1 Paediatrics	1	335	Mean Difference (IV, Random, 95% CI)	‐10.10 [‐18.97, ‐1.23]
31.2 Adults	6	1969	Mean Difference (IV, Random, 95% CI)	‐9.64 [‐14.39, ‐4.89]
32 Change in rescue‐free days (%) at 24 ‐ 26 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
32.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
33 Change in rescue‐free days (%) at 36 ‐ 52 weeks	2	1350	Mean Difference (IV, Fixed, 95% CI)	‐2.59 [‐4.97, ‐0.21]
33.1 Paediatrics	2	1350	Mean Difference (IV, Fixed, 95% CI)	‐2.59 [‐4.97, ‐0.21]
33.2 Adults	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
34 Change in proportion of symptom‐free days (%) at 4 ‐ 8 weeks	3	1154	Mean Difference (IV, Fixed, 95% CI)	‐10.46 [‐14.56, ‐6.36]
34.1 Adults	3	1154	Mean Difference (IV, Fixed, 95% CI)	‐10.46 [‐14.56, ‐6.36]
35 Change in proportion of symptom‐free days (%) at 12 ‐ 16 weeks	8	2423	Mean Difference (IV, Fixed, 95% CI)	‐8.89 [‐11.92, ‐5.87]
35.1 Paediatrics	1	335	Mean Difference (IV, Fixed, 95% CI)	‐6.40 [‐15.82, 3.02]
35.2 Adults	7	2088	Mean Difference (IV, Fixed, 95% CI)	‐9.18 [‐12.38, ‐5.98]
36 Change in proportion of symptom‐free days (%) at 24 ‐ 26 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
36.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
37 Change in proportion of symptom‐free days (%) at 36 ‐ 52 weeks	3	1190	Mean Difference (IV, Fixed, 95% CI)	‐5.49 [‐9.06, ‐1.91]
37.1 Paediatrics	2	575	Mean Difference (IV, Fixed, 95% CI)	‐4.90 [‐9.73, ‐0.08]
37.2 Adults	1	615	Mean Difference (IV, Fixed, 95% CI)	‐6.20 [‐11.53, ‐0.87]
38 Change from baseline quality of life (QOL) at 4 ‐ 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
38.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
39 Change from baseline quality of life (QOL) at 12 ‐ 16 weeks	2	1065	Mean Difference (IV, Fixed, 95% CI)	‐0.21 [‐0.34, ‐0.09]
39.1 Adults	2	1065	Mean Difference (IV, Fixed, 95% CI)	‐0.21 [‐0.34, ‐0.09]
40 Change from baseline quality of life (QOL) at 24 ‐ 26 weeks	2	1028	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [‐0.54, ‐0.21]
40.1 Adults	2	1028	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [‐0.54, ‐0.21]
41 Change from baseline quality of life (QOL) at 36 ‐ 52 weeks	1	541	Mean Difference (IV, Fixed, 95% CI)	‐0.13 [‐0.33, 0.07]
41.1 Paediatrics	1	541	Mean Difference (IV, Fixed, 95% CI)	‐0.13 [‐0.33, 0.07]
41.2 Adults	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
42 Days with use of β2‐agonists at 36 ‐ 52 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
42.1 Paediatrics	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
43 Change from baseline blood eosinophils at 4 ‐ 8 weeks	4	1294	Mean Difference (IV, Random, 95% CI)	0.06 [0.02, 0.10]
43.1 Adults	4	1294	Mean Difference (IV, Random, 95% CI)	0.06 [0.02, 0.10]
44 Change from baseline blood eosinophils at 12 ‐ 16 weeks	2	1013	Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.03, 0.02]
44.1 Adults	2	1013	Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.03, 0.02]
45 % Change in sputum eosinophils at 4 ‐ 8 weeks	2	117	Mean Difference (IV, Random, 95% CI)	0.71 [‐2.06, 3.47]
45.1 Adults	2	117	Mean Difference (IV, Random, 95% CI)	0.71 [‐2.06, 3.47]
46 % Change in sputum eosinophils at 36 ‐ 52 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
46.1 Paediatrics	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
47 LTC4 concentration (ng/mL) in nasal wash at 24 ‐ 26 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
47.1 Paediatrics	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
48 % Asthma control days during intervention period at 4 ‐ 8 weeks	2	1293	Mean Difference (IV, Fixed, 95% CI)	‐5.72 [‐10.86, ‐0.59]
48.1 Adults	2	1293	Mean Difference (IV, Fixed, 95% CI)	‐5.72 [‐10.86, ‐0.59]
49 % Asthma control days during intervention period at 24 ‐ 26 weeks	2	1185	Mean Difference (IV, Random, 95% CI)	‐8.19 [‐19.46, 3.07]
49.1 Adults	2	1185	Mean Difference (IV, Random, 95% CI)	‐8.19 [‐19.46, 3.07]
50 Change in PC20 at 4 ‐ 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
50.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
51 % rescue ‐ free days at 24 ‐ 26 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
51.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
52 Days off work or school at 24 ‐ 26 weeks	2	606	Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.01, 0.26]
52.1 Paediatrics	1	124	Mean Difference (IV, Fixed, 95% CI)	‐0.24 [‐1.31, 0.83]
52.2 Adults	1	482	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.00, 0.26]
53 Change in height (cm)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
53.1 Paediatrics	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
54 Patient's satisfaction at 4 ‐ 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
54.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
55 Physician's satisfaction at 4 ‐ 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
55.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
56 Overall Withdrawals	42	10939	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.08, 1.38]
56.1 Paediatrics	18	3397	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.88, 1.21]
56.2 Adults	24	7542	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.11, 1.54]
57 Withdrawal due to poor asthma control/exacerbations	26	7669	Risk Ratio (M‐H, Fixed, 95% CI)	2.56 [2.01, 3.27]
57.1 Paediatrics	7	1219	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [1.20, 3.94]
57.2 Adults	19	6450	Risk Ratio (M‐H, Fixed, 95% CI)	2.64 [2.02, 3.45]
58 Withdrawals due to adverse effects	25	8518	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.95, 1.63]
58.1 Paediatrics	8	2330	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.70, 2.33]
58.2 Adults	17	6188	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.91, 1.67]
59 Overall Adverse effects	22	7818	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.95, 1.05]
59.1 Paediatrics	3	1460	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.90, 1.15]
59.2 Adults	19	6358	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.94, 1.05]
60 Elevated liver enzymes	7	1761	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.58, 2.19]
60.1 Paediatrics	1	118	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.03, 7.68]
60.2 Adults	6	1643	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.60, 2.36]
61 Upper respiratory tract infections	8	2729	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.29]
61.1 Paediatrics	5	1514	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.81, 1.36]
61.2 Adults	3	1215	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.69, 1.50]
62 Headache	24	8872	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.89, 1.11]
62.1 Paediatrics	6	2589	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.81, 1.37]
62.2 Adults	18	6283	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.86, 1.10]
63 Nausea	17	5563	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.64, 1.08]
63.1 Paediatrics	2	465	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.28, 2.31]
63.2 Adults	15	5098	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.64, 1.09]
64 Oral candidiasis	3	865	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.05, 1.19]
64.1 Adults	3	865	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.05, 1.19]
65 Hoarseness	2	734	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.24]
65.1 Adults	2	734	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.24]
66 Death	13	5489	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [0.32, 29.26]
66.1 Paediatrics	2	1114	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 73.46]
66.2 Adults	11	4375	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 75.82]
67 Primary outcome ‐ stratified by anti‐leukotrienes	21	6077	Odds Ratio (M‐H, Random, 95% CI)	1.61 [1.20, 2.16]
67.1 Monelukast	15	4352	Odds Ratio (M‐H, Random, 95% CI)	1.55 [1.14, 2.12]
67.2 Zafirlukast	6	1725	Odds Ratio (M‐H, Random, 95% CI)	1.92 [0.88, 4.20]
68 Primary outcome ‐ stratified by duration of intervention	21	6077	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.17, 1.96]
68.1 4‐8 weeks	9	2346	Risk Ratio (M‐H, Random, 95% CI)	1.74 [0.78, 3.87]
68.2 12‐16 weeks	7	1541	Risk Ratio (M‐H, Random, 95% CI)	2.06 [1.43, 2.96]
68.3 24‐26 weeks	2	657	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.55, 2.45]
68.4 36‐52 weeks	3	1533	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.87, 1.91]
69 Main outcome ‐stratified by severity of airway obstruction	21	6077	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.17, 1.96]
69.1 Mean FEV1 60‐80% of predicted	11	3922	Risk Ratio (M‐H, Random, 95% CI)	2.03 [1.41, 2.91]
69.2 Mean FEV1 ≥80% of predicted	10	2155	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.97, 1.61]
70 Primary outcome ‐ stratified by methodological quality	21	6061	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.17, 1.96]
70.1 High quality	11	4366	Risk Ratio (M‐H, Random, 95% CI)	1.62 [1.29, 2.03]
70.2 Poor quality	10	1695	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.74, 2.43]
71 Primary outcome‐ stratified by funding source	21	6077	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.17, 1.96]
71.1 Funded by producers of ICS	9	2638	Risk Ratio (M‐H, Random, 95% CI)	1.71 [1.05, 2.80]
71.2 Funded by producers of AL	5	2797	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.99, 2.35]
71.3 No industry funding or not reported	7	642	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.90, 1.66]
72 Primary outcome ‐ stratified by HFC‐BDP equivalent	21	6077	Odds Ratio (M‐H, Random, 95% CI)	1.61 [1.20, 2.16]
72.1 100‐150 μg HFA‐BDP equivalent	3	216	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.26, 2.08]
72.2 200‐250 μg HFA‐BDP equivalent	15	5767	Odds Ratio (M‐H, Random, 95% CI)	1.75 [1.29, 2.38]
72.3 400‐500 μg HFA‐BDP equivalent	3	94	Odds Ratio (M‐H, Random, 95% CI)	0.54 [0.11, 2.78]

1.7. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 7 FEV₁ irrespective of time of treatment.

1.8. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 8 Responders (defined as change from baseline in FEV₁ >= 7.5%.

1.9. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 9 Change from baseline FEV₁ (%) at 4 ‐ 8 weeks.

1.29. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 29 Change from baseline mean daily use of β₂‐agonists at 36 ‐ 52 weeks.

1.32. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 32 Change in rescue‐free days (%) at 24 ‐ 26 weeks.

1.37. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 37 Change in proportion of symptom‐free days (%) at 36 ‐ 52 weeks.

1.38. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 38 Change from baseline quality of life (QOL) at 4 ‐ 8 weeks.

1.42. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 42 Days with use of β₂‐agonists at 36 ‐ 52 weeks.

1.46. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 46 % Change in sputum eosinophils at 36 ‐ 52 weeks.

1.51. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 51 % rescue ‐ free days at 24 ‐ 26 weeks.

1.54. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 54 Patient's satisfaction at 4 ‐ 8 weeks.

1.55. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 55 Physician's satisfaction at 4 ‐ 8 weeks.

1.65. Analysis.

Comparison 1 Anti‐leukotriene (AL) vs. Inhaled glucocorticoids (in HFC‐BDP equivalent), Outcome 65 Hoarseness.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abadoglu 2005.

Methods	DESIGN: Randomised clinical study Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 24 WITHDRAWALS: Not mentioned AGE in years ± SD: 35.65 ± 10.75 GENDER (male %): 20.83% ASTHMA SEVERITY: Mild persistent asthma ASTHMA DURATION: less than 5 years: 62.5% 5‐10 years: 27.75% more than 10 years: 9.75% % pred. FEV1 (%, ± SD): 89.3 ± 14.85% MEAN ( ± SD) β2‐AGONIST USE (puffs/day): Not described DOSE OF inhaled corticosteroids AT STUDY ENTRY AND AT RUN‐IN: Not mentioned ATOPY (% of patients): 54.16% ELIGIBILITY CRITERIA: A history of recurrent symptoms of wheezing, shortness of breath, cough; Demonstration of objective signs of reversible airway obstruction by means of at least 12 % increase in FEV1 after 15 minutes with an inhalation of 200 μg salbutamol; A PC20 methacholine < 8 mg/mLas stated by the American Thoracic Society and International Asthma Guidelines. Asthma severity was determined by the frequency of asthma symptoms, pulmonary function tests. EXCLUSION CRITERIA: On inhaled corticosteroids, leukotriene receptor antagonists, theophylline and long acting β2‐agonists within the preceding 12 months of the study; airway infection for at least 6 weeks before investigation.
Interventions	PROTOCOL DURATION Run‐in = Not mentioned Intervention = 4 weeks TEST GROUP: Montelukast CONTROL GROUP: Fluticasone propionate DEVICE: Not mentioned CRITERIA FOR WITHDRAWAL FROM STUDY: Not mentioned
Outcomes	ANALYSIS: Not by intention‐to‐treat analysis OUTCOMES: Reported at 4 weeks; Report outcomes are reported as pre‐ and post‐values (not change from baseline) PULMONARY FUNCTION TESTS: Only pretreatment FEV1 was reported as not difference was observed after treatment FUNCTIONAL STATUS: Not reported INFLAMMATORY MEDIATORS: Eosinophils count; Apoptotic eosinophils; Apoptotic ratio ADVERSE EVENTS: Not mentioned WITHDRAWALS: Not mentioned
ICS dose in HFA beclomethasone ‐ equivalent	250 μg
Notes	Full paper (2005) Funding not available
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	There is no report as to whether some patients withdrew from the study after randomisation
Selective reporting (reporting bias)	Low risk	All primary and secondary data are presented
Other bias	Low risk	No apparent other bias

Basyigit 2004.

Methods	DESIGN: Randomised clinical study Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 24 WITHDRAWALS: Not mentioned AGE in years (± SD): 35.65 ± 10.75 GENDER (male%): 20.83% ASTHMA SEVERITY: Mild persistent asthma ASTHMA DURATION: less than 5 years: 62.5% 5‐10 years: 27.75% more than 10 years: 9.75% % pred. FEV1(%, ± SD): 89.3 ± 14.85% MEAN ( ± SD) β2‐AGONIST USE (puffs per day): Not described DOSE OF inhaled corticosteroids AT STUDY ENTRY AND AT RUN‐IN: Not mentioned ATOPY (% of patients): 54.16% ELIGIBILITY CRITERIA: mild persistent asthma; FEV1 more than 80%; Non smoker or ex‐smoker for more than 5 years; No exacerbation in the last 3 months; No history of cardiopulmonary disease other than asthma EXCLUSION CRITERIA: Not mentioned
Interventions	PROTOCOL DURATION: Run‐in = 15 days; Intervention = 8 weeks TEST GROUP: Zafirlukast TEST GROUP 2: Theophylline CONTROL GROUP: Budesonide DEVICE: Not mentioned CRITERIA FOR WITHDRAWAL FROM STUDY: Not mentioned
Outcomes	ANALYSIS (ITT) OUTCOMES: Reported at 8 weeks; report outcomes are reported as pre‐ and post‐values (not change from baseline) PULMONARY FUNCTION TESTS: Spirometry FUNCTIONAL STATUS: Not mentioned INFLAMMATORY MEDIATORS: ECP levels; Total cell count; Eosinophils count ADVERSE EVENTS: Not mentioned WITHDRAWALS: Not mentioned
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full paper (2004) Funding not available Confirmation of methodology and data extraction
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All data presented, withdrawal rate was not observed
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined but no bias is observed
Other bias	Low risk	No apparent other bias

Baumgartner 2003.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial. Confirmation of methodology obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 730 M: 313 BDP: 314 Placebo: 103 WITHDRAWALS: M: 22 (7%) BDP: 19 (6%) Placebo: 10 (10%) AGE in years ± SD: M: 35.9 ± 14.9 BDP:35.5 ± 15.0 Placebo:35.5 ± 14.6 GENDER (% male): M: 33% BDP: 38 % ASTHMA SEVERITY: Not described ASTHMA DURATION: Not reported % Pred. FEV1 % ± SD: M: 69 ± 12 BDP: 68 ± 11 Placebo: 68±12 MEAN ± SD β2‐AGONIST USE (puffs/day): M: 5.2 ± 3.7 BDP: 5.1 ± 3.3 Placebo: 5.5 ± 3.9 ATOPY: M: 69% BDP: 68% ELIGIBILITY CRITERIA: Age >= 15 years, Current tx with only β2‐agonist, Asthma history x 1 year, >= 50 and <= 85% FEV1 Pred, Reversibility >= 15% after two puffs short‐acting β2‐agonist, Daily use of β2‐agonist > 2 puffs/day during run‐in, Non‐smokers for more than 1 year, EXCLUSION: ED tx in past 1 month, Hospital admission for asthma in past 3 months, URTI in past 3 weeks, Significant sinus disease, Systemic corticosteroids in past month, inhaled corticosteroids in past 2 weeks, Astemizole within 3 months or xanthine derivatives, Oral or long‐acting inhaled B‐agonists, Cromolyn sodium or nedocromil, inhaled anticholinergic agents, oral leukotriene receptor antagonists or leukotriene synthesis inhibitors within 1 week before the start
Interventions	PROTOCOL Duration Run‐in Period: 2 weeks Intervention Period: 6 weeks TEST GROUP: Montelukast 10 mg per day CONTROL GROUP 1: Beclomethasone 200 ug twice a day CONTROL GROUP 2: Placebo DEVICE: MDI (actuation inhaler) CO‐INTERVENTION: Not specified CRITERIA FOR WITHRAWAL FROM STUDY: Not described
Outcomes	ANALYSIS BY MODIFIED INTENTION‐TO‐TREAT OUTCOMES reported at 6 weeks PULMONARY FUNCTION TESTS: Change from baseline FEV1 SYMPTOM SCORES: Change in mean asthma score (6‐point) FUNCTIONAL STATUS: Change from baseline mean daily β2‐agonist use, * %Asthma control days (<= 2 puffs of β2‐agonist use, no night‐time awakenings, no unscheduled asthma care, and no systemic corticosteroid rescue required), Patients with exacerbations requiring systemic corticosteroids, Physician global evaluation INFLAMMATORY MEDIATORS: Change from baseline in serum eosinophils ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Merck Research Labratories Confirmation of methodology and data extraction received from Dr Theodore Reiss
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented with reasons for withdrawal by group and adverse effects by group, analysis wad done with intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary endpoint was described
Other bias	Low risk	No apparent other bias

Bleecker 2000.

Methods	DESIGN: Parallel‐group Confirmation of methodology obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 451 Z: 220 FP: 231 WITHDRAWALS: Z: 23 % FP: 13% AGE ( ± SD): Z: 31 (12‐66) FP: 31 (12‐68) GENDER (% male): Z: 49% FP: 52% ASTHMA SEVERITY: Not described % mean pred. FEV1: Z: 68 FP: 67 Mean ( ± SD) β2‐agonist use (puffs per day): Not reported ATOPY: Z: 43 % FP: 46% ASTHMA DURATION (years): 10 years ELIGIBILITY CRITERIA Age: >= 12 years, Persistent asthma for >= 6 months, 50‐80% pred. FEV1, Reversibility >= 12% after two puffs short‐acting β2‐agonist, Use of β2‐agonist > 2 puffs, During run‐in: use of rescue β2‐agonist >‐ 5 days or asthma symptom score >= 2 (on a 5‐point scale) on >= 3 days. EXCLUSION: AL < 2 weeks, Inhaled or systemic corticosteroids < 2 months, Life‐threatening asthma, >= 3 bursts of systemic corticosteroids in < 1 year, Tobacco < 1 year or > 10 pack‐year, Respiratory infection < 2 weeks
Interventions	PROTOCOL Duration Run‐in Period: 8‐14 days Intervention Period: 12 weeks TEST GROUP: Zafirlukast 20 mg twice a day CONTROL GROUP: Inhaled Fluticasone 100 μg twice a day DEVICE: Not described CO‐INTERVENTION: None allowed
Outcomes	ANALYSIS ( ITT ) OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS *Change from baseline FEV1 Change from baseline in morning PEF SYMPTOM SCORES: Change in mean symptom score (average/week) FUNCTIONAL STATUS: Change from baseline mean daily β2‐agonist use (puffs/day) Change in night‐time awakenings Change in symptom‐free days Change in rescue‐free days Patients with exacerbations requiring systemic corticosteroids Patients with exacerbations requiring hospital admission INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Glaxo Wellcome Confirmation of methodology and data extraction received from Gerry Hogan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation of block of 4
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported with intention‐to‐treat analysis, adverse events were reported
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

Boushey 2005.

Methods	DESIGN: Parallel‐group, randomised, placebo controlled, clinical trial
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 149 Z: 76 BD: 73 WITHDRAWALS: Z: 18.42 % BD: 7.89 % AGE (years±SD): Z: 33.6 ± 11.1 BD: 33.2 ± 9.5 GENDER (% male): Z: 38 % BD: 34 % ASTHMA SEVERITY: Not described % Pred. FEV1 (mean ± SD) Z: 88.2 ± 14.4 BD: 90.5 ± 12.6 Mean ( ± SD) β2‐agonist use (puffs/day): Not reported ATOPY: Not reported ASTHMA DURATION (years): Z: 20.9 ± 13.1 BD: 17.1 ± 11.0 ELIGIBILITY CRITERIA Age: 18‐61 years, Persistent asthma for >= 6 months, 70 percent of the predicted value of FEV1, Reversibility >= 12% with short‐acting β2‐agonist or a fall in FEV1 of at least 20 percent after inhaling a concentration of methacholine of less than 16 mg/mL (PC20; lower concentrations indicate greater reactivity). EXCLUSION: Cigarette smoking, Respiratory tract infection, Corticosteroid use in the previous six weeks, Hospitalisation or two or more visits to the emergency department for asthma in the previous year.
Interventions	PROTOCOL Duration Run‐in Period: 4 weeks Intervention Period: 52 weeks TEST GROUP: Zafirlukast 20 mg twice a day CONTROL GROUP: Inhaled Budesonide 200 μg twice a day DEVICE: Turbuhaler CO‐INTERVENTION: None allowed
Outcomes	ANALYSIS: Not reported OUTCOMES reported at 52 weeks PULMONARY FUNCTION TESTS: *Morning PEF% Morning PEF post‐PICT (%) FEV1 (%) (Pre‐bronchodilator, Post‐bronchodilator, Post‐PICT) SYMPTOM SCORES: Change in mean symptom score FUNCTIONAL STATUS Change in asthma quality of life score Change in asthma symptom‐free days Change in PC20(log2) INFLAMMATORY MEDIATORS: Change in Sputum eosinophils(%) Change in exhaled nitric oxide(%) ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by National Institute of Health
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: stratified adaptive randomisation to balance the effect of PC20, age, racial or ethnicity
Allocation concealment (selection bias)	Unclear risk	No details provided
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The withdrawal rate was unbalanced between groups: 8.2% and 18.4% in budesonide and zafirlukast group, respectively; the reasons for withdrawal are reported but not by group. There was no report of intention‐to‐treat analysis; although this was appropriate for the main outcome (time to event), it may have biased the interpretation of the some secondary outcomes
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were defined
Other bias	Low risk	No apparent other bias

Bousquet 2005.

Methods	DESIGN: Parallel‐group, randomised, clinical trial
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 645 M: 325 FP: 320 WITHDRAWALS: M: 24 (7.4%) FP: 17 (5.3)% AGE: years ± SD: M: 35.9 ± 14.3 FP: 36.6 ± 13.8 GENDER: n (% male): M: 126 (38.8%) FP: 113 (35.3%) ASTHMA SEVERITY: Mild persistent asthma as defined by Global Initiative for Asthma (GINA) guidelines ASTHMA DURATION: Not described % Pred. FEV1 ± SD M: 90.5 ± 12.2 FP: 88.2 ± 12.2 β2‐AGONIST USE (puffs per day): M: 1.28 ± 1.1 FP: 1.38 ± 1.3 ATOPY: n (%) M: 42 (12.9%) FP: 45 (14.1%) ELIGIBILITY CRITERIA Nonsmoking males and females, 15 to 80 years of age, with a history of asthma for at least 4 months, Baseline FEV1 value 80% of predicted, b2‐agonist reversibility of at least 12% (FEV1 or PEF) or a positive exercise challenge test within the previous month. Have demonstrated daytime symptoms and short‐acting b2‐agonist use on at least 2 days—but not every day—of the first week of the run‐in period. Patients were to be in need of, but not on, controller medication, and at the time of enrolment could only be taking b‐agonists. EXCLUSION: Treated in an emergency department within 1 month, Hospitalized for asthma within 3 months, or having unresolved symptoms, Signs of upper respiratory tract infection within 3 weeks, On corticosteroids within 1 month; cromolyn, nedocromil, or leukotriene‐receptor antagonists within 2 weeks; theophylline, oral or long‐acting b‐agonists, or inhaled anticholinergics within 1 week; or terfenadine, fexofenadine, loratadine, or cetirizine within 48 hours of the first visit. On immunotherapy within 6 months; however, a patient taking immunotherapy longer than 6 months prior to entry were allowed to be included if dosage was consistent throughout the duration of the study.
Interventions	PROTOCOL Duration Run‐in Period: 3 weeks Intervention Period: 12 weeks TEST GROUP: Montelukast 10 mg per day CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Metered dose inhaler (MDI)
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS FEV1 (L, % change) FEV1 (% of predicted) AM PEF (L/min) SYMPTOM SCORES: Days with symptoms (%) FUNCTIONAL STATUS *Asthma‐free days (%) “As needed” b‐agonist use Days with b‐agonist use (%) Exacerbations requiring ED visits Days with b‐agonist use (%) Asthma rescue medication‐free days (%) Asthma rescue medication‐free days with normal lung function (%) Nocturnal awakenings (%) Asthma specific Quality of life score INFLAMMATORY MEDIATORS: Eosinophil count (103/μL) ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Merck & Co., Inc. Confirmation of methodology and data extraction: not obtained USER‐DEFINED ORDER:
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented; intention‐to‐treat analysis, reasons for withdrawal by group and adverse effects by group presented,
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were defined
Other bias	Low risk	No apparent other bias

Brabson 2002.

Methods	DESIGN: Parallel‐group, multi‐centre , randomised, double‐blind, double‐dummy, clinical trial Confirmation of methodology not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 440 Z: 216 FP: 224 WITHDRAWALS: Z: 45 (21%) FP: 17 (8)% AGE (± SD): Z: 35 (± 16) FP: 36 (± 14) GENDER (% male): Z: 75 (35%) FP: 90 (40%) ASTHMA SEVERITY: Not described ASTHMA DURATION: Not described % Pred. FEV1 (± SD): Z: 73 ± 7 FP: 73 ± 7 MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported DOSE OF inhaled corticosteroids AT STUDT ENTRY AND AT RUN‐IN: BDP 256 ± 80ug/d T 600 ± 213ug/d BDP271 ± 73 μg/d T 603 ± 169 μg/d ATOPY: Not described ELIGIBILITY CRITERIA Age: >= 12 years, Asthma, Low‐dose inhaled corticosteroids (excluding Fluticasone, Flunisolide) at least 8 weeks ‐60 and 85 % pred FEV1 at screening and prior to randomisation EXCLUSION: During run‐in >4 puffs of albuterol/day >1 night‐time awakening during 7 days before randomisation At screening: Any oral or parenteral corticosteroids within 6 weeks > 1 burst of oral corticosteroids within 6 months Inhaled fluticasone or flunisolide within 4 weeks Leukotriene modifiers within 1 week
Interventions	PROTOCOL Duration Run‐in Period: 8 days Intervention Period: 6 weeks TEST GROUP: Zafirlukast 20 mg twice daily CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Metered‐dose inhaler CRITERIA FOR WITHDRAWAL FROM STUDY > 20 % decrease in baseline FEV1 > 3 days with > 12 puffs of rescue albuterol > 4 days where PF decreased by >= 20% of baseline > 3 nights with awakenings due to asthma
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 6 weeks PULMONARY FUNCTION TESTS: *Change from baseline FEV1 (L) Change from baseline in morning PEF (L/s) Change from baseline in evening PEF(L/s) SYMPTOM SCORES: Change in symptom‐free days (%) Change in mean symptom score (6‐point) FUNCTIONAL STATUS: Change from baseline in use of rescue β2‐agonist use (puffs/day) Change in rescue free days (%) Exacerbations requiring systemic corticosteroids Exacerbations requiring ED visits Change in nights with uninterrupted sleep Physician‐rated global assessment of Rx effectiveness INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Glaxo SmithKline Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Details were not provided
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported including side effects; withdrawal rate with reasons by group
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

Busse 2001a.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial Confirmation of methodology obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 338 Z: 111 FP: 113 Placebo (not used):114 WITHDRAWALS: Z: 19% FP: 14% AGE (± SD): 12‐75 years Z: 33.8 ± 13.1 FP: 29.6 ± 11.4 GENDER (% male): 50% Z: 41 % FP: 58% ASTHMA SEVERITY: % moderate: Z: 82% FP: 77% % Pred. FEV1 (mean ± SD): 66‐67% Z: 69.1 ± 7.5 FP: 68.1 ± 8.3 Mean (± SD) β2‐agonist use (puffs/day) Z: 4.7 (SE 0.27) FP: 4.8 (SE:0.26) ATOPY: Z: 42% FP: 23% ASTHMA DURATION (years): at least 10 years Z:69% FP: 65% ELIGIBILITY CRITERIA Age: >= 12 years, Regular use of short‐acting β2‐agonist for at least 6 weeks, 50‐80% pred. FEV1, Reversibility >= 12% after two puffs short‐acting β2‐agonist EXCLUSION: Life‐threatening asthma, Use of tobacco within 1 year or smoking history of > 10 packs‐year, Systemic corticosteroids within 6 months, Inhaled corticosteroids < 1 month, Use of leukotriene modifier < 1 week
Interventions	PROTOCOL Duration Run‐in Period: 8‐14 days to establish baseline respiratory function Intervention Period: 12 weeks TEST GROUP: Zafirlukast 20 mg twice a day po CONTROL GROUP: Inhaled Fluticasone 100 μg twice a day (2 puffs of 50 μg twice a day) DEVICE: Metered dose inhaler (no spacer) CO‐INTERVENTION: None allowed other than rescue β2‐agonist and systemic corticosteroids
Outcomes	ANALYSIS ( ITT ) OUTCOMES reported at 6 and 12 weeks (also documented at 2, 4, 8 weeks) PULMONARY FUNCTION TESTS: *Change from baseline FEV1 Change from baseline in morning and evening PEF SYMPTOM SCORES: Weekly average symptom score (6‐point scale) FUNCTIONAL STATUS: Change from baseline mean daily β2‐agonist use, averaged over 1 week (puffs/day) Change in night‐time awakenings (waking/nights) averaged over 1 week Change in symptom‐free days Change in rescue‐free days Change in QoL (Juniper) Work or school loss days Patients with exacerbations requiring systemic corticosteroids Patients with exacerbations requiring hospital admission Patient satisfaction Physicians rated effectiveness INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Glaxo Wellcome Confirmation of methodology and data extraction obtained from Shailesh Patel and Rob Pearson, Nov 2, 2001
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated in block of 6
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

Busse 2001b.

Methods	DESIGN: Parallel‐group, randomised, clinical trial Confirmation of methodology obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 533 M: 262 FP: 271 WITHDRAWALS: M: 29% FP: 28% AGE (± SD) years: M: 34.4 (15‐67) FP: 35.4 (15‐83) GENDER (% male): M: 42 % FP: 47% ASTHMA SEVERITY: not described % Pred. FEV1 (mean ± SD): M: 65.4 ± 8.2 FP: 65.6 ± 9.2 Mean (± SD) β2‐agonist use (puffs/day): Not reported ATOPY: Not reported ASTHMA DURATION (years): Not reported ELIGIBILITY CRITERIA: Age: >= 15 years, Persistent asthma for >= 6 months, 50‐80% pred. FEV1, Reversibility >= 15% after two puffs short‐acting β2‐agonist, Regular use of β2‐agonist > 3 months, During run‐in: use of rescue β2‐agonist >‐ 6 of 7 days and asthma symptom score >= 2 (on a 5‐point scale) on >= 4 of 7 days. EXCLUSION: Inhaled corticosteroids < 2 months, Tobacco use < 1 year or >10 pack‐year, Hospital admission for asthma in <3 months, Respiratory infection < 4 weeks
Interventions	PROTOCOL Duration Run‐in Period: 8‐14 days Intervention Period: 24 weeks TEST GROUP: Montelukat 10 mg per day CONTROL GROUP: Inhaled Fluticasone 100 μg twice a day DEVICE: Metered dose inhaler CO‐INTERVENTION: None allowed
Outcomes	ANALYSIS ( ITT ) OUTCOMES reported at 4, 8, 12, 16, 24 weeks PULMONARY FUNCTION TESTS: *Change from baseline FEV1 (L and %) Change from baseline PEF (L/min) SYMPTOM SCORES: Change in mean symptom score/week (6‐point scale) FUNCTIONAL STATUS Change from baseline mean daily β2‐agonist use (puffs/day) Change in night‐time awakenings Change in % symptom‐free days Change in % rescue‐free days Change in qol (Juniper) Days off work or school Exacerbations requiring systemic corticosteroids Exacerbations requiring hospital admission INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Glaxo Wellcome Confirmation of methodology and data extraction and additional unpublished data obtained from and Shailesh Patel and Rob Pearson
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated in block of 4
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented including reasons for withdrawals and adverse effects, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were defined
Other bias	Low risk	No apparent other bias

Caffey 2005.

Methods	DESIGN: Three‐way cross‐over, placebo controlled, randomised, clinical trial
Participants	MILD TO MODREATE PERSISTENT ASTHMA MEETING NAEPP CRITERIAS RANDOMISED: N = 24 WITHDRAWALS: 16.67% AGE: years(range): 8.92 (5‐12) GENDER (% male): Not reported ASTHMA SEVERITY: Mild to moderate as per NAEPP criteria % Pred. FEV1: mean(range)%: 88 (47‐111) % ATOPY: Not reported ASTHMA DURATION (years): Not reported ELIGIBILITY CRITERIA: Age: 5‐12 years, Mild to moderate persistent asthma meeting NAEPP criteria diagnosed by physician, Clinically stable on only one long‐term controller drug, Who were capable of performing spirometry EXCLUSION: Any known hypersensitivity to any study medication, Inability to meet study requirements, Chronic respiratory disease other than asthma, Current or past history of smoking, Use of systemic corticosteroids within 1 month of the run‐in period, Acute viral respiratory infection within 3 weeks of the run‐in period, Use of two long‐term controller medications for control of asthma, Severe asthma as defined by NAEPP, known renal or adrenal disease
Interventions	PROTOCOL Duration Run‐in Period: 2 weeks Intervention Period: 4 weeks TEST GROUP: Montelukat 10 mg qd CONTROL GROUP: Inhaled Fluticasone 50 μg twice a day DEVICE: Aerochamber CO‐INTERVENTION: None allowed
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 2, 4 weeks PULMONARY FUNCTION TESTS: *FEV1 (L/s) AM and PM PEF (L/min; data not presented as there was no difference between groups) SYMPTOM SCORES: Daily PM asthma symptom score (6‐point scale) FUNCTIONAL STATUS: Mean daily β2‐agonist use (puffs/day) Exacerbations requiring systemic corticosteroids INFLAMMATORY MEDIATORS: *Fractional exhaled nitric oxide (FeNO) ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full‐text publication Funded by GlaxoSmithKline and by National Health Institute
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, reasons for withdrawal by group and adverse effects by group presented, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were described
Other bias	Low risk	No apparent other bias

Dempsey 2002a.

Methods	DESIGN: Cross‐over, randomised, clinical trial Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 21 WITHDRAWALS: Not mentioned AGE (years): N = 33.5 GENDER (% male): Not mentioned ASTHMA SEVERITY: Mild persistent atopic asthma ASTHMA DURATION: Not described % Pred. FEV1: N = 96.3% MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported DOSE OF inhaled corticosteroids AT STUDY ENTRY AND AT RUN‐IN: Not mentioned ATOPY: Not described ELIGIBILITY CRITERIA: Mild persistent asthma EXCLUSION: Not mentioned
Interventions	PROTOCOL Duration Run‐in Period: 1‐2 weeks Intervention Period: 4 weeks CONTROL GROUP: Hfa‐triamcinolone acetonide 450 μg od TEST GROUP: Montelukast 10 mg od DEVICE: Not mentioned Criteria for withdrawal from study: Not mentioned
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: *Change from baseline FEV1 Change from baseline in morning PEF Change from baseline in evening PEF SYMPTOM SCORES: Change in mean symptoms FUNCTIONAL STATUS: Change from baseline in night‐time use of rescue β2‐agonist use (puffs/day) INFLAMMATORY MEDIATORS Change from baseline in blood eosinophils Change from baseline in exhaled NO ADVERSE EVENTS: Not reported WITHDRAWALS: Not reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	112.5 μg
Notes	Abs 2001 Funding not mentioned Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Single blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

FLTA4030.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	PARTICIPANTS WHO ARE RECEIVING β2‐AGONISTS ALONE RANDOMISED: N = 209 Z: 108 FP: 101 WITHDRAWALS: Z: 9 (8%) FP: 8 (8)% AGE (± SD): Z: 33.5 (± 12.8) FP: 32.9 (± 12.7) GENDER (% male): Z: 40.74% FP: 42.57% ASTHMA SEVERITY: Not described ASTHMA DURATION: Not described % Pred. FEV1 (±SD): Not described MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported DOSE OF INHALED CORTICOSTEROIDS AT STUDT ENTRY AND AT RUN‐IN: Not described ATOPY: Not described ELIGIBILITY CRITERIA Age: ≥12 years, Asthma consistent with American Thoracic Society definition FEV1: 50 and 85 % of pred With at least 12% reversibility with albuterol MDI Medica history of using short‐acting β2‐agonists at least for 3 months EXCLUSION: Not described
Interventions	PROTOCOL Duration Run‐in Period: 1‐2 weeks Intervention Period: 12 weeks CONTROL GROUP: Fluticasone propionate 88 μg twice a day TEST GROUP: Zafirlukast 20 mg twice a day DEVICE: Metered dose inhaler Criteria for withdrawal from study: Reported
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS: *Morning pre‐medication FEV1 AM and PM peak expiratory volume in one second SYMPTOM SCORES: Asthma symptoms score, Percent symptom free days, FUNCTIONAL STATUS: Albuterol MDI use, Percent rescue‐free days, Night‐time awakenings due to asthma, Duration of asthma stability, Physician global assessments. INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200
Notes	Funding not reported but trials conducted by pharmaceutical company Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

FLTA4031.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	PARTICIPANTS WHO ARE RECEIVING β2‐AGONISTS ALONE RANDOMISED: N = 224 Z: 111 FP: 113 WITHDRAWALS: Z: 21 (19%) FP: 16 (14%) AGE (± SD): Z: 33.8 (± 13.1) FP: 29.6 (±11.4) GENDER (% male): Z: 40.54% FP: 58.41% ASTHMA SEVERITY: Not described ASTHMA DURATION: Not described FEV1 (± SD): Z: 2.41 (± 0.63) FP: 2.52 (± 0.53) MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported DOSE OF INHALED CORTICOSTEROIDS AT STUDT ENTRY AND AT RUN‐IN: Not described ATOPY: Not described ELIGIBILITY CRITERIA: Age: ≥12 years, Asthma consistent with American Thoracic Society definition FEV1: 50 and 85 % of pred With at least 12% reversibility with albuterol MDI Medica history of using short‐acting β2‐agonists at least for 3 months EXCLUSION: Not described
Interventions	PROTOCOL Duration Run‐in Period: 1‐2 weeks Intervention Period: 12 weeks CONTROL GROUP: Fluticasone propionate 88 μg twice a day TEST GROUP: Zafirlukast 20 mg twice a day DEVICE: Metered dose inhaler Criteria for withdrawal from study: Reported
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 1, 2, 4, 6, 8, 12 weeks PULMONARY FUNCTION TESTS: *Morning pre‐medication FEV1 AM and PM peak expiratory volume in one second SYMPTOM SCORES: Asthma symptoms score, Percent symptom free days, FUNCTIONAL STATUS: Albuterol MDI use, Percent rescue‐free days, Night‐time awakenings due to asthma, Duration of asthma stability, Physician global assessments. INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200
Notes	Funding not reported but trials conducted by pharmaceutical company Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

FMS40012.

Methods	DESIGN: Randomised clinical study
Participants	PARTICIPANTS WITH MILD ASTHMA RANDOMISED: N = 16 Z: 8 FP: 8 WITHDRAWALS: Z: 1 (13%) FP: 0 (0%) AGE (± SD): Z: 26.3 (± 4.5) FP: 31.8 (± 12.2) GENDER (% male): Z: 87.5% FP: 62.5% ASTHMA SEVERITY: Not described ASTHMA DURATION: Not described FEV1 (± SD): Z: 4.06 (± 1.0) FP: 3.54 (± 0.94) MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported DOSE OF INHALED CORTICOSTEROIDS AT STUDT ENTRY AND AT RUN‐IN: Not described ATOPY: Described ELIGIBILITY CRITERIA: Atopic participants aged: 18‐50 years, Willing to undergo repeated sputum induction procedure, Non‐smoker, With clinical history of asthma EXCLUSION: Received corticosteroid therapy, With respiratory infection in the month prior to entering the study Experienced exacerbation in the three months prior to enrolment, History of life‐threatening asthma, Undergone major surgery within six months prior to study Received an investigational drug within a month of entry Had a positive drug or alcohol screen, Had clinically significant history of hepatic, renal, haematological, bleeding, cardiac, endocrine, gastrointestinal, metabolic, muscle or neurological diseases, tremors or seizure, Had donated blood within 30 days, Received warfarin, antihistamines at the time of enrolment.
Interventions	PROTOCOL Duration Run‐in Period: not reported Intervention Period: 4 weeks CONTROL GROUP: Fluticasone propionate 50 μg twice a day TEST GROUP: Zafirlukast 20 mg twice a day DEVICE: Metered dose inhaler Criteria for withdrawal from study: Reported
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 1, 4 weeks PULMONARY FUNCTION TESTS: FEV1 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not reported. INFLAMMATORY MEDIATORS: *Change in percentage of sputum eosinophils Change in total eosinophils Change in ECP in sputum Change in histamine PC20 ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	100
Notes	Funding not reported but trials conducted by pharmaceutical company Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

FPD40013.

Methods	DESIGN: Parallel‐group, multi centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	PARTICIPANTS WITH PERSISTENT ASTHMA RANDOMISED: N = 341 MON: 168 FP: 173 WITHDRAWALS: MON: 28 (17%) FP: 27 (16%) AGE (± SD): MON: 9.4 (± 1.9) FP: 9.5 (± 1.9) GENDER (% male): MON: 60.71% FP: 58.96% ASTHMA SEVERITY: Not described ASTHMA DURATION: Not described % Pred. FEV1 (± SD): MON: 75.7 (± 7.0) FP: 76.1 (± 6.6) MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported DOSE OF INHALED CORTICOSTEROIDS AT STUDT ENTRY AND AT RUN‐IN: Not described ATOPY: Not described ELIGIBILITY CRITERIA: Aged 6‐12 years, Clinically diagnosed asthma for at least 6 months, FEV1 60‐85%, EXCLUSION: Life‐threatening asthma, Hospitalized for asthma within 3 months of visit 1, Any other significant disease.
Interventions	PROTOCOL Duration Run‐in Period: Not reported Intervention Period: 12 weeks CONTROL GROUP: Fluticasone propionate 50 μg twice a day TEST GROUP: Montelukast 5 mg QD DEVICE: Diskus Criteria for withdrawal from study: Reported
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS: *Percen change from baseline in morning pre‐dose FEV1 (L), Change from baseline in morning PEFR SYMPTOM SCORES: Change from baseline in percent of symptom‐free days FUNCTIONAL STATUS: Change from baseline in total albuterol use INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	100
Notes	Funding not reported but trials conducted by pharmaceutical company Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

Garcia Garcia 2005.

Methods	DESIGN: Parellel‐group, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 994 M: 495 FP: 499 WITHDRAWALS: M:7.3% FP:6.6% AGE: years (range): M: 9 (6‐14) FP: 9 (5‐15) GENDER (% male): M: 64.8% FP: 58.5% ASTHMA SEVERITY: Mild persistent asthma at step 2 of GINA guidelines % Pred. FEV1 ± range: M: 86.8 (34.2‐129.0) FP: 87.7(51.8‐12.5‐0) β2‐agonist use (puffs per day): median (range) M: 5(0.0‐77.9) FP: 4.8 (0.0‐78.3) ATOPY: Not reported ASTHMA DURATION: (years): Not reported HISTORY OF ALLERGY:(%) M: 61.4 FP: 61.9 ELIGIBILITY CRITERIA: Age: 6‐14 years, With a clinical history of mild asthma at step of the GINA guidelines of 12 months, FEV1 of 80% of the predicted value (pre bronchodilator measurement),while ‐receptor agonist was withheld for 6 hours, at least twice in the run‐in period, Diagnosis of mild asthma was defined on the basis of (1) an increase in FEV1 or peak expiratory flow rate of 12% (absolute value), 20 to 30 minutes after inhaled ‐receptor agonist administration, at visits 1, 2, or 3; (2) a positive methacholine or histamine provocative concentration causing a 20% decrease in FEV1 of 8 mg/mL; or (3) a decrease in FEV1 of 15% after an exercise challenge. Had to demonstrate symptoms requiring β2‐receptor agonist use on 2 and 6 days of the week for the 2 weeks before visit 3, Had to be in good general health except for asthma, as indicated by medical history, physical examination, and routine laboratory data. EXCLUSION: Not reported
Interventions	PROTOCOL Duration Run‐in Period: 4 weeks Intervention Period: 52 weeks CONTROL GROUP: Fluticasone 100 μg twice a day TEST GROUP: Montelukast 5‐mg oral tablet [10 mg if the patient turned 15 years of age during the study], once at bedtime DEVICE: Metered dose inhaler Criteria for withdrawal from study: Described
Outcomes	ANALYSIS ( ITT ) OUTCOMES reported at 52 weeks PULMONARY FUNCTION TESTS: Change from baseline FEV1 (L and %) SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: *Percentage of rescue free days (i.e.. ‐receptor agonists, systemic corticosteroids, or other asthma rescue medications), *Pecentage of asthma‐related health resource utilization (i.e.. an unscheduled visit to a physician, urgent/emergency care, or hospitalizations), Percentage of patients requiring anti‐asthma medications other than ‐receptor agonist, Percentage of patients with an asthma attack (defined as any period with worsening asthma that required an unscheduled visit to the doctor’s office, emergency department, or hospital for treatment of asthma or treatment with systemic corticosteroids, as recorded on the diary cards), Percentage of days with ‐receptor agonist use, Quality of life questionnaire (7‐point scale), Exacerbations requiring hospital admission, Asthma control, Asthma‐related patient school loss, Parental work loss INFLAMMATORY MEDIATORS: Peripheral blood eosinophils level ADVERSE EVENTS: Described WITHDRAWALS: Described * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Merck and Co.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: electronically generated randomisation using blocking factor of 4
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, reasons for withdrawal by group and adverse effects by group presented, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary, secondary and tertiary outcomes were described
Other bias	Low risk	No apparent other bias

Hughes 1999 (BDP).

Methods	DESIGN: Parallel‐group, clinical trial. Confirmation of methodology obtained (08/01)
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 71 M: 25 FP: 23 BDP: 23 WITHDRAWALS: M: 0 (0%) FP: 1 (4%) BDP:0 (0%) AGE (± SD): M: 29.0 ± 11.7 FP: 30.7 ± 10.7 BDP: 31.6 ± 9.6 GENDER (% male): M: 39% FP:60% BDP: 64% ASTHMA SEVERITY: Mild % Pred. FEV1 % ± SD: M: 83.0 ± 11.7 FP:85.3 ± 10.7 BDP:84.9 ± 11.0 Mean (± SD) β2‐agonist use (puffs/day): M: 1.2 ± 1.0 FP: 1.4 ± 1.5 BDP: 1.2 ± 1.5 ATOPY or ALLERGIC RHINITIS: M:84% FP:96% BUD:78% ELIGIBILITY CRITERIA: Age>= 15 years old, Recruited from managed care affiliated sites, 6‐month history of asthma, FEV1 % Pred >= 70, Airway reversibility >= 12% twice, β2‐agonist use 1‐6 days/wk, FEV1/FVC < 80% if FEV1 reversibility 10‐12%, Non or ex‐smoker (< 15 pack years), No pregnancy or on birth control for women EXCLUSION CRITERIA: < 15 years, Known intolerance to study medications, Unable to perform spirometry, Within 2 weeks of run‐in and prior to randomisation: any exacerbation requiring unscheduled visit to MD, emergent or urgent care visit, hospital admission or rescue oral corticosteroids, Intake of oral or inhaled corticosteroids, nedocromil, cromolyn, salmeterol, theophylline within 1 week of study entry
Interventions	PROTOCOL Duration Run‐in Period: 2 weeks Intervention Period: 4 weeks TEST GROUP: Montelukast 10 mg CONTROL GROUP 1: Fluticasone 100 μg twice a day CONTROL GROUP 2: Budesonide 200 μg twice a day DEVICE: Aerosol inhaler for Fluticasone and Dry powder inhaler for Budesonide CO‐INTERVENTION: None allowed other than rescue B2‐agonist and systemic corticosteroids
Outcomes	ANALYSIS ( ITT) (if received at least one study medication) OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: Change from baseline FEV1 (L) Change from baseline in PEFR (L/min) SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: % Change from baseline median daily β2‐agonist use (puffs/day) *Change from baseline in percentage of "rescue‐free" days (no unscheduled office visit, ER, or hospitalizations) INFLAMMATORY MEDIATORS: Change from baseline in serum eosinophils ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Abstract & Poster (1999) Funded by Merck Letter, meth sent to Hughes December 1999 Confirmation of methodology, data extraction and additional data provided by Merck Laboratories.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Low risk	Allocation by opaque consecutive numbered envelopes containing assignment
Blinding (performance bias and detection bias) All outcomes	High risk	Open label
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, withdrawal and adverse effects, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary outcome was described
Other bias	Low risk	No apparent other bias

Hughes 1999 (FP).

Methods	as above
Participants	as above
Interventions	as above
Outcomes	as above
ICS dose in HFA beclomethasone ‐ equivalent	as above
Notes	as above
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Low risk	Allocation by opaque consecutive numbered envelopes containing assignment
Blinding (performance bias and detection bias) All outcomes	High risk	Open label
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, withdrawal and adverse effects, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary outcome was described
Other bias	Low risk	No apparent other bias

Israel 2002.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 782 M = 339 BDP = 332 Placebo = 111 WITHDRAWALS: n (%) M: 11 (3.2%) BDP: 14 (4.2%) Placebo: 5(4.5%) AGE: years (range): M = 33.5 (15‐71) BDP = 33.9 (15‐74) placebo = 33.3 (15‐64) GENDER: n (% male) M = 162 (47.8%) BDP = 156 (47%) Placebo = 54 (48.7%) ASTHMA SEVERITY: Not mentioned ASTHMA DURATION: Not mentioned % PRED. FEV1% ±SD: M = 67.4 ± 11.1 BDP = 65.9 ± 11.7 P = 66.8 ± 12.3 MEAN (± SD) β2‐AGONIST USE (puffs/day): M = 5.6 ± 2.9 BDP = 5.8 ± 2.9 Placebo=5.7 ± 2.6 DOSE OF inhaled corticosteroids AT STUDY ENTRY AND DURING RUN‐IN: Not reported ATOPY: Not described ELIGIBILITY CRITERIA: >= 15 years, >= 1 year history of clinical symptoms of asthma, Use of only B‐agonist for asthma treatment, FEV1 between 50%‐80%, >= 15% increase in FEV1 after albuterol use, > 2 puffs per day during run‐in, Non‐smokers for at least 1 year with smoking history of no more than 7 packs‐year EXCLUSION Inhaled corticosteroids for 2 weeks prior to 1st visit, URTI within 3 weeks, ER visit for asthma within 1 month, Hospitalization for asthma in past 3 months, Systemic corticosteroids for 1 month before 1st visit
Interventions	PROTOCOL DURATION Run‐in: 2 weeks Intervention: 6 weeks TEST GROUP: Montelukast: 10 mg once daily CONTROL GROUP 1: BDP: 200 μg twice a day CONTROL GROUP 2: Placebo DEVICE: MDI + spacer CRITERIA FOR WITHDRAWAL FROM STUDY: Not described CO‐INTERVENTION: Short‐acting anti‐histamines
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 6 weeks PULMINARY FUNCTION TESTS *Change from baseline FEV1 SYMPTOM SCORES: % of days with asthma control FUNCTIONAL STATUS Change from baseline in use of β2‐agonist(puffs/day) Asthma exacerbations Rescue corticosteroid use (%) % Asthma controlled days defined as a day with <= 2 puffs of albuterol, no night‐time awakenings, and no asthma attacks INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported *primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Merck Confirmation of methodology and data extraction not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: blinded allocation schedule produced by the study sponsor
Allocation concealment (selection bias)	Low risk	A block of allocation numbers that were assigned sequentially to consecutively randomised patients
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, withdrawal rate per group was mentioned
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were specified
Other bias	Low risk	No apparent other bias

Jayaram 2002.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 50 M = 19 FP = 18 WITHDRAWALS: Not mentioned AGE (years): Not mentioned GENDER (% female): Not mentioned ASTHMA SEVERITY: Not described ASTHMA DURATION: Not mentioned % PRED. FEV1% ± SD: Not mentioned MEAN ± SD β2‐AGONIST USE (puffs/day): Not mentioned DOSE OF inhaled corticosteroids AT STUDY ENTRY AND DURING RUN‐IN: Not reported ATOPY: Not described ELIGIBILITY CRITERIA: Corticosteroid‐naive asthma Sputum eosinophils (Eo) count of > 3.5% EXCLUSION± Not mentioned
Interventions	PROTOCOL DURATION Run‐in: Not mentioned Intervention: 8 weeks TEST GROUP: Montelukast (dose un‐specified: probably 10 mg per day) CONTROL GROUP 1: Fluticasone (dose un‐specified) DEVICE: Not described CRITERIA FOR WITHDRAWAL FROM STUDY: Not described
Outcomes	ANALYSIS (ITT not specified) OUTCOMES ‐reported at 8 weeks Report outcomes are reported as pre‐ and post‐values (not change from baseline) PULMINARY FUNCTION TESTS FEV1 Morning PEFR (L/min) Evening PEFR (L/min) SYMPTOM SCORES: Change in symptoms FUNCTIONAL STATUS: Change from baseline in use of β2‐agonist INFLAMMATORY MEDULATOR: *Change in sputum Eo (%) ADVERSE EVENTS: Not reported WITHDRAWALS: Not reported *primary outcomes
ICS dose in HFA beclomethasone ‐ equivalent	Not reported
Notes	Abstract 2002 Funding not mentioned Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

Jayaram 2005.

Methods	DESIGN: Parallel‐group, randomised, multicentric, placebo controlled, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED N = 37 M:19 FP:18 WITHDRAWALS: N (%) M: 1 (5.26%) FP: 1 (5.56%) AGE: years ± SD M: 31.4 ± 9.9 FP: 35.4 ± 13.9 GENDER: N (% male) M: 8 (42.11) FP:8 (44.44) ASTHMA SEVERITY: Persistent symptomatic asthma % Pred. FEV1 % (± SD) M: 76.7 (15.9) FP: 72.0 (16.0) β2‐agonist use (puffs per day) Mean (± SD): M: 3.3 (3.1) FP: 3.3 (2.6) ATOPY: M:84.21% FP:88.89% ELIGIBILITY CRITERIA: Adult with persistent symptomatic asthma who had only taken a short acting bronchodilator for at least 2 months, Asthma was diagnosed by NAEPP criteriaS or by AHR to methacholine with a PC20 of 8 mg/ml if the FEV1/SVC was 70%, No symptoms of a cold or flu during the month before the start of the study, Eosinophilia > 3.5 in induced sputum samples.
Interventions	PROTOCOL DURATION Run‐in: not mentioned Intervention: 8 weeks TEST GROUP: Montelukast (10 mg qd) CONTROL GROUP: Fluticasone (250 μg per day) DEVICE: Not described CRITERIA FOR WITHDRAWAL FROM STUDY: Not described
Outcomes	ANALYSIS: (ITT not specified) OUTCOMES Reported at 8 weeks Report outcomes are reported as pre‐ and post‐values and graph of change in values PULMINARY FUNCTION TESTS FEV1(L) Morning and evening PEFR (L/min) measured but not presented SYMPTOM SCORES: Change in symptoms (5‐35 score) FUNCTIONAL STATUS: Pre and post use of β2‐agonist INFLAMMATORY MEDULATOR: *Change in sputum Eosinophils (%) ADVERSE EVENTS: Reported WITHDRAWALS: Reported *primary outcomes
ICS dose in HFA beclomethasone ‐ equivalent	250 μg
Notes	Full‐text publication Funded by Glaxo Wellcome Inc;
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	High risk	Data on symptom severity, methacholine tests, PEF, skin prick test were mentioned in methodology but not described in results
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were defined
Other bias	Low risk	No apparent other bias

Jenkins 2005.

Methods	DESIGN: Cross‐over, active controlled, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 58 WITHDRAWALS: n(%): 4 (6.90) AGE: years (range): N = 38.5 (16–70) GENDER (% male): 60.35 ASTHMA SEVERITY: Mild to moderate asthma ASTHMA DURATION: Not described % Pred. FEV1: mean±SD: N = 76.1 ± 11.9 β2‐AGONIST USE: puffs per day (range): 3.0 (1.0–5.5) ATOPY: 93% ELIGIBILITY CRITERIA: Age: 16‐75 years, Previous use of a short‐acting b2‐agonist with/without an inhaled corticosteroids equal or more than 500 beclomethasone equivalent FEV1 of 50–90% of predicted and/or a ratio of FEV1/FVC equal or less than 70%, Reversible airway obstruction (FEV1 increase equal or more than 15% pred or 200 mL after 200 salbutamol) within 6 months, Asthma symptoms or short acting β2‐agonist use equal or more than 4 days/week, Moderate airway hyper responsiveness (AHR), defined as the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) equal or less than 2 mmol at the end of a run‐in period EXCLUSION CIRTERIA: Current smoking or smoking history 10 pack–yrs. Coexisting lung disease, recent asthma exacerbation or respiratory infectionNot mentioned, Current smoking or smoking history equal or more than 10 pack‐yrs
Interventions	PROTOCOL DURATION Run‐in: 2 weeks Intervention: 6 weeks TEST GROUP: Montelukast (over‐encapsulated montelukast 10 mg tablet q.d.) CONTROL GROUP: Fluticasone propionate (Accuhaler/Diskus 250 mg twice a day) DEVICE: (Accuhaler/Diskus) CRITERIA FOR WITHDRAWAL FROM STUDY: Described
Outcomes	ANALYSIS: (ITT) OUTCOMES Reported at 6 weeks Report outcomes are reported as pre‐ and post‐values PULMINARY FUNCTION TESTS: FEV1(L), *PEF PD20 methacholine mmol SYMPTOM SCORES: *Change in symptoms (1‐6 score) FUNCTIONAL STATUS: Day symptom score, Night symptom score, Symptom‐free days, Waking‐free nights, Day salbutamol use, puffs/day, Night salbutamol use, puffs/day, Total QoL score, Global assessment of asthma control, INFLAMMATORY MEDULATOR: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported *primary outcomes
ICS dose in HFA beclomethasone ‐ equivalent	500 μg
Notes	Full‐text publication Funding: Not reported;
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, intention‐to‐treat analysis,reasons for withdrawal by group and adverse effects by group described
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were defined
Other bias	Low risk	No apparent other bias

Kanazawa 2007.

Methods	DESIGN: Parallel‐group, active and placebo controlled, clinical trial.
Participants	ASTHMA PATIENTS RANDOMISED: N = 30 M: 15 FP: 15 WITHDRAWALS: Not reported AGE: years ± SD M: 34.9 ± 5.5 FP: 36.1 ± 6.4 GENDER: % male M: 80% FP: 80% ASTHMA SEVERITY: Not mentioned % Pred. FEV1 % (± SD) M: 91.0 (± 5) FP: 90 (± 3) β2‐agonist use (puffs/day) Mean (± SD): Not reported ATOPY: Not reported Exhaled NO, parts per billion (± SD) M: 12.5 (4.8) FP: 13.4 (3.9) SPUTUM EOSINOPHILS, % (± SD) M: 11.0 (2.8) FP: 12.1 (3.9) SPUTUM ECP, ng/mL (± SD) M: 470 (170) FP: 500 (170) ELIGIBILITY CRITERIA: Asthmatic patients on short‐acting 2‐agonists on demand, No patients were receiving oral or inhaled corticosteroids, Clincally stable and none had a history of respiratory infection for at least the 4‐week period preceding the study.
Interventions	PROTOCOL DURATION Run‐in: 2 weeks Intervention: 12 weeks TEST GROUP: Montelukast capsule (10 mg at night) CONTROL GROUP: Fluticasone propionate (200 μg twice a day) DEVICE: Not mentioned CRITERIA FOR WITHDRAWAL FROM STUDY: Not mentioned
Outcomes	ANALYSIS: (ITT not mentioned) OUTCOMES Reported at 12 weeks Outcomes are reported as pre‐ and post‐values PULMINARY FUNCTION TESTS: FEV1(L), FEV1/FVC, % PD20 methacholine, mg/mL SYMPTOM SCORES: Not reported FUNCTIONAL STATUS AND INFLAMMATORY MEDULATOR: Exhaled Nitric oxide, Eosinophil cationic protein (ECP), VEGF, Angiopoietin‐1, Aangiopoietin‐2, Albumin, ADVERSE EVENTS: Not reported WITHDRAWALS: Not reported
ICS dose in HFA beclomethasone ‐ equivalent	400 μg
Notes	Full‐text publication Funding: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined but no bias is observed
Other bias	Low risk	No apparent other bias

Kanniess 2002.

Methods	DESIGN: Cross‐over, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 40 WITHDRAWALS: Not reported AGE mean years (range): 37 (18‐60) GENDER: 24 male (60%) ASTHMA SEVERITY: Moderate allergic bronchial asthma FEV1 % pred (Mean ±SD): 74.2 (10.6) MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported ATOPY: 100% of patients ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: FEV1 within 15% at screening value 20% fall in FEV1(PC20) Atopic patients according to skin‐prick test Bronchodilator effect of > 15% after 200μg of salbutamol EXCLUSION: Smokers Acute exacerbation or respiratory tract infection within 4 weeks before each visit Inhaled corticosteroids within 3 months Systemic corticosteroids within 6 months Antihistamines or theophylline within 4 weeks
Interventions	PROTOCOL DURATION Run‐in: 1‐2 weeks Treatment: 4 weeks Wash‐out: 3‐8 weeks TEST GROUP: Fluticasone 100 μg twice a day CONTROL GROUP: Montelukast 10 mg at night‐time DEVICE: Diskus CRITERIA FOR WITHDRAWAL FROM STUDY: Not described CO‐INTERVENTION: Not permitted
Outcomes	ANALYSIS (not by ITT) OUTCOMES Reported at 4 weeks PULMINARY FUNCTION TESTS: % Change from baseline FEV1 Bronchial responsiveness to methacholine (PC20) Morning Peakflow rate SYMPTOM SCORES: Symptom score daytime and night‐time (range 0‐4) FUNCTIONAL STATUS: Change from baseline in use of β2‐agonist Occurence of asthma attacks and asthma flare‐ups Rescue corticosteroid use INFLAMMATORY MEDIATORS: Sputum eosinophils (geometric means) Exhaled NO (sievers) (geometric means) ADVERSE EVENTS: Reported WITHDRAWALS: Not reported PRIMARY OUTCOMES: Not reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by GlaxoSmithKline, d20354 Hamburg, Germany Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not mentioned
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented
Selective reporting (reporting bias)	Low risk	Not found
Other bias	Low risk	No apparent other bias

Khan 2008.

Methods	DESIGN: Parallel‐group, active controlled, randomised, clinical trial.
Participants	ASTHMA PATIENTS RANDOMISED: N = 60 M: 30 BC: 30: WITHDRAWALS: Not reported AGE: years±SD: Not mentioned GENDER: % male M: 100% BC:100% ASTHMA SEVERITY: Not mentioned % Pred. FEV1 % (± SD): Not reported β2‐agonist use (puffs/day) Mean (± SD): Not reported ATOPY: Not reported ELIGIBILITY CRITERIA Not mentioned EXCLUSION CRITERIA: Smokers Patients showing clinical signs of other diseases including diabetes mellitus, Ischaemic heart disease, pulmonary tuberculosis, chronic liver disease and rheumatoid arthritis
Interventions	PROTOCOL DURATION run‐in: Not mentioned treatment: 8 weeks TEST GROUP: Beclomethasone 250 μg daily CONTROL GROUP: Montelukast 10 mg at night‐time DEVICE: Not reported CRITERIA FOR WITHDRAWAL FROM STUDY: Not described CO‐INTERVENTION: Not permitted
Outcomes	ANALYSIS (ITT Not reported) OUTCOMES Reported at 8 weeks PULMINARY FUNCTION TESTS: Peak expiratory flow rate SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not reported INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Not reported WITHDRAWALS: Not reported PRIMARY OUTCOMES: Not reported
ICS dose in HFA beclomethasone ‐ equivalent	125 μg
Notes	Full‐text publication Funded : Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Open label study
Incomplete outcome data (attrition bias) All outcomes	High risk	No proper statistical analysis was performed; severity of patient was not determined using any guideline,
Selective reporting (reporting bias)	Unclear risk	Primary and secondary outcomes were not defined but no bias is observed
Other bias	High risk	No details on ethical committee approval mentioned; no details on informed consent was mentioned

Kim 2000.

Methods	DESIGN: Parallel‐group, clinical trial. Confirmation of methodology: Obtained
Participants	ASYMPTOMATIC PARTICIPANTS RANDOMISED: N = 437 Z: 221 FP: 216 WITHDRAWALS: Z: 46 (21%) FP:19 (9%) AGE (years, range): Z: 32.9 (12‐71) FP: 35.5 (12‐81) GENDER (%male): Z: 19 % FP: 18 % ASTHMA SEVERITY: Mild stable FEV1 (Mean ± SD): Z: 2.53 ± 0.04 FP: 2.58 ± 0.04 Mean (± SD) β2‐agonist use (puffs/day): Not reported ATOPY: Z: 58% FP: 56% ASTHMA DURATION: 10 years ELIGIBILITY CRITERIA: Age >= 12 years 60‐85% Pred FEV1 >= 12% improvement after inhaled β2‐agonist use of low doses of inhaled corticosteroids (BDP 200‐400/day or triamcinolone 400‐800 μg/day for >= 8 weeks use of β2‐agonist use prn. during run‐in: stable asthma, i.e., <= 4 rescue puffs/day of short‐acting β2‐agonist, <= 1 night awakening FEV1 between 60% and 85% EXCLUSION: Life‐threatening asthma >= 1 burst of systemic corticosteroids in < 6 months Smoking in < 12 months Respiratory infection in < 2 weeks
Interventions	PROTOCOL Duration Run‐in Period: 1 week Intervention Period: 6 weeks TEST GROUP: Zafirlukast 20 mg twice a day CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: MDI CO‐INTERVENTION: None
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT OUTCOMES reported at 6 weeks PULMONARY FUNCTION TESTS: *Change from baseline FEV1 (L) Change in morning PEFR (L/min) SYMPTOM SCORES: Change in mean symptom score (6‐point scale) FUNCTIONAL STATUS: Change from baseline daily mean B2‐agonist use (puffs/day) Change in night‐time awakenings Change in symptom‐free days Change from baseline quality of life scores change in rescue‐free days patients with exacerbations requiring systemic corticosteroids Patients requiring hospital admission INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by Glaxo Wellcome Confirmation of methodology and data extraction received from Gerry Hogan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated in block of 4
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented including withdrawal with reasons by group and adverse effects by group, analysis was done by intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary out come was presented
Other bias	Low risk	No apparent other bias

Koenig 2008.

Methods	DESIGN: Parellel‐group, randomised, clinical trial.
Participants	ASTHMA PATIENTS RANDOMISED: N = 323 M: 164 FP: 159 WITHDRAWALS: Not reported AGE: years (SD): M: 40.1 (13.9) FP: 42.0 (14.5) GENDER (%male): M: 55 % FP: 57 % ASTHMA SEVERITY: Asthma patients with FEV1 between 40% and 85% of predicted normal FEV1 % of predicated: Mean: M: 72 FP: 74 ATOPY: Not reported ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA Age 15 years and older, Diagnosis of asthma using the American Thoracic Society definition, 40‐85% Pred FEV1, Reversibility in FEV1 of ≥ 12% within 30 minutes after inhalation of albuterol, On inhaled corticosteroids at a fixed daily dosing regimen for at least 4 weeks prior to screening EXCLUSION: Life‐threatening asthma, Asthma instability, Concurrent respiratory disease, Intermittent and seasonal asthma or exercise‐induced bronchospasm alone, Any other concurrent condition/ disease that would put the safety of the participants at risk, Concurrent use of medications that could have affected the course of asthma or interacted with study medications was prohibited, Use of systemic corticosteroid within 4 weeks of screening
Interventions	PROTOCOL Duration Run‐in Period: 2 week Intervention Period: 16 weeks TEST GROUP: Montelukast 10 mg qd CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Flovent Diskus CO‐INTERVENTION: None
Outcomes	ANALYSIS (ITT Not reported) OUTCOMES reported AM PEF: at every week up to 16 weeks FEV1 (L): at every 4 week up to 16 weeks Other parameters: baseline and at the end of 16 weeks PULMONARY FUNCTION TESTS: FEV1 (L) *Morning PEFR (L/min) SYMPTOM SCORES: Change in mean symptom score (0‐5 point scale) FUNCTIONAL STATUS: Mean change from baseline at endpoint in morning pre‐dose FEV1 Patient‐rated satisfaction with treatment, Percentages of symptom‐free days, Rescue‐free days INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funding: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented; analysis by intention‐to‐treat; reasons for withdrawal and adverse effects described
Selective reporting (reporting bias)	Low risk	Primary and secondary end outcomes were described
Other bias	Low risk	No apparent other bias

Kooi 2008.

Methods	DESIGN: Parellel‐group, randomised, clinical trial.
Participants	CHILDREN WITH ASTHMA LIKE SYMPTOMS RANDOMISED: N = 63 M: 18 FP: 25 WITHDRAWALS: Reported AGE: mean years ± SD: M: 3.8 ± 1.4 FP: 3.9 ± 1.1 GENDER (% male): M: 66.67 % FP: 52 % ASTHMA SEVERITY: Children with asthma‐like symptoms (wheeze, cough and/or shortness of breath) of sufficient severity to justify the use of prophylactic asthma treatment ATOPY: M: 89 % FP: 84 % ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: Age 2‐5 years, With asthma‐like symptoms (wheeze, cough and/or shortness of breath) of sufficient severity to justify the use of prophylactic asthma treatment EXCLUSION: Use of systemic corticosteroids in the last 2 months, Hospitalization for asthma‐related symptoms in the last 2 weeks, Respiratory disorders other than asthma and poorly controlled systemic diseases, Children with symptoms on less than 4 days of the 2‐week run‐in period or children who used anti‐inflammatory medication in the run‐in period
Interventions	PROTOCOL Duration Run‐in Period: 2 week Intervention Period: 12 weeks TEST GROUP: Montelukast 4 mg chewable tablet qd CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Metered dose inhaler via a plastic spacer device (Aerochambers) CO‐INTERVENTION: None
Outcomes	ANALYSIS by intention‐to‐treat manner OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS: Respiratory resistance (hPa/L/s/Hrz) Forced oscillation technique SYMPTOM SCORES: *Symptom score (wheeze, cough, shortness of breath) as recorded by caregivers in a symptom diary card FUNCTIONAL STATUS: Rescue medication free days, INFLAMMATORY MEDIATORS: Blood eosinophils ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funding: from Merck Sharp and Dohme.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented; intention‐to‐treat analysis; reasons for withdrawal and adverse effects were described by group;
Selective reporting (reporting bias)	Low risk	Primary and secondary end outcomes were defined
Other bias	Low risk	No apparent other bias

Kumar 2007.

Methods	DESIGN: Parellel‐group, randomised, clinical trial.
Participants	MILD PERSISTENT ASTHMA PATIENTS RANDOMISED: N = 62 M: 30 BD: 32 WITHDRAWALS: M: 4 BD: 2 AGE: years±SD M: 8.6 ± 2.14 BD: 9.87 ± 2.35 GENDER (%male): M: 83.33 % BD: 78.13 % ASTHMA SEVERITY: Mild persistent asthma was defined as asthma symptoms occurring more than two times in a week but < 1 episode per day and exacerbation may affect activity, night‐time symptoms more than two times a month and peak expiratory flow rate (PEFR) more than or equal to 80% of the predicted FEV1 % of predicted: Mean(range) M: 73.5 (66.55–81.44) BD: 76 (67.99–83.50) ATOPY: Not reported ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA Age: 5‐15 years of either sex, Recently diagnosed mild persistent asthma, Asthma symptoms occurring more than two times in a week but < 1 episode per day and exacerbation may affect activity, night‐time symptoms more than two times a month PEFR more than or equal to 80% of the predicted,, EXCLUSION: With any other chronic illness like tuberculosis, cystic fibrosis, Unable to use inhaler with spacer/to perform spirometry
Interventions	PROTOCOL Duration Run‐in Period: Not reported Intervention Period: 12 weeks TEST GROUP: Montelukast 10 mg qd CONTROL GROUP: Budesonide 400 μg per day DEVICE: Metered dose inhaler CO‐INTERVENTION: None
Outcomes	ANALYSIS (ITT Not reported) OUTCOMES reported: at every 4 weeks up to 12 weeks PULMONARY FUNCTION TESTS: FEV1 (L) FEV1% of predicted Morning PEFR (L/min) SYMPTOM SCORES: Symptom score FUNCTIONAL STATUS Need for rescue drug, Duration of rescue drug, Symptom free days INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Not reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funding: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Low risk	Packets of drugs for each patient were labelled according to randomisation sequence by a person not involved in initial or subsequent assessment of the patients.
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy, identical MDIs or tables of drugs were used
Incomplete outcome data (attrition bias) All outcomes	High risk	Total of 13.3% (4) and 6.25% (2) patients withdrew from montelukast and budesonide group, respectively and the reasons for withdrawals were reported by group.
Selective reporting (reporting bias)	Low risk	Analysis was not done with intention‐to‐treat analysis; the data on secondary outcomes was insufficiently reported to be aggregated;  no data on visit to emergency or local practitioner.
Other bias	Low risk	No apparent other bias

Laitinen 1997.

Methods	DESIGN: Parallel‐group, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 481 Z80: 159 Z20: 162 BDP: 160 WITHDRAWALS: Z80:10 (6.3%) Z20:14 (8.6%) BDP:13 (8.1)% AGE: Z80:38.7 ± 12.6 Z20:37.8 ± 14.0 BDP:38.3 ± 13.6 GENDER (% male): Z80: 50.9% Z20: 53.1% BDP: 48.1% % Pred. FEV1 (mean ± SD): Z80: 79 ± 12.8 Z20:78.9 ±12.9 BDP:80.8 ± 12.7 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY/ALLERGIC RHINITIS: Z80: 88 (55%) Z20: 86 (53%) BDP: 86 (54%) ASTHMA DURATION (Years, SD): Z80:13.4 ± 11 Z20:11.3 ± 10 BDP:13.3 ± 12 ELIGIBILITY CRITERIA: Age: 12‐70 years FEV1 >=60% of Pred Improvement >15% FEV1 after B2‐agonist use Prn short‐acting β2‐agonist with or without inhaled corticosteroids<=500 BUD or BDP or <=250 FP Daytime asthma score >‐10 in past 7 days EXCLUSION: Abnormal LFT Use of other asthma Rx other than prn β2‐agonist during run‐in Respiratory infection during run‐in
Interventions	PROTOCOL Duration Run‐in Period: not described Intervention Period: 6 weeks TEST GROUP 1: Zafirlukast (Accolate) 20 mg twice a day p.o. TEST GROUP 2: Zafirlukast (Accolate) 80 mg twice a day p.o. CONTROL GROUP: Inhaled beclomethasone dipropionate 200‐250 μg twice a day DEVICE: Not described CO‐INTERVENTION: Not specified
Outcomes	ANALYSIS (ITT not specified) OUTCOMES reported at 6 weeks PULMONARY FUNCTION TESTS Change from baseline FEV1 (L) Change from baseline AM PEFR (L/min) SYMPTOM SCORES: Change from baseline daytime symptom scores (max = 21) FUNCTIONAL STATUS Change from baseline mean daily B2‐agonist use (puffs/day) Change from baseline nocturnal awakenings/night INFLAMMATORY MARKERS: Change in eosinophil counts ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	225 μg
Notes	Abstract (1997) Funded by Zeneca Confirmation of methodology and data extraction
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation with block of 6
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, withdrawals and adverse effects were reported by groups,
Selective reporting (reporting bias)	Low risk	Not found
Other bias	Low risk	No apparent other bias

Laviolette 1999.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 642 M: 201 BDP: 200 Placebo: 48 M+BDP: 193 WITHDRAWALS: M: 42 (21%) BDP: 22 (11%) AGE: M:38 (15‐75) BDP:39 (15‐78) GENDER (% male): M: 49% BDP: 52% % Pred. FEV1 (mean ±SD): M: 72 ± 12 BDP: 72 ± 12 Mean (± SD) β2‐agonist use (puffs/day): M: 3.5 ± 2.3 BDP: 3.5 ± 2.5 ATOPY/ALLERGIC RHINITIS: M: 74% BDP: 74% ELIGIBILITY CRITERIA: Age: > 15‐years old Healthy, non‐smoking History of >=one year of intermittent or persistent asthma symptoms Inhaled corticosteroids treatment >= 6wks prior to pre‐study visit (inhaled corticosteroids dose comparable to beclomethasone 400‐500 μg) 50‐85% FEV1 Pred Improvement >15% FEV1 after B2‐agonist use
Interventions	PROTOCOL Duration Run‐in Period: 4 weeks Intervention Period: 16 weeks TEST GROUP 1: Montelukast 10 mg per day + Placebo (after blind beclomethasone removal) TEST GROUP 2: Montelukast 10 mg per day + inhaled beclomethasone 200 μg twice a day (not used in this review) CONTROL GROUP 1: Placebo + inhaled beclomethasone 200 μg twice a day CONTROL GROUP 2: Placebo + Placebo (not used in this review) DEVICE: Aero‐Chamber spacer device CO‐INTERVENTION: Not specified
Outcomes	ANALYSIS ( Intention‐to‐treat) OUTCOMES reported at 6 and 16 weeks PULMONARY FUNCTION TESTS Change from baseline FEV1 Change from baseline Am PEFR SYMPTOM SCORES: Change from baseline daytime asthma symptoms scores (6‐point scale) FUNCTIONAL STATUS: % Change from daily mean use of β2‐agonists Change from baseline nocturnal awakenings (nights/week) INFLAMMATORY MARKERS: Change from baseline peripheral blood eosinophil counts ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full Text publication (1999) Funded by Merck Confirmation of methodology and data received from Reiss 01 Sept 1999
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation with block of 6
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	High risk	All data presented, 20.9% and 11.0% withdrawal in montelukast and beclomethasone respectively, no intention‐to‐treat analysis.
Selective reporting (reporting bias)	Low risk	Not found
Other bias	Low risk	No apparent other bias

Lazarus 2007.

Methods	DESIGN (ONLY DATA OF NONSMOKER PATIENTS ARE PRESENTED IN THIS REVIEW) Cross‐over, multicentric, randomised, clinical trial.
Participants	CORTICOSTEROID‐NAIVE ASTHMATIC PATIENT RANDOMISED: N = 44 WITHDRAWALS: 1 (4.6%) AGE: mean years: 28.98 ± 5.92 GENDER (% male): Not reported % Pred. FEV1 (mean ± SD): 80.16 ± 9.16 Mean (±SD) β2‐agonist use (puffs/day): Not reported ATOPY/ALLERGIC RHINITIS: Not reported DURATION OF ASTHMA: More than 10 years ELIGIBILITY CRITERIA: Corticosteroid‐naive male and female people aged 18 to 50 years old, History of asthma, Prebronchodilator FEV1 values of 70 to 90% of predicted Airway reactivity as indicated by 12% or greater reversibility after albuterol inhalation, PC20 (provocative concentration causing a 20% fall in FEV1) methacholine of less than 8 mg/ml, Nonsmokers: a total lifetime smoking history of less than 2 pack‐years, and no smoking for at least 1 year
Interventions	PROTOCOL Duration Run‐in Period: 2‐4 weeks Intervention Period: 16 weeks TEST GROUP 1: Montelukast 10 mg qd TEST GROUP 2: Inhaled beclomethasone 160 μg twice daily DEVICE: Inhaled (HFA)–beclomethasone dipropionate or QVAR CO‐INTERVENTION: Not specified
Outcomes	ANALYSIS (ITT‐ Not reported) OUTCOMES reported at 8 weeks PULMONARY FUNCTION TESTS *Change from baseline FEV1 Change from baseline FEV1% predicted Change from baseline spirometry PEFR Change from baseline AM peak flow Change from baseline PEFR variability, Change from baseline log 2 (PC20), SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: AQOL average score INFLAMMATORY MARKERS: Change from baseline Sputum eosinophils Change from baseline Sputum neutrophils, Change from baseline eosinophil cationic protein, Change from baseline tryptase, ADVERSE EVENTS: Not reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	400 μg
Notes	Full Text publication Funded: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: randomisation was performed online from the data coordinating centre
Allocation concealment (selection bias)	Low risk	Matching placebos were used; Treatment medication for each subject was packaged with unique number and distributed to the clinical centres
Blinding (performance bias and detection bias) All outcomes	Low risk	Triple blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All data presented; analysis was not done using intention‐to‐treat analysis; data for drop out patients was not addressed
Selective reporting (reporting bias)	Low risk	Not found
Other bias	Low risk	No apparent other bias

Lu 2009.

Methods	DESIGN: Cross‐over, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 406 (including all other groups) M:46 BECLO: 63 WITHDRAWALS: Not reported group wise AGE: 34.11 ± 11.85 GENDER (% male): N: 48.0% % PRED FEV1 (mean, SD): Not reported Mean (± SD) β2‐agonist use (puffs/day): Not reported ATOPY: Not reported ASTHMA DURATION (years): Not reported ELIGIBILITY CRITERIA: Adult patients 15 to 65 years of age with a ≥ 1‐year clinical history of asthma symptoms, FEV1 of 50% to 85% of predicted, Airflow reversibility of ≥ 15%, Minimum predetermined level of β2‐agonist use and daytime asthma symptoms. EXCLUSION: Received oral cromolyn or nedocromil or inhaled or intranasal corticosteroids within 2 weeks before the first visit Received anti‐leukotriene agents, xanthine compounds, long‐acting β2‐agonists, or inhaled anticholinergics within 1 week before the first visit. Patients who had used long‐acting antihistamines within 2 weeks of the first visit, short‐acting antihistamines within 48 hours, or astemizole within 3 months With gastroesophageal reflux disease (GERD) and environmental triggers such as allergic rhinitis and smoking history.
Interventions	PROTOCOL Duration Run‐in Period: 2 weeks Intervention Period: 6 weeks Wash‐out Period: 2 weeks TEST GROUP: Montelukast 10 mg per day at bedtime p.o. CONTROL GROUP 1: Beclomethasone 200 μg twice a day CONTROL GROUP 2: Placebo (not used in this review) DEVICE: Not reported
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT ANALYSIS OUTCOMES reported at 6 weeks PULMONARY FUNCTION TESTS: % change from baseline FEV1 Morning PEF Evening PEF SYMPTOM SCORES: Daytime asthma symptoms score FUNCTIONAL STATUS: Total daily β2‐agonist use INFLAMMATORY MARKERS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full Text publication Funded: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All data presented, intention‐to‐treat analysis, clinical and laboratory adverse experiences were reported however withdrawal were not reported by group
Selective reporting (reporting bias)	Low risk	Primary, secondary and tertiary outcomes were defined
Other bias	Low risk	No apparent other bias

Malmstrom 1999.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 895 M:387 BDP:251 PLACEBO:257 WITHDRAWALS: M: 33 (8.5%) BDP:18 (7.2%) AGE: M: 35 (15‐78) BDP: 35 (15‐74) GENDER (% male): M: 40% BDP: 35% ‐%PRED FEV1 (mean, SD): M : 65 ± 10 BDP: 65 ± 10 Mean (± SD) β2‐agonist use (puffs/day): M: 5.4 ± 3.4 BDP: 5.5 ± 4.2 ATOPY: M: 62 % BDP:61 % ASTHMA DURATION years(range): M: 17 (1‐67) BDP: 18 (0.5‐65) ELIGIBILITY CRITERIA: Age: >= 15 years old History of chronic asthma for >= one year 50‐85% FEV1 Pred Improvement >15% FEV1 after B2‐agonist use Average daily use of >= one puff of β2‐agonist Minimal predefined daytime asthma symptom score (64 of a possible of 336) EXCLUSION: Inhaled or oral corticosteroids, cromolyn, or nedocromil in < 4 weeks Use of long‐acting β2‐agonist, antimuscarinic or new tx with theophylline in < 2 weeks
Interventions	PROTOCOL Duration Run‐in Period: 2 weeks Intervention Period: 12 weeks Wash‐out Period: 3 weeks TEST GROUP: Montelukast 10 mg per day at bedtime p.o. CONTROL GROUP 1: Beclomethasone 200 μg twice a day CONTROL GROUP 2: Placebo (not used in this review) DEVICE: Spacer for Beclomethasone CO‐INTERVENTION: Theophylline (10%)
Outcomes	ANALYSIS ( ITT not specified) OUTCOMES reported at 6 and 12 weeks PULMONARY FUNCTION TESTS: *% Change from baseline FEV1 Change from baseline AM PEFR SYMPTOM SCORES: Change from baseline daytime symptom scores FUNCTIONAL STATUS Change from baseline nocturnal awakenings (nights/week) Change from baseline quality of life scores (Juniper) % Change from baseline mean daily B2‐agonist use (puffs/day) INFLAMMATORY MARKERS: Change from baseline peripheral blood eosinophil counts ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full Text publication (1999) Funded by Merck Confirmation of methodology and data extraction obtained.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation with block of 7
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, reasons for withdrawal and adverse effects were mentioned by group
Selective reporting (reporting bias)	Low risk	Not found
Other bias	Low risk	No apparent other bias

Maspero 2001.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 124 M: 83 BDP: 41 WITHDRAWALS: M: 5 (6%) BDP: 3 (7%) AGE: 6‐11 years M: 9.5 ± 1.8 (6‐12) years BDP:9.7 ± 1.4 (7‐12) years GENDER (% male): M: 64 % BDP: 51% BASELINE SEVERITY: Moderate Mean % Predicted FEV1: M: 82 ± 13 BDP:82 ± 17 ATOPY/ALLERGEN TRIGGERS: M: 66% BDP:61% ASTHMA DURATION (years): Not reported ELIGIBILITY CRITERIA: Age: 6‐11 years within 40% pf the 5 to 95% weight range non smoker baseline FEV1 >= 60 and <= 85% predicted Improvement >= 12% after β2‐agonist need for rescue β2‐agonist 7/14 days of the run‐in EXCLUSION: ED asthma visit in past month Admission for asthma in past 3 months Prior intubation Unresolved URTI in past 3 weeks Significant sinus infection Cromolyn use within 1 month Inhaled or systemic corticosteroids use in past 2 weeks or >= 3 short courses of systemic corticosteroids in past 6 months Long‐acting β2‐agonist, anticholinergics, long‐acting anti‐histamine, theophylline in past 2 weeks
Interventions	PROTOCOL Duration Run‐in Period: unspecified Primary RCT Period: 10 weeks Extension Period: 6 months TEST GROUP: Montelukast 5 mg per day at bedtime p.o. CONTROL GROUP: Inhaled BPD 100 μg tid DEVICE: MDI, spacer optional CO‐INTERVENTION: Not specified
Outcomes	ANALYSIS by Intention‐to‐treat OUTCOMES reported at 12, 24 weeks PULMONARY FUNCTION TESTS: Change from baseline FEV1 (L) SYMPTOM SCORES: Not reported FUNCTIONAL STATUS Days off work for parents Days off school for children Number of exacerbations requiring systemic corticosteroids Number of exacerbations requiring admission INFLAMMATORY MEDIATORS: *LTC4 in nasal wash ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	150 μg
Notes	Full‐text publication of primary and extension study (1999) Funded by Merck Frosst confirmation of methodology and data extraction obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not mentioned
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias) All outcomes	High risk	Open label, the criteria for election of participants from last study not mentioned
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented
Selective reporting (reporting bias)	Unclear risk	Peak expiratory flow rate was mentioned in method but data was not presented in results, primary and secondary outcomes not specified
Other bias	Low risk	No apparent other bias

Meltzer 2002.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 522 M = 264 FP = 258 WITHDRAWALS; N (%) M: 67(25%) FP: 60 (23%) AGE: mean (range) M: 35.4 (15‐77) years FP: 36.2 (15‐73) years GENDER (% male): M: 41 % FP: 51 % BASELINE SEVERITY: Moderate % Predicted FEV1 (Mean ± SE): M: 65.9 ± 9.1 FP: 65.6 ± 8.9 ATOPY/ALLERGEN TRIGGERS: Not reported ASTHMA DURATION (years) M: 74% for >= 10 years FP: 78% for >= 10 years ELIGIBILITY CRITERIA: Non‐smoking male and female Age: >= 15 years old Diagnosis of asthma as per the ATS criteria for >= 6 months Use of an inhaled or oral short‐acting β2‐agonist on a regular or as‐needed basis during the preceding 3 months 50‐80% FEV1 Pred pre‐bronchodilator Improvement >= 15% FEV1 after 200 μg of B2‐agonist use At the end of the run‐in period: FEV1 of 50‐80% that was within 15% of the FEV1 at screening Use of albuterol to relieve asthma symptom on at least 6 to 7 days before randomisation An asthma symptom score of 2 or more (based on a 1‐5‐point scale) on at least 4 of the 7 days EXCLUSION: History of life‐threatening or unstable asthma known hypersensitivity to study medication Respiratory tract infections within 4 weeks of screening Pregnancy Smoking history of more than 10 pack‐years Inhaled or systemic corticosteroids, inhaled cromolyn or nedocromil, leukotriene modifiers, anticholinergics, and theophylline products
Interventions	PROTOCOL Duration Run‐in Period: 8‐14 days Intervention: 24 weeks TEST GROUP: Montelukast 10 mg per day at bedtime p.o. CONTROL GROUP: Inhaled FP 100 μg twice a day DEVICE: MDI with spacer CO‐INTERVENTION: Rx permitted: antihistamines, nasal decongestants, intranasal medications (including corticosteroids) for the treatment of rhinitis
Outcomes	ANALYSIS by intention‐to‐treat OUTCOMES reported at 24 weeks or endpoint PULMONARY FUNCTION TESTS *% Change from baseline FEV1 Change from baseline AM PEFR Change from baseline PM PEFR Change in mean diurnal variation in PEF SYMPTOM SCORES Change from baseline daytime symptom scores (scale of 0 to 5) Change in night‐time awakening (specify /week or /night) (scale of 0 to 5) % symptom‐free days % symptom‐free nights FUNCTIONAL STATUS Exacerbations requiring systemic corticosteroids Exacerbations requiring admission Global assessment of medication effectiveness Patient satisfaction Change in AQLQ INFLAMMATORY MARKERS: Not reported ADVERSE EVENTS: Not reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication (2002) Funded by GlaxoSmithKline Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated in block of 4
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented including withdrawal with reasons by group and adverse effects by group, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were defined
Other bias	Low risk	No apparent other bias

MK0479‐332.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	PARTICIPANTS WITH PERSISTENT ASTHMA RANDOMISED: N = 683 MON: 347 FP: 336 WITHDRAWALS: MON: 51 (14.70%) FP: 50 (14.88%) AGE (± SD): MON: 37.7 (± 10.4) FP: 38.4 (± 10.7) GENDER (% male): MON: 53.03% FP: 56.25% ASTHMA SEVERITY: Not described ASTHMA DURATION: Not described % Pred. FEV1 (±SD): MON: 75.7 (± 7.0) FP: 76.1 (± 6.6) MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported DOSE OF INHALED CORTICOSTEROIDS AT STUDT ENTRY AND AT RUN‐IN: Not described ATOPY: Not described ELIGIBILITY CRITERIA: Aged 18‐55 years, Subjects with chronic asthma who actively smoke at least 0.5 to no more than 2 packs of cigarettes a day, EXCLUSION:: Subjects with chronic obstructive pulmonary disease.
Interventions	PROTOCOL Duration Run‐in Period: not reported Intervention Period: 12 weeks CONTROL GROUP: Fluticasone propionate 250 twice a day TEST GROUP: Montelukast 10 mg QD DEVICE: Not reported Criteria for withdrawal from study: Reported
Outcomes	ANALYSIS: Not reported OUTCOMES reported at 24 weeks PULMONARY FUNCTION TESTS: Change from baseline in morning PEFR SYMPTOM SCORES: Change from baseline in mean day time symptom score FUNCTIONAL STATUS: *Percentage of asthma‐control days over the 6‐month treatment period, INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	500
Notes	Funding not reported but trials conducted by pharmaceutical company Confirmation of methodology and data extraction: not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation:not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

Nathan 2001.

Methods	DESIGN: Parallel‐groups, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 294 Z = 150 FP = 144 WITHDRAWALS; N (%): Z: 12 (8%) FP: 5 (3%) AGE: Mean ( range) Z: 32 (12‐70) FP: 31 (12‐54) GENDER (% male): Z: 65 (43%) FP: 65 (45%) BASELINE SEVERITY: Not mentioned % Pred. FEV1 (Mean ± SD): Z: 68.9 ± 7.6 FP: 68 ± 8.5 MEAN (± SD) β2‐AGONIST USE (puffs/day): Z = 4.4 ± 2.7 FP = 4.4 ± 2.6 ATOPY: Not reported ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: >= 12 years old History of asthma according to ATS 50‐80% FEV1 pred. Reversibility >= 12% after 2 puffs of albuterol Using inhaled or oral short acting β2‐agonist for longer than 6 weeks Not using inhaled corticosteroids within 30 days EXCLUSION: Life‐threatening or unstable asthma Significant uncontrolled disease other than asthma URTI within 2 weeks Used oral or parenteral corticosteroids within 60 days Used an investigational medication within 30 days
Interventions	PROTOCOL Duration Run‐in Period: 7‐14 days Intervention: 4 weeks TEST GROUP: Zafirlukast 20 mg twice a day CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Not reported CO‐INTERVENTION: None permitted
Outcomes	PER PROTOCOL ANALYSIS (not ITT) OUTCOMES reported at 4 and endpoint PULMONARY FUNCTION TESTS *Change from baseline in morning predose FEV1 (L) Change from baseline AM PEFR Change from baseline PM PEFR SYMPTOM SCORES Change from baseline in symptom score (scale of 0 to 4) % symptom‐free days asthma exacerbations defined as worsening of asthma requiring a change in patient's asthma therapy other than increased use of supplemental albuterol FUNCTIONAL STATUS: % Change from baseline mean daily B2‐agonist use (puffs/day) INFLAMMATORY MARKERS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication (2001) Funded by: Not reported Confirmation of methodology and data extraction obtained/not requested/not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All data presented, adverse events by group were mentioned, 3% and 8% patients were withdrawn in fluticasone and zafirlukast, not a intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined, but no bias was observed
Other bias	Low risk	No apparent other bias

NCT00442559.

Methods	DESIGN: Parallel‐groups, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 191 M = 100 ICS = 91 WITHDRAWALS; N (%): M: 34 (34%) ICS: 35 (38.5%) AGE: Mean ( years, SD): M: 5.4 (3.0) ICS: 6.1 (2.6) GENDER: n (% male): 39 (20.4%) BASELINE SEVERITY: Not mentioned % Pred. FEV1 (Mean ± SD): Not reported β2‐AGONIST USE (puffs per day): MEAN (± SD): Not reported ATOPY: Not reported ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: Between 2 and 14 years old Diagnosed with asthma, classified as mild persistent asthma according to Global Initiative Asthma Guidelines (GINA) Diagnosed with comorbid allergic rhinitis EXCLUSION: Patients with suspected with nasal‐sinus infection Prior treatment with high dose inhaled corticosteroid requiring a dose higher than beclomethasone dipropionate 400 μg per day, or equivalent, other medications used in severe cases
Interventions	PROTOCOL Duration Intervention: 12 weeks TEST GROUP: Montelukast 4 ‐ 5 mg per day CONTROL GROUP: ICS DEVICE: Not reported CO‐INTERVENTION: None permitted
Outcomes	PER PROTOCOL ANALYSIS (not ITT) OUTCOMES reported at 12 week endpoint PULMONARY FUNCTION TESTS: Not reported SYMPTOM SCORES: *Change from baseline for daytime asthma symptom score Change from baseline for daily allergic rhinitis symptom score FUNCTIONAL STATUS: Not reported INFLAMMATORY MARKERS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	Not reported
Notes	Unpublised data (2008) Funded by: Merck
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Open‐label
Incomplete outcome data (attrition bias) All outcomes	Low risk	High withdrawal rate but balanced in both groups
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were reported
Other bias	Low risk	No apparent other bias

Ng 2007.

Methods	DESIGN: Cross over, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N =19 M = 13 BD = 15 WITHDRAWALS; N (%) M: 5 (38%) BD: 7 (47%) AGE: Mean±SD M: 8.53 ± 2.17 BD: 8.39 ± 2.57 GENDER (% male): M: 8 (61.54%) BD: 9 (60%) BASELINE SEVERITY: Not mentioned % Pred. FEV1 (Mean ± SD): Not mentioned β2‐AGONIST USE (puffs per day): MEAN (± SD): Not mentioned ATOPY: Not mentioned ASTHMA DURATION: Not mentioned ELIGIBILITY CRITERIA: Male and female patients between 6‐ to 14‐year of age with a history of newly diagnosed mild persistent asthma, FEV1 ≥80% of the predicted value (after withholding β2‐agonist for ≥ 6 hours) and to improve by ≥15% after inhaled β2‐agonist, or if they have symptoms ≥ 1 time a week but < 1 time a day, or if their night‐time symptoms are >2 times a month, EXCLUSION: Prior use of budesonide DPI, previous intubation for asthma, A history of chronic pulmonary disease other than asthma, upper respiratory tract infection within 3 weeks before the first study visit, or a history of an acute sinus disease requiring antibiotic treatment 1 week before the start of the study, History of taking following medication: astemizole within three months; oral, inhaled or parenteral corticosteroids within one month; cromolyn, nedocromil, oral or long‐acting β2‐agonist, antimuscarinics, cimetidine, metoclopramide, phenobarbital, phenytoin, terfenadine, loratadine, or anticholinergic agents within two weeks and theophylline within one week before the pre‐study visit; Patients on immunotherapy.
Interventions	PROTOCOL Duration Intervention: 4 weeks TEST GROUP: Zafirlukast 20 mg twice a day CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Not reported CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT ANALYSIS OUTCOMES reported at 8 week endpoint PULMONARY FUNCTION TESTS: *FEV‐1 % predicted SYMPTOM SCORES: Proportion of symptom‐free day FUNCTIONAL STATUS: % Change from baseline mean daily B2‐agonist use (puffs/day) INFLAMMATORY MARKERS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication (2007) Funded by: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: randomisation table was prepared by pharmacist
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Dobule blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented; intention‐to‐treat analysis was done; reason for drop outs by groups were mentioned
Selective reporting (reporting bias)	High risk	Primary outcome was presented; however the day time asthma symptoms and nocturnal awakenings (secondary outcomes) were not presented in details
Other bias	Low risk	No apparent other bias

Ostrom 2005.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	ASTHMATIC PATIENTS WITH AT LEAST 6‐MONTH HISTORY OF CHRONIC ASTHMA AS PER ATS GUIDELINES RANDOMISED: N = 342 M = 170 FP = 172 WITHDRAWALS; N(%) M: 21% FP: 13% AGE: Mean years (range): M: 9.6 (6‐12) FP: 9.1 (5‐12) GENDER (% male): M: 68% FP: 63% BASELINE SEVERITY: ‐FEV1 of 60% to 85% of predicted % Pred. FEV1 (Mean ± SD) M: 76.4 ± 8.5 FP: 75.4 ± 9.4 MEAN ± SD) β2‐AGONIST USE (puffs/day) M=2.42 ± 0.12 FP=2.26 ± 0.12 ATOPY: Not reported ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: Age: 6‐12 years, At least a 6‐month history of chronic asthma as per ATS, On short‐acting b2‐agonist bronchodilators over the 3 months immediately before the study, FEV1 of 60% to 85% of predicted values, Equal or more than 12% increase in FEV1 within 30 minutes after two puffs of albuterol, EXCLUSION: Life‐threatening asthma, Hospitalization for asthma within 3 months before the study, Acute viral respiratory infections within 2 weeks before the study, Use of inhaled or systemic corticosteroids, inhaled long‐acting b2‐agonists, anticholinergics, or anti‐leukotriene agents within pre‐defined intervals before the study Inability of the parent or guardian to provide informed consent or to comply with the use of the study medications in the child
Interventions	PROTOCOL Duration Run‐in Period: 8‐14 days Intervention: 12 weeks TEST GROUP: Montelukast sodium chewable tablet 5 mg once daily CONTROL GROUP: Fluticasone propionate 50 μg twice daily DEVICE: DISKUS multi‐dose powder inhaler CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS by intention‐to‐treat OUTCOMES reported at 12 weeks or endpoint PULMONARY FUNCTION TESTS *% Change from baseline FEV1 Change from baseline AM and PM PEFR SYMPTOM SCORES Daytime symptom scores, Night‐time symptom scores FUNCTIONAL STATUS Total albuterol use Daytime albuterol use Night‐time albuterol use Percent rescue‐free days Daytime symptom scores, Night‐time symptom scores, Percent symptom‐free days INFLAMMATORY MARKERS: Not reported ADVERSE EVENTS: Not reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full‐text publication Funded: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details were not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All outcomes are reported including withdrawal rate and reasons for withdrawals were well described by group, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary outcomes was defined
Other bias	Low risk	No apparent other bias

Overbeek 2004.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	ATOPIC MILD ASTHMA PATIENTS RANDOMISED: N = 36 M = 19 BDP = 17 WITHDRAWALS; % Total: 0% AGE: mean (range) years M = 24.5 (19–49) BDP = 31.6 (19–57) GENDER (% male): 55.56% % Pred. FEV1 Mean ± SE M = 88.3 ± 13.6 BDP = 84.9 ± 9.7 ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: Non‐smoker, atopic, mild asthma inhaled corticosteroids receiving 4800 μg of beclomethasone dipropionate or equivalent, Subjects were required to have a FEV1 of equal or more than 60% of the predicted value, Change in FEV1 equal or more than 12% to salbutamol and a provocative concentration of methacholine (MCh) to cause a 20% drop in FEV1 (PC20MCh) of equal or less than 4 mg/mL, Positive skin prick tests to HDM, EXCLUSION: History of respiratory infection or exacerbation of asthma in the month preceding the run‐in period, Use oral or systemic corticosteroids 1 month prior to the run‐in period
Interventions	PROTOCOL Duration Run‐in Period: 8 weeks Intervention: 8 weeks TEST GROUP: Montelukast sodium capsule (10 mg nocte) CONTROL GROUP: Fluticasone propionate (100 μg twice a day) by Diskus inhaler DEVICE: DISKUS multi‐dose inhaler CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS by intention‐to‐treat. Not reported OUTCOMES reported at 8 weeks PULMONARY FUNCTION TESTS Change from baseline FEV1 Change from baseline FEV1 % predicated Change from baseline PC20 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not reported INFLAMMATORY MARKERS: Total number of blood eosinophils, Blood ECP Serum IL‐5 UIrinary 9a,11b‐PGF2 and LTE4 ADVERSE EVENTS: Not reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded by GlaxoSmithKline R&D, UK
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not mentioned
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was no withdrawal rate; all patients completed the study
Selective reporting (reporting bias)	Low risk	All outcomes reported in the manuscript are reported, including adverse events
Other bias	Low risk	No apparent other bias

Peroni 2005.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	MILD ASTHMATIC CHILDREN ALLERGIC TO HOUSE DUST MITE RANDOMISED: N = 24 M = 12 BDP = 12 WITHDRAWALS; N(%): 3 (12.5%) AGE: range years: 6‐13 years GENDER (% male): 41.67% % Pred. FEV1 (Median%) M = 99% BDP = 108% ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA Subjects with aged 6‐13 years, Having mild to moderate asthma according to the American Thoracic Society definition, Positive skin prick tests to HDM, EXCLUSION: History of respiratory infection or exacerbation of asthma in at least 2 months before the beginning of the study, Allergic to furred pets.
Interventions	PROTOCOL Duration Intervention: Not clear TEST GROUP: Montelukast (5 mg administered once a day in the evening), CONTROL GROUP: Budesonide (100 µg twice daily) DEVICE: Turbuhaler CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS by intention‐to‐treat: Not reported PULMONARY FUNCTION TESTS Change from baseline FEV1 FENO level SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not reported INFLAMMATORY MARKERS: Sputum eosinophil cell count (%) ADVERSE EVENTS: Not reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funding source: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: used randomisation table prepared by a person not included in the study
Allocation concealment (selection bias)	Unclear risk	Sealed envelope were used to allocate drug however the concealment method is not described
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind; centralized randomisation table and placebo preparation
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Analysis was not done by intention‐to‐treat; Data from 8.3% and 16.6% of patients were not evaluated due to lack of compliance to treatment.
Selective reporting (reporting bias)	Low risk	Primary outcome was not defined but not bias was observed
Other bias	Low risk	No apparent other bias

Peters 2007.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	ASTHMATIC PATIENTS RANDOMISED: N = 500 M = 165 FP = 169 WITHDRAWALS; N (%) M = 20 FP = 13 AGE: Mean ± SD M = 32.4 ± 15.4 FP = 29.3 ± 14.6 GENDER (% male): M = 42.8 FP = 39.1 % of predicted value: mean ± SD At randomisation M = 91.9 ± 11.1 BDP = 92.8 ± 10.4 ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: Adequate adherence (i.e., completion of at least 10 of the previous 14 days of daily diary cards and fluticasone treatment for at least 21 of the previous 28 days), A pre‐bronchodilator FEV1 of at least 80% of the predicted value, A score on the Asthma Control Questionnaire17 of less than 1.5 (range, 0 to 6, with lower values indicating less‐severe asthma, and 0.5 unit as the minimal clinically important difference), Fewer than 16 puffs of a rescue β2‐agonist used per week during the final 2 weeks of the run‐in period (except as medication before exercise), No hospitalizations, urgent medical care (for asthma), oral corticosteroid use, or use of additional asthma medication during the run‐in period, Absence of febrile illness (temperature exceeding 38.0°C, or 100.4°F) within the previous 24 hours.
Interventions	PROTOCOL Duration Run‐in Period: 4‐6 weeks Intervention: 16 weeks TEST GROUP: Montelukast (Singulair, GlaxoSmithKline), 5 mg once daily for children ages 6 to 14 years and 10 mg once daily for persons 15 years or older CONTROL GROUP: Inhaled fluticasone propionate (100 μg twice daily) DEVICE: Flovent Diskus CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS by intention‐to‐treat OUTCOMES reported at 16 weeks PULMONARY FUNCTION TESTS: Treatment failure — no. of patients (%) Percentage of predicted FEV1 value Percentage of predicted FVC value Percentage of predicted PEF value SYMPTOM SCORES Asthma control score Asthma symptom unit index Mini‐AQLQ score FUNCTIONAL STATUS ≥ 1 Nocturnal awakening Symptoms and use of medication INFLAMMATORY MARKERS: Not reported ADVERSE EVENTS: Reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funding source: Unrestricted grant from GlaxoSmithKline, a grant from the American Lung Association.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: randomised using permuted‐block design stratified by clinic and age of patient.
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Placebo and matching montelukast tablets used for the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported in detail, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary and secondary data were well defined
Other bias	Low risk	No apparent other bias

Riccioni 2001.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 48 Z = 12 BUD = 12 Z+BUD = 12 Control = 12 WITHDRAWALS; Z = 2 (16%) BUD = 1 (8%) Z+BUD = 2 (16%) AGE: mean (± SD) years Z: 33.75 (± 11.24) BUD: 32.15 (± 10.27) Z+BUD: 33.44 (± 11.12) Control: 29.15 (± 10.34) GENDER: N (% male): Z: 6 (50) BUD: 6 (50) Z+BUD: 6 (50) Control: 6 (50) BASELINE SEVERITY: Mild persistent % Predicted FEV1 (Mean ± SD) Z: 94.75 ± 7.68 BUD: 92.75 ± 9.87 Z+BUD: 92.16 ± 5.06 Control: 95.75 ± 5.84 ATOPY/ALLERGEN TRIGGERS: Not reported ASTHMA DURATION (years): 1 year ELIGIBILITY CRITERIA: 1 year of mild persistent bronchial asthma PEF > 80% pred. and PEF daily variability in 20‐30% range with positive salbutamol reversibility test EXCLUSION: URTI in last 3 weeks Hospitalizations for asthma in the last 3 months Treatment with antihistamines, anticholinergic, inhaled corticosteroids, theophylline drugs Presence of autoimmune, hepatic, or renal disorders Malabsorption, drug or alcohol addiction Pregnancy or lactation
Interventions	PROTOCOL Duration Run‐in Period: 2 weeks Intervention: 8 weeks TEST GROUP: Zafirlukast 20 mg twice a day TEST GROUP 2: Zafirlukast 20 mg twice a day + Budesonide 400 μg twice a day CONTROL GROUP: Budesonide 400 μg twice a day CONTROL GROUP 2: Placebo DEVICE: Not reported CO‐INTERVENTION: Not reported
Outcomes	ANALYSIS PER PROTOCOL (not by ITT) OUTCOMES Reported at 8 weeks PULMONARY FUNCTION TEST Pre‐ and post FVC values Pre‐ and post FEV1 Pre‐ and post PC20 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not reported INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Not mentioned WITHDRAWALS: Not reported Primary outcome: Not specified.
ICS dose in HFA beclomethasone ‐ equivalent	400 μg
Notes	Full‐text publication (2001) Funded by University Confirmation of methodology and data extraction: obtained from Graziano Riccioni, Oct 2003
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	Data on asthma diary, number of puffs used, compliance of treatment were mentioned in methodology but not addressed in the results
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined, but no bias was observed
Other bias	Low risk	No apparent other bias

Riccioni 2002a.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology: Obtained (Oct 2003)
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 40 M = 20 BUD = 20 WITHDRAWALS: Reported AGE: years ± SD M = 25.16 ± 7.68 BUD = 26.18 ± 6.15 GENDER (% male): M = 11 (55) BUD = 10 (50) ASTHMA SEVERITY: Mild and persistent ASTHMA DURATION: Not mentioned % Pred. FEV1: M = 93.15 ± 12.17 BUD = 94.73 ± 10.18 Mean (± SD) β2‐agonist use (puffs per day): Not described ATOPY: M = 12 (60%) BUD = 10 (40%) PARTICIPANTS WITH ALLERGIC RHINITIS: M: 2 (10%) BUD: 2 (10%) ELIGIBILITY CRITERIA: Mild persistent asthma FEV1 >80% Daily variability of 20‐30% in PEF Diagnosed with asthma by a specialist EXCLUSION CRITERIA: URTI in last 3 weeks Hospitalizations for asthma in last 3 months Inhaled and systemic corticosteroids
Interventions	PROTOCOL Duration Run‐in: 2 weeks Intervention: 16 weeks TEST GROUP: 10 mg Montelukast per day CONTROL GROUP: 400 μg Budesonide twice a day DEVICE: Turbuhaler CRITERIA FOR WITHDRAWAL: Mentioned CO‐INTERVENTION: Not permitted
Outcomes	ANALYSIS PER PROTOCOL (no ITT analysis mentioned) OUTCOMES: Reported at 16 weeks PULMONARY FUNCTION TEST: Change from baseline in FVC Change from baseline in FEV1 Change from baseline in PC20 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not mentioned INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported (overall, not in details) WITHDRAWALS: Reported Primary outcome: not specified
ICS dose in HFA beclomethasone ‐ equivalent	400 μg
Notes	Full‐text publication Funded by the University "G. D'Annunzio"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Unclear risk	not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind (patient and assessor)
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined but no bias was observed
Other bias	Low risk	Not found

Riccioni 2002b.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. CONFIRMATION OF METHODOLOGY: obtained (Oct 2003)
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 45 M = 15 BUD = 15 M+BUD = 15 WITHDRAWALS: M = 1 (7%) BUD = 1 (7%) M+BUD = 1 (7%) AGE: years ± SD M = 26.7 ± 8.6 BUD = 26.9 ± 12.3 M+BUD = 28.2 ± 10 GENDER: N (% male): M = 9 (60) BUD = 8 (53.3) M+BUD = 5(33.7) ASTHMA SEVERITY: Mild ASTHMA DURATION: 1 year % Pred. FEV1: mean (range): M = 97 (85‐123) BUD = 97 (76‐123) M+BUD = 99 (84‐131) Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY: 100% (Definition not mentioned) ELIGIBILITY CRITERIA: Asthma as per ATS criteria Confirmation of the presence of BHR by methacholine on the initial visit Regular attendance of the outpatient clinic over 4 months from the initial visit PEF >= 80% of predicted PEF variability <= 20% as per NIH criteria EXCLUSION: ER visit for asthma exacerbation within 1 month URTI in the past 4 weeks Hospitalizations for asthma in past 6 months Treatment with antihistamines, anticholinergics, theophylline and chromones, LABA, inhaled and oral corticosteroids Bronchiectasis Gastroesophageal reflux Poor knowledge of the Italian language
Interventions	PROTOCOL Duration Run‐in: 4 weeks Intervention: 16 weeks TEST GROUP 1: 10 mg Montelukast once daily TEST GROUP 2: 10 mg Montelukast once daily + 400 μg Budesonide twice a day CONTROL GROUP: 400 μg Budesonide twice a day DEVICE: Turbo haler CRITERIA FOR WITHDRAWAL: Not described CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS PER PROTOCOL: not by ITT OUTCOMES: Reported at 16 weeks PULMONARY FUNCTION TEST: Change from baseline in FVC Change from baseline in FEV1 Change from baseline in PC20 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Change in AQOL (Asthma Quality of Life Questionnaire ‐ Juniper) in each of 4 domains Asthma exacerbations (defined as requiring systemic corticosteroids or hospital admission or ED treatment for worsening asthma or decrease in morning PEF >25% INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Not mentioned WITHDRAWALS: Reported Primary outcome: Not specified
ICS dose in HFA beclomethasone ‐ equivalent	400 μg
Notes	Full‐text publication Funded by University Confirmation of methodology and data extraction: obtained by Graziono Riccioni, Oct 2003
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	Data on compliance of treatment and adverse effects were mentioned in methodology but not addressed in the results
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined, but no bias was observed
Other bias	Low risk	No apparent other bias

Riccioni 2003.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	ATOPIC NON‐SMOKING MILD‐PERSISTENT BRONCHIAL ASTHMATICS RANDOMISED: N = 45 N = 51 M = 12 BUD = 14 WITHDRAWALS: Not mentioned AGE: years ± SD: M = 26.16 ± 5.07 BUD = 25.85 ± 10.46 GENDER (% male): M = 58.33% BUD = 57.14% ASTHMA SEVERITY: Mild ASTHMA DURATION: 1 year % Pred. FEV1: mean ± SD: M=94.75 ± 7.68 BUD = 99.85 ± 12.92 ATOPY: 100% (Dermatophagoides Pteronyssinus) ELIGIBILITY CRITERIA: Asthma based on typical symptoms improvement in pre‐bronchodilator forced expiratory volume in one second (FEV1) ± 15% after salbutamol, FEV1 between 60 and 85% of predicted value as per NIH criteria EXCLUSION: Emergency treatment for an asthma exacerbation within one month, URTI in the past 3 weeks, Hospitalization for asthma in past 3 months previous to enrolment, Treatment with antihistamines, anticholinergics, theophyline and chromones, b2‐long acting, inhaled and oral corticosteroids Presence of autoimmune, hepatic or renal disorders, malabsorption, drug or alcohol‐addiction Pregnancy or lactation
Interventions	PROTOCOL Duration Run‐in: 2 weeks Intervention: 12 weeks TEST GROUP 1: 10 mg Montelukast once daily CONTROL GROUP: 400 μg Budesonide twice a day DEVICE: Not mentioned CRITERIA FOR WITHDRAWAL: Not described CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS : Not mentioned OUTCOMES Reported at 12 weeks PULMONARY FUNCTION TEST: Baseline and end values of %FEV1 of predicted Baseline and end values of PEF % of predicted Bronchial responsiveness baseline and end values PC20 SYMPTOM SCORES: Not reported INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Not mentioned WITHDRAWALS: Not reported Primary outcome: Not specified
ICS dose in HFA beclomethasone ‐ equivalent	400 μg
Notes	Full‐text publication Funded: Not reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	There is no report as to whether some patients withdrew from the study after randomisation
Selective reporting (reporting bias)	High risk	The primary outcome was not specified. The data on several outcomes was insufficiently reported to be aggregated namely,  number of puffs used each day; daily asthma diary; adverse events, FVC, compliance of treatment were not reported
Other bias	Low risk	No apparent other bias

Sheth 2001.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: unclear if stratified randomisation on baseline FEV1 value FEV1 > 70% N = 152 Z = 55 FP = 51 Placebo = 46 FEV1 < 70% N = 177 Z = 52 FP = 60 Placebo = 65 WITHDRAWALS: Not reported AGE: mean (± SD) years: Not reported GENDER (% male): Not reported BASELINE SEVERITY: Not reported % Predicted FEV1: (FEV1 > 70%) Z: 75% FP:76% Placebo: 76% (FEV1 < 70%) Z: 63% FP: 62% Placebo: 63% ATOPY/ALLERGEN TRIGGERS: Not reported ASTHMA DURATION (years): Not reported ELIGIBILITY CRITERIA: ≽12 years old Symptomatic on β2‐agonists EXCLUSION: Not reported
Interventions	PROTOCOL Duration Intervention: 12 weeks TEST GROUP: Zafirlukast 20 mg twice a day CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Not mentioned CRITERIA FOR WITHDRAWAL: Not mentioned CO‐INTERVENTION: Not mentioned
Outcomes	ANALYSIS (ITT) OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS *Change from baseline FEV1 (L) Change from baseline in morning PEF (L/s) SYMPTOM SCORES: Change in symptom‐free days (%) FUNCTIONAL STATUS: Change from baseline in rescue β2‐agonist use (puffs/day) INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Not reported WITHDRAWALS: Not reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Abstract Funding not mentioned, probably by GSK Confirmation of methodology and data extraction: Not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated randomisation
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind ‐double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Primary outcome was defined
Other bias	Low risk	No apparent other bias

Sorkness 2007.

Methods	DESIGN: Parallel‐group, clinical trial.
Participants	CHILDREN WITH MILD TO MODERATE PERSISTENT ASTHMA RANDOMISED: N = 285 M = 95 FP = 96 WITHDRAWALS: M: 12 (12.63%) FP: 10 (9.6%) AGE: mean ± SD years M: 9.6 ± 2.2 FP: 9.8 ± 2.2 GENDER: % male M: 60.0% FP: 59.4% ASTHMA SEVERITY: Mild to moderate % Pred. FEV1 (mean ± SD): M: 97.7 ± 13.6 FP:97.8 ± 12.2 ATOPY or ALLERGIC RHINITIS: M: 76.8% FP: 78.1% ELIGIBILITY CRITERIA: Age 6 to <= 14 years Ability to perform reproducible spirometry, an FEV1 (measured more than 4 hours since the most recent use of a bronchodilator) 80% predicted normal at screening and 70% predicted normal at randomisation, Methacholine FEV1 PC20 12.5 mg/mL, Children with mild‐moderate persistent asthma, as defined by diary‐reported symptoms or β2‐agonist use (not including pre exercise) or peak flows < 80% calculated from the mean of morning and evening peak flows obtained during the final week of the run‐in period, on average at least 3 times per week EXCLUSION: Other lung diseases Respiratory tract infection, asthma exacerbation, or systemic corticosteroid use within 4 weeks; 2 or more asthma hospitalizations in the past year, History of a life‐threatening asthma exacerbation, 4 courses of systemic corticosteroids in the past year, Cigarette smoking within the past year, Pregnancy or lactation, Failure to practice abstinence or use a medically acceptable birth Control method, History of adverse reactions to the PACT medications
Interventions	PROTOCOL Duration Run‐in Period: 2‐4 weeks Intervention Period: 486 weeks TEST GROUP: Montelukast 10 mg qd p.o. CONTROL GROUP 1: Fluticasone propionate 100 μcg morning and 100 μcg evening DEVICE: Flovent Diskus; GlaxoSmithKline CO‐INTERVENTION: None permitted
Outcomes	ANALYSIS by Intention‐to‐treat OUTCOMES reported at 48 weeks PULMONARY FUNCTION TESTS: FEV1, % predicted FEV1/FVC (%) AM PEF, % predicted PM PEF, % predicted SYMPTOM SCORES: Asthma control questionnaire FUNCTIONAL STATUS: *Asthma control days, % of treatment days Episode‐free days, % Growth, cm INFLAMMATORY MEDIATORS: ENO, % ADVERSE EVENTS: Reported WITHDRAWALS: Reported *Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication Funded: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: randomisation was stratified by centre
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind; double‐dummy with identical placebo
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Approximately 12% of withdrawal, balanced between  groups but the reasons for withdrawal were not specified by group.
Selective reporting (reporting bias)	Low risk	All outcomes reported in the manuscript are reported, including adverse events
Other bias	Low risk	No apparent other bias

Stelmach 2002a.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology: Obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 91 M: 18 Triamcinolone: 19 Formoterol: 18 Placebo: 36 WITHDRAWALS: M: 3 (17%) Triamcinolone: 3 (17%) AGE: years ± SD: (without withdrawals): M: 11.1 ± 1.8 yr Triamcinolone:12.2 ± 2.1 yr GENDER (% male): M: 60% Triamcinolone:55% ASTHMA SEVERITY: Moderate % Pred. FEV1 % (± SD): M: 78.1 ± 3.1 Triamcinolone:73.5 ± 4.3 Mean (± SD) β2‐agonist use (puffs/day): Not described ALLERGIC RHINITIS: M: 15% Triamcinolone: 10% ATOPY (to dust mites): M: 100% Triamcinolone: 100% DURATION OF ASTHMA: M: 3.8 ± 0.6 Triamcinolone:3.7 ± 0.5 ELIGIBILITY CRITERIA: Age: 6‐18 years Asthma definition as per the NIH 1997 Improvement in FEV1 >= 15% after 200 μg salbutamol Current tx with only β2‐agonist Use of β2‐agonist daily, attacks that limit daily activity, night‐time symptoms >1 / week, PEF 60‐80% of predicted, PEF variability >30% EXCLUSION: Co‐existent diseases (hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, malignancy, other pulmonary or hematologic disease, active upper respiratory tract infections. Medication: B‐blockers, astemizole, oral corticosteroids, immunotherapy.
Interventions	PROTOCOL Duration Run‐in Period: 4 weeks Intervention Period: 8 weeks TEST GROUP: Montelukast 5 mg per day if <=14 years (10 mg per day, otherwise) CONTROL GROUP 1: Inhaled Triamcinolone acetonide 100ug/day qid CONTROL GROUP 2: Placebo (not used in this review) CONTROL GROUP 3: Formoterol 12 μg twice a day (not used in this review) DEVICE: MDI (actuation inhaler) CO‐INTERVENTION: No other Rx allowed other than rescue b2‐agonists or rescue oral corticosteroids
Outcomes	ANALYSIS per protocol OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: Change from baseline FEV1 ‐Change from baseline in PC 20 SYMPTOM SCORES: Total score (3‐point for daytime symptoms + 3‐point for night‐time symptoms + 3 points for use of rescue β2‐agonists) FUNCTIONAL STATUS: Patients with exacerbations requiring systemic corticosteroids INFLAMMATORY MEDIATORS: Change from baseline in serum eosinophils Change from baseline in serum IL‐10 Change from baseline in serum ECP ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome not specified
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full Text publication (2002) Self‐funded by authors Confirmation of methodology and data obtained from I. Stelmach June 2003
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation schedule
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, reasons for withdrawal were mentioned
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined, but no bias was observed
Other bias	Low risk	No apparent other bias

Stelmach 2002b.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N =154 M: 27 Triamcinolone: 28 Formoterol: 28 Nedocromil: 26 Placebo: 45 WITHDRAWALS (N = 14) M: 11% (3/27) Triamcinolone: 11 % (3/28) Formoterol: 11% (3/28) Nedocromil: 0% Placebo: 12% (40/45) AGE: years ± SD: M: 12.8 ± 1.7 yr Triamcinolone:13,1 ± 2.4 yr GENDER (% male): M: 48.1% Triamcinolone:53.6 % ASTHMA SEVERITY: Moderate asthma % Pred. FEV1 % ±SD: ‐ after withdrawals M: 73.7 ± 5.4 Triamcinolone:73.2 ± 3.8 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY (described as chronic atopic): M: 100% Triamcinolone: 100% ALLERGIC RHINITIS: Montelukast: 7.1% Triamcinolone:10.7% DURATION OF ASTHMA (years): M: 3.8 ± 0.5 Triamcinolone: 3.7 ± 0.6 ASTHMA SYMPTOMS: M: 6.2 ± 1.0 Triamcinolone: 7.1 ± 0.9 (score of 0‐9) ELIGIBILITY CRITERIA: Age= 9‐17 years Asthma definition according to NIH 1997 Reversibility: improvement in FEV1 >= 15% after 200 μg salbutamol Use of β2‐agonist daily, attacks that limit daily activity, night‐time symptoms >1 / week, PEF 60‐80% of predicted, PEF variability >30% EXCLUSION: Co‐existent diseases (hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, malignancy, other pulmonary or haematologic disease, active upper respiratory tract infections.
Interventions	PROTOCOL Duration Run‐in Period: 4 weeks Intervention Period: 4 weeks TEST GROUP: Montelukast 5 mg per day if <= 14 years (10 mg per day, otherwise) CONTROL GROUP 1: Inhaled Triamcinolone acetonide 200ug twice a day CONTROL GROUP 2: Placebo (not used in this review) CONTROL GROUP 3: Formoterol 12 μg twice a day (not used in this review) CONTROL GROUP 4: Nedocromil 0.002 g/inhalation 2 inhalations qid (not used in this review) DEVICE: MDI (actuation inhaler) CO‐INTERVENTION: No other Rx allowed other than rescue β2‐agonist or rescue systemic corticosteroids.
Outcomes	ANALYSIS per protocol OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: Change from baseline FEV1 ‐Change from baseline in PC 20 SYMPTOM SCORES: Total score (3‐point for daytime symptoms + 3‐point for night‐time symptoms + 3 points for use of rescue β2‐agonists) FUNCTIONAL STATUS Patients with exacerbations requiring systemic corticosteroids INFLAMMATORY MEDIATORS: Change from baseline in serum eosinophils Change from baseline in serum ECP ADVERSE EVENTS: Not reported WITHDRAWALS: Reported overall (not by group) Primary outcome: Not specified
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full Text publication (2002) Self‐Funded Confirmation of methodology and data obtained from I. Stelmach June 2003
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation schedule
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, overall reasons for withdrawal were mentioned
Selective reporting (reporting bias)	Low risk	Primary outcome was not defined but no bias was observed
Other bias	Low risk	Not found

Stelmach 2004.

Methods	DESIGN: Three armed, parallel‐group, randomised, clinical trial.
Participants	CHILDREN WITH HISTORY OF ASTHMA AND SENSITIVE TO HOUSE DUST MITES (DERMATOPHAGOIDES PTERONYSSINUS AND/OR DERMATOPHAGOIDES FARINE) RANDOMISED: N =250 M: 80 Triamcinolone: 83 WITHDRAWALS: N = 4 M: 2.5% Triamcinolone: 2.41% AGE: years ± SD: M: 12.6 ± 2.097 yr Triamcinolone:11.9 ± 1.51 yr GENDER (% male): M: 57.69 % Triamcinolone:54.32 % ASTHMA SEVERITY: Mild to moderate asthma % Pred. FEV1 % ±SD ‐ after withdrawals: M: 76.2 ± 5.16 Triamcinolone:74.3 ± 3.88 ATOPY (described as chronic atopic): M: 100% Triamcinolone: 100% DURATION OF ASTHMA (years): M: 3.9 ± 0.58 Triamcinolone: 3.7 ± 0.54 ASTHMA SYMPTOMS: M: 6.6 ± 1.05 Triamcinolone: 6.9 ± 0.99 ELIGIBILITY CRITERIA: Age= 6‐18 years Diagnosis of bronchial asthma with a duration of at least 6 months before the first visit Had been no exacerbations or need for any other treatment for 6 months and no hospitalizations for asthma occurred within 6 months of the pre study visit
Interventions	PROTOCOL Duration Run‐in Period: Not mentioned Intervention Period: 4 weeks TEST GROUP: Montelukast 5 mg tablets in children aged 6–14 yr or 10 mg tablets in children over 14 yr of age CONTROL GROUP 1: Inhaled Triamcinolone acetonide two puffs twice a day (400 μg/day), DEVICE: Azmacort, Aventis, USA CO‐INTERVENTION: No other Rx allowed other than rescue b2‐agonists or rescue oral corticosteroids
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT: Not reported OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: Baseline and end point FEV1% of predicted Baseline and end point in PC20 SYMPTOM SCORES: Total asthma score INFLAMMATORY MEDIATORS: Eosinophil blood count ADVERSE EVENTS: Not reported WITHDRAWALS: Reported overall (not by group) Primary outcome not specified
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full Text publication Funded: Not mentioned
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation schedule
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Open labelled
Incomplete outcome data (attrition bias) All outcomes	Low risk	The withdrawal rate was low (2%) and balanced between  groups and the reasons for withdrawal were specified by group.
Selective reporting (reporting bias)	High risk	The primary  outcome was not specified and the results of the Paediatric asthma quality of life questionnaire and adverse effects were not presented. The data was not reported as analysed by intention‐to‐treat analysis.
Other bias	Low risk	No apparent other bias

Stelmach 2005.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	CHILDREN WITH NEWLY DIAGNOSED ASTHMA AND SENSITIVE TO HOUSE‐DUST MITES (DERMATOPHAGOIDES PTERONYSSINUS AND/OR DERMATOPHAGOIDES FARINE) RANDOMISED: N = 51 M: 17 Medium dose BD (400 mg/day): 16 High dose BD (800 mg/day): 18 WITHDRAWALS: N = 2 M: 5.88% Medium dose BP (400 mg/day): 6.25% AGE: years ± SD M: 12.1 ± 1.6 Medium dose BD (400 mg/day): 11.6 ± 1.4 High dose BD (800 mg/day): 11.6 ± 1.8 GENDER: % male: M: 56.3 Medium dose BD (400 mg/day): 60 High dose BD (800 mg/day): 55.6 ASTHMA SEVERITY: Newly diagnosed asthma and sensitive to house‐dust mites (Dermatophagoides pteronyssinus or/and Dermatophagoides farinae) % Pred. FEV1 % ±SD ‐ after withdrawals: M: 83.4 ± 0.4 Medium dose BD (400 mg/day): 84.3 ± 0.5 High dose BD (800 mg/day): 83.4 ± 0.3 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY (described as chronic atopic): Not described ALLERGIC RHINITIS: Not described DURATION OF ASTHMA (years): Not described ASTHMA SYMPTOMS: Not described ELIGIBILITY CRITERIA: Age: 6–18 Newly diagnosed asthma and sensitive to house‐dust mites (Dermatophagoides pteronyssinus or/and Dermatophagoides farinae), Diagnosis of asthma based on typical symptoms and improvement in the pre bronchodilator forced expiratory volume in 1 sec (FEV1) of R15% after salbutamol (200 mg). Not received corticosteroids and anti‐leukotriene therapy prior to the study.
Interventions	PROTOCOL Duration Run‐in Period: Not mentioned Intervention Period: 6 months TEST GROUP: Montelukast sodium 5 mg tablets in children aged 6–14 yr or 10 mg tablets in children over 14 yr of age CONTROL GROUP 1 (Medium dose): Inhaled Budesonide 400 mg/day CONTROL GROUP 2 (High dose): Inhaled Budesonide 800 mg/day DEVICE: Dry powder capsule (Miflonide, Novartis, Switzerland) CO‐INTERVENTION:: No other Rx allowed other than rescue b2‐agonists
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT: Not reported OUTCOMES reported at 6 months PULMONARY FUNCTION TESTS: FEV1% of predicted SYMPTOM SCORES: Total asthma score INFLAMMATORY MEDIATORS: *Total IgE (IU/ml) *Dermatophagoides pteronyssinus (IU/ml) *Dermatophagoides farinae (IU/ml) ADVERSE EVENTS: Not reported WITHDRAWALS: Reported by group *Primary outcomes
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full Text publication Funded: Not mentioned
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation schedule
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Doubl blind, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	The withdrawal rate was low, balanced between groups with reasons for withdrawal reported by group.
Selective reporting (reporting bias)	Low risk	All outcomes reported in the manuscript are reported, including adverse events
Other bias	Low risk	No apparent other bias

Stelmach 2007.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	CHILDREN WITH NEWLY DIAGNOSED ASTHMA AND SENSITIVE TO HOUSE‐DUST MITES (DERMATOPHAGOIDES PTERONYSSINUS AND/OR DERMATOPHAGOIDES FARINE) RANDOMISED: N = 51 M: 29 BD: 29 M + BD: 29 Formoterol + BD: 29 Placebo: 29 WITHDRAWALS: N = 2 M: 0 BD: 0 M + BD: 0 Formoterol + BD: 0 Placebo: 2 AGE: years ± SD M: 10.4 ± 2.9 BD: 12 ± 3.1 M + BD: 11 ± 3.2 Formoterol + BD: 8.79 ± 2.4 Placebo: 11.4 ± 3.3 GENDER: % male M: 62.1 BD: 69 M + BD: 69 Formoterol + BD: 58.6 Placeboe: 70.4 ASTHMA SEVERITY: Newly diagnosed asthma and sensitive to house‐dust mites (Dermatophagoides pteronyssinus or/and Dermatophagoides farinae) % Pred. FEV1 % ± SD: M: 95.5 ± 2.1 BD: 94.4 ± 1.8 M + BD: 94.8 ± 2.1 Formoterol + BD: 93.1 ± 2.3 Placebo: 94.8 ± 1.8 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY (described as chronic atopic): Not described ALLERGIC RHINITIS: Not described DURATION OF ASTHMA (years ± SD): M: 3.85 ± 0.61 BD: 3.97 ± 0.52 M + BD: 3.79 ± 0.58 Formoterol + BD: 3.93 ± 0.63 Placebo: 3.88 ± 0.47 ASTHMA SYMPTOMS: Not described ELIGIBILITY CRITERIA: INCLUSION CRITERIAS: Male and female outpatients, Aged 6–18, With a clinical diagnosis of bronchial asthma with a duration of at least 6 months before the first visit With current history of moderate persistent asthma EXCLUSION CRITERIAS: With active upper respiratory tract infection within 3 weeks before the study and acute sinus disease requiring antibiotic treatment within 1 month before the study, previous intubation, or asthma hospitalisation during the 3 months before the first visit. Other clinically significant pulmonary, hematologic, hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, and/or psychiatric diseases or malignancy that either put the patient at risk when participating in the study or could influence the results of the study or the patient’s ability to participate in the study as judged by the investigator. On beta‐blockers (eye drops included), astemizole within 3 months, or oral corticosteroids within 1 month before the first visit. Patients who were receiving immunotherapy
Interventions	PROTOCOL Duration Run‐in Period: Not mentioned Intervention Period: 4 weeks TEST GROUP: Montelukast sodium 5 mg tablets in children aged 6–14 yr or 10 mg tablets in children over 14 yr of age CONTROL GROUP 1: Inhaled Budesonide 200 mg/day CONTROL GROUP 2: Montelukast 5 or 10 mg tablets and Inhaled Budesonide200 mg/day CONTROL GROUP 3: Formoterol mg/day and Inhaled Budesonide200 mg/day CONTROL GROUP 4: Placebo DEVICE: Turbuhaler
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT: Not reported OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: FEV1% of predicted FEF25–75 (% pred.) SRaw (% pred.) Rint (% pred.) SYMPTOM SCORES: Not described INFLAMMATORY MEDIATORS: Not described ADVERSE EVENTS: Not reported WITHDRAWALS: Reported by group
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full Text publication Funded: Grants from the Medical University of Lodz, Poland
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation schedule
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind; double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, balanced numbers in all groups, reason for withdrawal by group reported,
Selective reporting (reporting bias)	Low risk	Primary and secondary outcome was not specified but no bias was observed
Other bias	Low risk	No apparent other bias

Stelmach 2008.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	CHILDREN WITH SYMPTOMATIC ASTHMA AND SENSITIVE TO HOUSE‐DUST MITES (DERMATOPHAGOIDES PTERONYSSINUS AND/OR DERMATOPHAGOIDES FARINE) RANDOMISED: N =100 M: 20 BD: 20 M + BD: 20 Formoterol + BD: 20 Placebo: 20 WITHDRAWALS: N = 9 M: 3 BD: 0 M + BD: 3 Formoterol + BD: 2 Placebo: 1 AGE: years (range) M: 11.8 (7‐17) BD: 11.9 (6‐16) M + BD: 12.2 (7‐18) Formoterol + BD: 11.3 (6‐18) Placebo: 12.1 (7‐15) GENDER (% male): Not reported ASTHMA SEVERITY: Not reported % Pred. FEV1 % ±SD: M: 93.5 ± 11.4 BD:92.2 ± 13.5 M + BD: 90.2 ± 10.2 Formoterol + BD: 91.1 ± 11.2 Placebo: 92.4 12.7 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY (described as chronic atopic): Not described ALLERGIC RHINITIS: Not described DURATION OF ASTHMA (years): Not reported ASTHMA SYMPTOMS: Not reported INCLUSION CRITERIAS: Male and female outpatients, Age 6 to 18, With a clinical diagnosis of bronchial asthma with a duration of at least 6 months before the first visit FEV1 of 70% or more and a documented decrease in FEV1 of 20% or more after a standard exercise challenge test. EXCLUSION CRITERIAS: With active upper respiratory tract infection within 3 weeks before the study and acute sinus disease requiring antibiotic treatment within 1 month before the study, previous intubation, or asthma hospitalizations during the 3 months before the pre study visit. Other clinically significant pulmonary, hematologic, hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, and/or psychiatric diseases or malignancy that either put the patient at risk when participating in the study or could influence the results of the study or the patient’s ability to participate in the study as judged by the investigator. On β2‐blockers (eye drops included) or oral corticosteroids within 1 month before the first visit. On immunotherapy
Interventions	PROTOCOL Duration Run‐in Period: Not mentioned Intervention Period: 4 weeks TEST GROUP: Montelukast sodium 5 mg tablets in children aged 6–14 yr or 10 mg tablets in children over 14 yr of age CONTROL GROUP 1: Inhaled Budesonide 200 mg/day CONTROL GROUP 2: Montelukast 5 or 10 mg tablets and Inhaled Budesonide200 mg/day CONTROL GROUP 3: Formoterol mg/day and Inhaled Budesonide200 mg/day CONTROL GROUP 4: Placebo DEVICE: Turbuhaler
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT: Not reported OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: AUC0‐20min of FEV1 Maximum % fall in FEV1 SYMPTOM SCORES: Not described INFLAMMATORY MEDIATORS: Not described ADVERSE EVENTS: Not reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full Text publication Funded: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation schedule
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind; double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The overall withdrawal rate was 10% (N = 9)  but it was not presented by group. This might be of importance as the only reason for withdrawal was poor efficacy.
Selective reporting (reporting bias)	Low risk	Primary outcome was not  pre‐specified however no bias was observed
Other bias	Low risk	No apparent other bias

Szefler 2005.

Methods	DESIGN: Cross‐over, randomised, clinical trial.
Participants	PATIENTS WITH MILD TO MODERATE PERSISTENT ASTHMA RANDOMISED: N = 144 WITHDRAWALS: no (%) N = 17, (11.81%) M: 11 (7.64%) FP: 6 (4.17%) AGE: years ± SD: Not reported GENDER (% male): Not reported ASTHMA SEVERITY: Not reported % Pred. FEV1 % ± SD: Not reported Mean (± SD) β2‐agonist use (puffs/day): Not reported ATOPY: Not reported ALLERGIC RHINITIS: Not reported DURATION OF ASTHMA (years): Not reported ASTHMA SYMPTOMS:Not reported INCLUSION CRITERIAS: Children with 6 to 17 years of age with mild‐to‐moderate asthma Had asthma symptoms or rescue bronchodilator use on average of 3 or more days per week during the previous 4 weeks Improvement in FEV1 of 12% or greater after maximal bronchodilation or methacholine PC20 of 12.5 mg/mL or less. Had no corticosteroid treatment within 4 weeks, no leukotriene‐modifying agents within 2 weeks, No history of respiratory tract infection within 4 weeks of enrolment EXCLUSION CRITERIAS: Had severe asthma or FEV1 of less than 70% of predicted value,
Interventions	PROTOCOL Duration Run‐in Period: not reported Intervention Period: 52 weeks TEST GROUP: Montelukast sodium 5‐mg chewable tablet for those 6 to 14 years of age and 10‐mg tablet for those 15 to 18 years of age CONTROL GROUP 1: Flovent Diskus, 100 μg per inhalation administered as one inhalation twice a day DEVICE: Diskus
Outcomes	ANALYSIS NOT BY INTENTION‐TO‐TREAT OUTCOMES reported at 8 weeks PULMONARY FUNCTION TESTS: *Prebronchodilator FEV1 % predicted Prebronchodilator FEV1/FVC (%) FUNCTIONAL TESTS: Bronchodilator use per week Maximum bronchodilator response (% change in FEV1) Methacholine PC20 (mg/mL) SYMPTOM SCORES: Not reported INFLAMMATORY MEDIATORS: eNO (ppb) Blood TEC (cells/mm3) Serum ECP (mg/L) Serum IgE (kU/L) uLTE4 (pg/mg creatinine) ADVERSE EVENTS: Reported by groups WITHDRAWALS: Reported *Primary outcomes
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full Text publication Funded: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: by minimization method for several factors
Allocation concealment (selection bias)	Unclear risk	Nnot reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	No intention‐to‐treat analysis, 8.4% and 15.1% of withdrawal in ICS and montelukast groups respectively
Selective reporting (reporting bias)	Low risk	Primary outcome was specified
Other bias	Low risk	No apparent other bias

Szefler 2007.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	PATIENTS WITH MILD PERSISTENT ASTHMA RANDOMISED: N = 395 M: 198 BD: 197 WITHDRAWALS: no (%) N = 115, (29.1%) M: 52 (26.40%) BD: 63 (31.98%) AGE: years ± SD M: 4.7 ± 1.9 BD: 4.6 ± 2.0 GENDER (% male): M: 118 ± 59.9 BD: 122 ± 61.9 ASTHMA SEVERITY: Not reported % Pred. FEV1 % ± SD: M: 91.67 ± 18.07 BD:89.88 ± 17.75 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY (described as chronic atopic): Not described ALLERGIC RHINITIS: Not described DURATION OF ASTHMA (years): Not reported ASTHMA SYMPTOMS: Not reported INCLUSION CRITERIAS: Children 2 to 8 years of age with symptoms of mild persistent asthma as determined by 2002 NAEPP guidelines1 or had, in the year before screening, History of 3 wheezing episodes that lasted > 1 day and affected sleep. A cumulative asthma symptom score (daytime plus night‐time) of 2 on 3 of 7 consecutive days, EXCLUSION CRITERIAS: History of severe or unstable asthma; Hypersensitivity to budesonide or montelukast sodium; A clinically significant disease (past or present) or other medical condition that, in the opinion of the investigator, could interfere with the study or place the subject at risk because of participation in the study; Acute exacerbation of asthma or a respiratory tract infection within 30 days before screening that, in the opinion of the investigator, could have affected the results of the study; Used montelukast or an inhaled corticosteroids within 1 week of screening, systemic corticosteroids within 2 weeks of screening or during the run‐in period, or omalizumab within 6 months of screening
Interventions	PROTOCOL Duration Run‐in Period: 3‐21 days Intervention Period: 52 weeks TEST GROUP: Montelukast sodium 4 or 5 mg tablets CONTROL GROUP 1: Budesonide inhalation suspension 0.5 mg/day DEVICE: Not described
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT OUTCOMES reported at 52 weeks PULMONARY FUNCTION TESTS: AM PEF PM PEF FEV1 (L) % Predicted FEV1 FUNCTIONAL TESTS: *Time to first additional asthma medication for mild or severe asthma exacerbation, Exacerbations Rescue medication–free days, % Asthma‐free days, % SYMPTOM SCORES AM asthma symptom score PM asthma symptom score INFLAMMATORY MEDIATORS: Not described ADVERSE EVENTS: Reported by groups WITHDRAWALS: Reported *Primary outcomes
ICS dose in HFA beclomethasone ‐ equivalent	250 μg
Notes	Full Text publication Funded: AstraZeneca LP
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Open labelled and study subjects could be discontinued at any time at the discretion of the investigators.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	the withdrawal data is presented by group, however the large withdrawal rate (29%), similar in both group, while acceptable for the main outcome (time to event) raise doubt about the validity of the secondary outcomes
Selective reporting (reporting bias)	Low risk	All outcomes are reported
Other bias	Low risk	No apparent other bias

Tamaoki 2008.

Methods	DESIGN: Parallel‐group, randomised, clinical trial.
Participants	NEWLY DIAGNOSED MILD INTERMITTENT ASTHMA PATIENTS RANDOMISED: N = 85 PRAN: 42 BD: 43 WITHDRAWALS: no (%) N = 11 (12.94%) PRAN: 6 (14.29%) BD: 5 (11.63%) AGE: years ± SD PRAN: 36 ± 3 BD: 38 ± 4 GENDER (% male) PRAN: 27.7 BD: 26.32 ASTHMA SEVERITY: Not reported % Pred. FEV1 % ± SD: PRAN: 84.6 ± 2.0 BD: 85.0 ± 2.1 Mean (±SD) β2‐agonist use (puffs/day): Not described ATOPY (described as chronic atopic): Not described ALLERGIC RHINITIS: Not described DURATION OF ASTHMA (years): PRAN: 1.6 ± 1.1 BD: 2.0 ± 1.2 ASTHMA SYMPTOMS SCORE: PRAN: 5.4 ± 0.4 BD: 5.7 ± 0.5 INCLUSION CRITERIAS: Newly diagnosed mild intermittent asthma aged 21 years, Whose daytime symptoms of less than once a week but at least once during 3 months before the study, FEV1 or PEF of 80% of predicted normal and diurnal variation of PEF 20% EXCLUSION CRITERIAS: Treated with inhaled or systemic corticosteroids, inhaled long‐acting 2‐agonists, theophylline, leukotriene receptor antagonists, or other controller medications within the previous 6 months On inhaled sodium cromoglycate, histamine H1‐antagonists or nonsteroidal anti‐inflammatory drugs used within 4 weeks before entry into this study. History of serious diseases or other lung conditions.
Interventions	PROTOCOL Duration Run‐in Period: 4 weeks Intervention Period: 8 weeks TEST GROUP: Pranlukast 225 mg twice a day CONTROL GROUP: Inhaled BDP 100 μg twice a day DEVICE: Metered‐dose inhaler using a spacing chamber
Outcomes	ANALYSIS BY INTENTION‐TO‐TREAT: Not reported OUTCOMES reported at 8 weeks PULMONARY FUNCTION TESTS: AM PEF PM PEF Change in FEV1 (L) FUNCTIONAL TESTS: Changes in the use of supplemental 2‐agonist SYMPTOM SCORES: Asthma symptom score INFLAMMATORY MEDIATORS: Eosinophil (%) Mast cell (%) ECP (ng/mL) Tryptase (ng/mL) ADVERSE EVENTS: Not reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	100 μg
Notes	Full Text publication Funded: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: randomised using balanced block of four
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, drop‐outs are reported by group and were balanced between the two groups
Selective reporting (reporting bias)	Low risk	No apparent other bias
Other bias	Low risk	No apparent other bias

Yamauchi 2001.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. ‐Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 30 P: 10 BDP: 10 Placebo: 10 (not used) WITHDRAWALS: Not reported AGE (± SD) years: P: 40.6 ± 2.02 BDP: 42.2 ± 3.32 GENDER (% male): M: 60% BDP: 70% ASTHMA SEVERITY: Mild persistent or mild intermittent % Pred. FEV1 (mean ± SD) P: 91.8 ± 3.21 BDP: 92.0 ±2.18 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY: P: 60% BDP: 60% ASTHMA DURATION (years): Not reported ELIGIBILITY CRITERIA: < 15% variability in PEF over preceding 2 weeks No upper respiratory tract infection in preceding 4 weeks Treatment with inhaled β2‐agonist on demand or oral slow‐release theophylline or oral β2‐agonist No inhaled or systemic corticosteroids EXCLUSION CRITERIA: Not described.
Interventions	PROTOCOL Duration Run‐in Period: not described if any Intervention Period: 4 weeks TEST GROUP: Pranlukast 450 mg/day CONTROL GROUP: Inhaled Beclomethasone 400 μg/day DEVICE: Not reported CO‐INTERVENTION: Theophylline M: 11% BCP: 10%
Outcomes	ANALYSIS ( ITT not specified) OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: Change in morning and evening PEFR SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not reported INFLAMMATORY MEDIATORS: Sputum eosinophil (%) Exhaled NO2 concentration (ppb) ADVERSE EVENTS: Not reported WITHDRAWALS: Not reported Primary outcome: Not specified
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication (2001) Funded by the Ministry of Education, Science, Sports and Culture in Japan Confirmation of data and methodology requested
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details on blinding provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All data presented, no intention‐to‐treat analysis and withdrawal rate is not reported
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were not defined, but no bias was observed
Other bias	Low risk	No apparent other bias

Yurdakul 2003.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 74 M: 25 BDP: 25 THEO: 24 (not used) WITHDRAWALS: Reported AGE (years ± SD): M: 34.3 ± 5 BDP: 34.9 ± 5 THEO: 33.5 ± 5 GENDER (% male): M: 20% BDP: 20% THEO: 25% ASTHMA SEVERITY: Mild persistent % Pred. FEV1 (mean ± SD): M: 84.8 ± 5.3 BDP: 84.5 ± 4.1 THEO: 86.6 ± 5.5 Mean (± SD) β2‐agonist use (puffs/day): Not described ATOPY: Not reported ASTHMA DURATION (years): Not reported INCLUSION CRITERIAS: Aged 23–45 years , Having mild persistent asthma according to the criteria of GINA, Baseline FEV1 at least 80% of the predicted normal value, with an increase of at least 15% in FEV1 from the baseline value after the inhalation of 400 mg of salbutamol. On inhaled budesonide at a dose of 200 mg a day or equivalent doses of beclomethasone dipropionate or fluticasone propionate and short‐acting b2‐agonist irregularly for at least 2 months prior to study. EXCLUSION CRITERIAS: With respiratory tract infection, smokers or had a respiratory disorder other than asthma disease, Had asthma exacerbations within the preceding 2 months, Pregnant or lactating women or with hypersensitivity to sympathomimetic amines, Women of childbearing potential who did not use a reliable contraceptive method.
Interventions	PROTOCOL Duration Run‐in Period: Not described if any Intervention Period: 4 weeks TEST GROUP: Pranlukast 450 mg/day CONTROL GROUP: Inhaled Beclomethasone 400 μg/day twice a day DEVICE: Not reported CO‐INTERVENTION: Theophylline M: 11% BCP: 10%
Outcomes	ANALYSIS ( ITT not specified) OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS: *AM PEFR FEV1 % predicted SYMPTOM SCORES: Day time symptom score Night‐time symptoms score FUNCTIONAL STATUS: Mean number of rescue inhalations, puffs/day INFLAMMATORY MEDIATORS: Not reported ADVERSE EVENTS: Reported exacerbation by groups WITHDRAWALS: Not reported *Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication (2003) Funded by: Not reported Confirmation of data and methodology: Not done
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: simple random sampling method according to random number table
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Open label
Incomplete outcome data (attrition bias) All outcomes	High risk	No intention‐to‐treat analysis and no reported withdrawal rate
Selective reporting (reporting bias)	Low risk	All outcomes reported in the manuscript are reported, including adverse events by group
Other bias	Low risk	No apparent other bias

Zedan 2009.

Methods	DESIGN: Parallel‐group, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 56 M: 27 FP: 29 WITHDRAWALS: Reported AGE: years ± SD: N: 9.45 ± 2.42 GENDER (% male): 64.15% ASTHMA SEVERITY: Moderate persistent asthma % Pred. FEV1 (mean ± SD): Not reported Mean (±SD) β2‐agonist use (puffs/day): Not described ATOPY: Not reported ASTHMA DURATION (years): N: 5.36 ELIGIBILITY CRITERIAS: Presence of typical asthma symptoms, Improvement in the pre bronchodilator FEV1 of ≥ 12% after administration of salbutamol (200 μg), Positive skin prick test for Dermatophagoides pteronyssimus and Dermatophagoides farinae, cat and dog epithelial cells, and molds and pollen antigens (Omega, Canada)
Interventions	PROTOCOL Duration Run‐in Period: 4 weeks Intervention Period: 4 weeks TEST GROUP: Montelukast 5 mg at bed time CONTROL GROUP: Fluticasone propionate (100 μg twice daily) DEVICE: Pressurized metered‐dose inhaler CO‐INTERVENTION: Short‐acting β2 agonists
Outcomes	ANALYSIS ( ITT not specified) OUTCOMES reported at 4 weeks PULMONARY FUNCTION TESTS: FEV1 SYMPTOM SCORES: Not reported FUNCTIONAL STATUS: Not reported INFLAMMATORY MEDIATORS: IgE, sIL‐2R, sICAM‐1, sVICAM‐1 Eosinophilic percentage ADVERSE EVENTS: Not reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full‐text publication (2009) Funded by: Not reported Confirmation of data and methodology: Not done
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Non‐blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented, withdrawal rate per group presented
Selective reporting (reporting bias)	Low risk	Not found
Other bias	Low risk	No apparent other bias

Zeiger 2005.

Methods	DESIGN: Parallel‐group, multi‐centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 380 M = 189 FP = 191 WITHDRAWALS; N (%): M: 25 (12.5%) FP: 28 (14%) AGE: Mean ( years ± SD): M: 33.9 ± 14.8 FP: 36.5 ± 13.8 GENDER (% male): M: 58 (30.2%) FP: 59 (30.9%) BASELINE SEVERITY: Mild and moderate % Pred. FEV1 ± SD: M: 93 ± 8.9 FP: 94.8 ± 10.8 MEAN (± SD) β2‐AGONIST USE (puffs/day): M = 3.4 ± 1.2 FP = 3.6 ± 1.4 ATOPY: Not reported ASTHMA DURATION: >=4 months ELIGIBILITY CRITERIA Asthmatic outpatients 15 to 85 years old Clinical history of asthma >= 4 months Average baseline FEV1 >= 80% pred. with no qualifying value below 70% Daytime symptoms and B‐agonist use on an average of >= and <= 6 days per week in the last 2 weeks of the run‐in period Reversibility by one of the following methods during baseline: FEV1 or PEFR, methacholine PC20 or exercise challenge EXCLUSION: Not reported
Interventions	PROTOCOL Duration Run‐in Period: 3 weeks Intervention: 12 weeks TEST GROUP: Montelukast 10 mg od CONTROL GROUP: Fluticasone 100 μg twice a day DEVICE: Not reported CO‐INTERVENTION: Not reported
Outcomes	ANALYSIS ( ITT not specified) OUTCOMES reported at 12 weeks PULMONARY FUNCTION TESTS: Change in FEV1 % predicted Change from baseline PEFR SYMPTOM SCORES: Asthma symptoms FUNCTIONAL STATUS: *% Change from baseline asthma rescue free days % change from baseline in days with B‐agonist use As needed albuterol use per day Asthma specific quality of life Asthma control INFLAMMATORY MARKERS: Blood eosinophil count ADVERSE EVENTS: Reported WITHDRAWALS: Reported * Primary outcome
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full paper (2005) Funded by Merck & Co. Inc Confirmation of methodology and data extraction: Not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: computer‐generated allocation schedule
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind,double dummies: "appropriate matching placebo'
Incomplete outcome data (attrition bias) All outcomes	Low risk	Modified intention‐to‐treat with low and similar withdrawal rate (6% LTRA versus  9% FP);
Selective reporting (reporting bias)	Unclear risk	Primary outcome (rescue‐free days) reported; poorly reported clinical and laboratory adverse health events
Other bias	Low risk	No apparent other bias

Zeiger 2006.

Methods	DESIGN: Cross over, multi‐centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 144 WITHDRAWALS; N (%): M: 25 (12.5%) FP: 28 (14%) AGE: Mean years ± SD: N: 17 ± 11.80% GENDER (% male): Not reported BASELINE SEVERITY: Mild and moderate persistent asthma % Pred. FEV1 (Mean ± SD): Not reported MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported ATOPY: Not reported ASTHMA DURATION: Not reported ELIGIBILITY CRITERIA: Absence of corticosteroid therapy within 4 weeks, leukotriene modifier agents within 2 weeks, and respiratory tract infection within 4 weeks of enrolment; Asthma symptoms or rescue bronchodilator use on average of 3 or more days/week for 4 weeks before enrolment; 12% or greater FEV1 reversibility after maximum bronchodilation or methacholine dose required to reduce baseline FEV1 by 20% (methacholine PC20 12.5 mg/mL); FEV1 of 70% of predicted value or greater.
Interventions	PROTOCOL Duration Intervention: 8 weeks TEST GROUP: Montelukast 5‐mg chewable tablet for those 6 to 14 years of age or as a 10‐mg for 15 to 18 years of age CONTROL GROUP: Fluticasone propionate 100 mg per inhalation administered as twice a day DEVICE: Flovent Diskus CO‐INTERVENTION: Not reported
Outcomes	ANALYSIS ( ITT not specified) OUTCOMES reported at 8 weeks PULMONARY FUNCTION TESTS: FEV1/FVC (%) Peak flow variability (%) Morning PEF R5 (kPa/L/s) AX (kPa/L) SYMPTOM SCORES: Average no. of ACDs (d/wk) ACQ overall score (units) FUNCTIONAL STATUS Asthma control days Albuterol use (no. of puffs/wk) INFLAMMATORY MARKERS: eNO ADVERSE EVENTS: Not reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full paper (2006) Funded by: Not reported Confirmation of methodology and data extraction: Not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Means of randomisation: minimization method
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind using double dummies: " placebo for the alternative drug"
Incomplete outcome data (attrition bias) All outcomes	High risk	No intention‐to‐treat analysis; withdrawal rate 12.5% and most withdrew because of treatment failure (i.e. requiring treatment with systemic corticosteroids with an imbalance between treatment period (2 FP and 10 in Montelukast)
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	No apparent other bias

Zielen 2010.

Methods	DESIGN: Parallel‐group, single centre, randomised, clinical trial. Confirmation of methodology: Not obtained
Participants	SYMPTOMATIC PARTICIPANTS RANDOMISED: N = 102 WITHDRAWALS; N M: 2 FP: 0 AGE: N: 4.94 GENDER (% male): N: 58.82% BASELINE SEVERITY: Episodic asthmatics % Pred. FEV1 (Mean ± SD): N: 98.8% MEAN (± SD) β2‐AGONIST USE (puffs/day): Not reported ATOPY: Not reported ASTHMA DURATION: Not reported INCLUSION CRITERIAS: Male or female patients age 4–7 years, Diagnosis of mild intermittent bronchial asthma in the past 6–12 months as stated by the investigator Use of inhaled β2‐agonists less than 1/week (max 3 puffs) Exacerbation‐free interval more than 4 weeks prior to visit 1 EXCLUSION CRITERIAS: Chronic persistent asthma, Severe concomitant diseases, Suspected non‐compliance, Age below 4 and age above 7 years
Interventions	PROTOCOL Duration Intervention: 6 weeks TEST GROUP: Montelukast 4‐mg chewable tablet for those 4 to 6 years of age or as a 5‐mg for older than 6 years CONTROL GROUP: Inhaled fluticasone 100 mg twice daily DEVICE: By spacer CO‐INTERVENTION: Inhaled salbutamol
Outcomes	ANALYSIS ( ITT not specified) OUTCOMES reported at 6 weeks PULMONARY FUNCTION TESTS: FEV1 pred. (%) FEV1/FVC Airway reversibility (%) PD20 FEV1 (mg) SYMPTOM SCORES: Asthma symptoms FUNCTIONAL STATUS: Number of exacerbations INFLAMMATORY MARKERS: Eosinophils Cumulative specific IgE (kU/L) ADVERSE EVENTS: Reported WITHDRAWALS: Reported
ICS dose in HFA beclomethasone ‐ equivalent	200 μg
Notes	Full paper (2010) Funded by: Disclosed for all funds for authors Confirmation of methodology and data extraction: Not obtained
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Means of randomisation: not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias) All outcomes	High risk	Open label
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data presented,
Selective reporting (reporting bias)	Low risk	Primary outcome and secondary outcomes reported, withdrawal by group reported
Other bias	Low risk	No apparent other bias

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Abbott Pharma 1996	Not a randomised controlled trial
Al Frayh 2008	Intervention was not anti‐leukotriene
Allayee 2007	Control intervention was not inhaled corticosteroid
Allen 1997	Not a randomised controlled trial
Allen‐Ramey 2003	Not a randomised controlled trial
Allen‐Ramey 2004	Not a randomised controlled trial
Allen‐Ramey 2006	Not a randomised controlled trial
Altman 1998k	Control intervention was not inhaled corticosteroid
Anonymous 1997	Not a randomised controlled trial
Armour 2007	Intervention was not anti‐leukotriene
Bacharier 2008	Intervention was given < 4 weeks
Bai 2010	Participants were not people with asthma
Balatsouras 2005	Participants were not people with asthma Control intervention was not inhaled corticosteroid
Baren 2006	Intervention was not anti‐leukotriene
Barnes 1996	Control intervention was not inhaled corticosteroid
Barnes 1997	Not a randomised controlled trial
Barnes 1997b	Control intervention was not inhaled corticosteroid
Barnes 2001	Not a randomised controlled trial (meta‐analysis)
Barnes 2007	Participants received additional non‐permitted co‐interventions (cetirizine with montelukast and intranasal beclomethasone with inhaled beclomethasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Barnes 2007a	Participants received additional non‐permitted co‐interventions (montelukast with inhaled budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Bartoli 2010	Intervention was not anti‐leukotriene
Bateman 1995	Control intervention was not inhaled corticosteroids
Bateman 2003	Participants received additional non‐permitted co‐interventions (fluticasone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Baumgartner 1999	Duplicate of published paper in Eur Respir J 2003;21:123‐128.
Benitez 2005	Participants received additional non‐permitted co‐interventions (budesonide with zafirlukast and oral loratadine/pseudoephedrine with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Berger 2006	Intervention was not anti‐leukotriene
Bilancia 2000	Participants received additional non‐permitted co‐interventions (combination of budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Bilderback 2004	Duplicate of published paper in Journal of Allergy & Clinical Immunology 2007;119(4):916‐923.
Bilderback 2005	Duplicate of published paper in Journal of Allergy & Clinical Immunology 2007;119(4):916‐923.
Bisgaard 1999	Control intervention was not inhaled corticosteroids. Participants received additional non‐permitted co‐interventions (inhaled steroids) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid. Outcomes did not reflect control of asthma (airway inflammation). Intervention < 4 weeks
Bisgaard 2000	Control intervention was not inhaled corticosteroid
Bisgaard 2005	Control intervention was not inhaled corticosteroid
Bjermer 2002	Control intervention was not placebo
Bjermer 2003	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone and salmeterole with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Bjermer 2004	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone and salmeterole with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Bleecker 2006	Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroid
Borker 2005	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone and salmeterole with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Bousquet 2005a	Not a randomised controlled trial
Bousquet 2007	Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroid
Brannan 2001	Intervention administered < 4 weeks Control intervention was not inhaled corticosteroid
Brocks 1996	Participants were not people with asthma
Bronsky 1997	Participants were not people with asthma
Brown 2005	Intervention was not anti‐leukotriene
Brown 2007	Intervention was not anti‐leukotriene
Brown 2010	Intervention was not anti‐leukotriene
Bruce 2002	Outcome measures did not reflect asthma control
Buchvald 2002	Duplicate of published paper in Annals of Allergy Asthma & Immunology 2003;91(3):309‐313.
Buchvald 2002a	Duplicate of published paper in Annals of Allergy Asthma & Immunology 2003;91(3):309‐313.
Buchvald 2003	Control intervention was not inhaled corticosteroid
Buckstein 2003	Not a randomised controlled trial
Burgess 2007	Intervention was not anti‐leukotriene
Busse 1999	Control intervention was not inhaled corticosteroid Participants received additional non‐permitted co‐interventions (inhaled steroids) other than short‐acting beta2‐agonists Outcomes did not reflect control of asthma (provocation challenge)
Buxton 2004	Intervention was not anti‐leukotriene
Cakmak 2000	Control intervention was not placebo
Cakmak 2004	Participants received additional non‐permitted co‐interventions (zafirlukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Calhoun 1997	Control intervention was not inhaled corticosteroid
Calhoun 2001	Participants received additional non‐permitted co‐intervention other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Calhoun 2004	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Camargo 2002	Acute asthma setting
Camargo 2003	Control intervention was not inhaled corticosteroid Acute asthma setting
Canino 2008	Not a randomised controlled trial Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroid
Capella 2001	Participants were non‐asthmatics (atopic dermatitis)
Ceylan 2004	Participants received additional non‐permitted co‐interventions (formoterol with budesonide and montelukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Chan 2003	Not a randomised controlled trial
Chand 2005	Participants received additional non‐permitted co‐interventions (montelukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Chanez 2010	Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroids
Chen 2006	Intervention was not anti‐leukotriene
Chiba 1997	Not a randomised controlled trial
Choi 2003	Intervention was not anti‐leukotriene
Chopra 2005	Intervention was not anti‐leukotriene
Chuchalin 2002	Intervention was not anti‐leukotriene
Chuchalin 2007	Intervention was not anti‐leukotriene
Chung 2000	Intervention was not anti‐leukotriene
Ciebiada 2009	Participants received additional non‐permitted co‐interventions (fexofenadine with montelukast and fexofenadine with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Claesson 1998	Not a randomised controlled trial
Cloud 1989	Control intervention was not inhaled corticosteroid
Covar 2008	Duplicate of published paper in Journal of Allergy & Clinical Immunology 2007;119(1):64‐72.
Cowan 2010	Participants received additional non‐permitted co‐interventions (cromoglycate, formoterol with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid; Intervention was given < 4 weeks
Currie 2003	Intervention was given < 4 weeks
Currie 2003a	Intervention was given < 4 weeks; Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Currie 2003b	Duplicate of published paper in Journal of Respiratory & Critical Care Medicine 2003;167(9):1232‐1238.
Cylly 2003	Ongoing trial
Dahlén 2002	Control intervention was not inhaled corticosteroid; Participants received additional non‐permitted co‐interventions (inhaled steroids) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Daikh 2003	Participants were not people with asthma
Davies 2004	Not a randomised controlled trial; All patients not received inhaled corticosteroid as controlled intervention
Daviskas 2007	Control intervention was not inhaled corticosteroid
Dekhuijzen 2006	Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroid
Delaronde 2005	Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroid
Dempsey 1999	Intervention administered for < 4 weeks
Dempsey 2000	Intervention administered <4 weeks
Dempsey 2000a	Control intervention was not placebo
Dempsey 2002b	Control intervention was not placebo
Demuro‐Mercon 2001	Control intervention was not inhaled corticosteroid
Dessanges 1999	Participants received additional non‐permitted co‐interventions (inhaled steroids) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid Intervention lasted <4 weeks Outcomes did not reflect control of asthma (provocation challenge)
Deykin 2007	Participants received additional non‐permitted co‐interventions (salmeterol with montelukast and salmeterol with beclomethasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Diamant 1997	Control intervention was not inhaled corticosteroidervention administered for < 4 weeks Outcomes were solely the result of provocation
Diamant 2009	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Dicpinigaitis 2002	Outcome measures did not reflect asthma control
Djukanovic 2010	Participants received additional non‐permitted co‐interventions (fluticasone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Dockhorn 2000	Control intervention was not inhaled corticosteroid Intervention administered for < 4 weeks
Dorinsky 2001	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Dorinsky 2002	Not a randomised controlled trial
Dorinsky 2004	Intervention was not anti‐leukotriene
Edelman 2000	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
El Miedany 2006	Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroid
Eliraz 2001	Intervention was not anti‐leukotriene
Ensom 2003	Not a randomised controlled trial Intervention was not anti‐leukotriene Control intervention was not inhaled corticosteroid
Fabbri 1996	Not a randomised controlled trial
Fagerson 2003	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Failla 2006	Intervention was not anti‐leukotriene
Fardon 2004	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Fardon 2007	Not a randomised controlled trial. Intervention was not anti‐leukotriene.
Faul 2002	Outcome measures did not reflect asthma control
Findlay 1992	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks
Finkelstein 2005	Not a randomised controlled trial. Intervention was not anti‐leukotriene
Finn 2000	Control intervention was not inhaled corticosteroid (but placebo). A small number of placebo‐treated patients also received co‐intervention with inhaled steroids (N = 42), but co‐intervention with inhaled steroids was not randomly assigned.
Fischer 1995	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Fischer 1997	Control intervention was not inhaled corticosteroid
Fish 1997	Control intervention was not inhaled corticosteroid
Fish 2000	Participants received additional non‐permitted co‐interventions (salmeterol with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Fish 2001	Co‐intervention with inhaled corticosteroid. Control intervention was not inhaled corticosteroid.
FitzGerald 2009	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Fogel 2010	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone and fluticasone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Franzen 1994	Not a randomised controlled trial
Fritsch 2006	Intervention was not anti‐leukotriene
Fujimura 1993	Control intervention was not inhaled corticosteroid
Gabrijelcic 2004	Not a randomised controlled trial. Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Gaddy 1990	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks, intravenously
Galbreath 2008	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Geha 2001	Intervention was not anti‐leukotriene
Gelb 2008	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Georgiou 1997	Control intervention was not inhaled corticosteroid. Participants were not asthmatics. Intervention administered for < 4 weeks.
Ghiro 2001	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Ghiro 2002	Outcome measures did not reflect asthma control
Gold 2001	Control intervention was not placebo
Gold 2001a	Control intervention was not placebo
Green 2002	Control intervention was not placebo. Co‐intervention with inhaled steroids.
Green 2002a	Intervention was not anti‐leukotriene
Green 2006	Participants received additional non‐permitted co‐interventions (montelukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Greenberger 2003	Not a randomised controlled trial
Grosclaude 2003	Participants received additional non‐permitted co‐interventions (montelukast with beclomethasone and salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Grossman 1995	Control intervention was not inhaled corticosteroid
Grossman 1997	Control intervention was not inhaled corticosteroid
Grzelewska‐Rzymowska 2003	Intervention was not anti‐leukotriene
Grzelewski 2006	Participants received additional non‐permitted co‐interventions (montelukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Guilbert 2004	Intervention was not anti‐leukotriene
Gupta 1999	Intervention was not anti‐leukotriene. Participants were not people with asthma.
Gupta 2007	Participants received additional non‐permitted co‐interventions (fluticasone+salmeterol with montelukast and salmeterol+levocetirizine with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Gylfors 2005	Duplicate of published paper in Journal of Allergy & Clinical Immunology 2006;118(1):78‐83.
Gyllfors 2003	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Gyllfors 2006	Intervention was not anti‐leukotriene
Haahtela 1994	Intervention was not anti‐leukotriene
Hakim 2007	Control intervention was not inhaled corticosteroid
Hamilton 1998	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Harmanci 2006	Control intervention was not inhaled corticosteroid
Hartwig 2004	Not a randomised controlled trial
Hassall 1998	Control intervention was not inhaled corticosteroid
Havlucu 2005	Participants received additional non‐permitted co‐interventions (formoterole with budesonide) other than short‐acting beta2‐agonists and/or short course of oral ccorticosteroid
Hay 1997	Not a randomised controlled trial
Hendeles 2004	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Henderson 1994	Not a randomised controlled trial
Hernandez 2002	Participants received additional non‐permitted co‐interventions (montelukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Hood 1999	Participants were not people with asthma. Intervention was not anti‐leukotriene. Intervention administered for < 4 weeks.
Hothersall 2008	Intervention was not anti‐leukotriene
Houghton 2004	Intervention was not anti‐leukotriene
Howland 1994	Control intervention was not inhaled corticosteroid
Hozawa 2009	Intervention was not anti‐leukotriene
Hsieh 1996	Intervention was not anti‐leukotriene
Huang 2003	Participants received additional non‐permitted co‐interventions (zafirlukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Huang 2003a	Duplicate of published paper in Chang Gung Medical Journal. 2003;26(8):554‐560
Hui K 1991	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks.
Igde 2009	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Ikeda 1997	Not a randomised controlled trial
Ilowite 2004	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Inoue 2007	Intervention was not anti‐leukotriene
Irvin 2003	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Irvin 2007	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Israel 1990	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Israel 1992	Control intervention was not inhaled corticosteroid
Israel 1993	Control intervention was not inhaled corticosteroid
Israel 1996	Control intervention was not inhaled corticosteroid
Jat 2006	Participants received additional non‐permitted co‐interventions (montelukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Jayaram 2002a	Duplication
Jayaram 2005a	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Jayaram 2006	Intervention was not anti‐leukotriene
Johnson 1999	Duplicate of published paper in J Fam Pract 2001;50:595‐602.
Johnston 2007	Participants received additional non‐permitted co‐interventions (montelukast with other antihistaminc drugs) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Jones 2002	Not a randomised controlled trial
Jonsson 2004	Intervention was not anti‐leukotriene
Juniper 1995	Control intervention was not inhaled corticosteroid
Kalberg 1999	Control intervention was not inhaled corticosteroid
Kanazawa 2004	Control intervention was not inhaled corticosteroid
Kane 1994	Not a randomised controlled trial
Kanniess 2002a	Control intervention was not placebo
Karaman 2007	Participants received additional non‐permitted co‐interventions (montelukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Karpel 2007	Intervention was not anti‐leukotriene
Katial 2010	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Keith 2009	Participants received additional non‐permitted co‐interventions (montelukast with inhaled coticosteroid and long acting beta2 agoinit with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Kemp 1995	Control intervention was not inhaled corticosteroid
Kemp 1996	Not a randomised controlled trial
Kemp 1998	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks.
Kemp 1998a	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Kemp 1999	Not a randomised controlled trial (meta‐analysis of RCTs)
Ketchell 2002	Intervention was not anti‐leukotriene
Khayyal 2003	Intervention was not anti‐leukotriene
Kippelen 2010	Intervention was not anti‐leukotriene
Kips 1991	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks, intravenously.
Knorr 1998	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Knorr 1999	Control intervention were not placebo
Koenig 2004	Duplication of paper in The Journal of Asthma 2008;45( 8):681‐687
Kohrogi 1997	Not a randomised controlled trial
Kondo 2006	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Kooi 2006	Duplication of paper in Pulmonary Pharmacology and Therapeutics 2008;21(5):798‐804
Korenblat 1998	Use of higher than licensed dose of leukotriene receptor antagonists (Pranlukast 600 mcg/day vs. 450 mcg/day)
Kuna 1997	Control intervention was not inhaled corticosteroid
Kylstra 1998	Control intervention was not inhaled corticosteroid
Laitinen 1995	Control intervention was not inhaled corticosteroid
Leaker 2010	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroids.
Lee 2004	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid Intervention administered for < 4 weeks
Lee 2004a	Intervention was not anti‐leukotriene
Lee 2004b	Control intervention was not inhaled corticosteroid
Lee 2004c	Duplication of paper in Chest 2004;125(4):1372‐1377
Lee 2005	Intervention was not anti‐leukotriene
Lee 2010	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroids.
Leff 1998	Control intervention was not inhaled corticosteroid. Outcomes were solely the result of provocation.
Leibman 2002	Duplication of paper in American Journal of Respiratory and Critical Care Medicine 2002. 165 (Suppl 8): B4
Leibman 2002a	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone and fluticasone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Leigh 2002	Intervention administered for < 4 weeks
Leigh 2002a	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Lemanske 2010	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Li 2001	Control intervention was not placebo
Liebke 2001	Control intervention was not placebo (it was sodium cromoglycate)
Lindemann 2009	Intervention was not anti‐leukotriene
Lipworth 1999	Ongoing trial
Lis 2001	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks.
Liu 1996	Control intervention was not inhaled corticosteroid
Lizaso 2003	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Lockey 1995	Control intervention was not inhaled corticosteroid
Lofdahl 1999	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Luppo 2005	Control intervention was not inhaled corticosteroid
Lyseng‐Williamson 2003	Not a randomised controlled trial
Macfarlane 2000	Not a randomised controlled trial
Magnussen 2008	Intervention was not anti‐leukotriene
Majak 2010	Participants received additional non‐permitted co‐interventions (ICS with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Malerba 2002	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Marchese 1998	Not a randomised controlled trial
Margolskee 1991	Control intervention was not inhaled corticosteroid
Marogna 2010	Participants received additional non‐permitted co‐interventions (formoterol/fluticasone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Maspero 2008	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Maspero 2008a	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Maspero 2008b	Participants received additional non‐permitted co‐interventions (salmeterol with budesonide) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Mastruzzo 2010	Intervention was given < 4 weeks
Matsunaga 2004	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks.
McCarthy 2003	Participants received additional non‐permitted co‐interventions (fluticasone with montelukast and salmeterol with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
McGill 1996	Not a randomised controlled trial
Mclvor 2009	Not a randomised controlled trial; Control intervention was not inhaled corticosteroid
Mehuys 2008	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Mendes 2004	Intervention administered for < 4 weeks
Mendes 2004a	Intervention administered for < 4 weeks
Menendez 2001	Duplicate of published paper in J Allergy Clin Immunol 2000;105:1123‐1129; Outcomes did not reflect control of chronic asthma
Meyer 2003	Not a randomised controlled trial
Micheletto 1997	Control intervention was not inhaled corticosteroid
Miraglia 2007	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Mitchell 2005	Intervention was not anti‐leukotriene
Miyamoto 1999	Control intervention was not placebo
Molitor 2005	Intervention was not anti‐leukotriene. Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Montani 2007	Duplicate of published paper in New Engl J of Med 2007;356(20):2027‐2039
Moreira 2008	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Morris 2010	Participants received additional non‐permitted co‐interventions (montelukast with other anti‐asthma therapies) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid. Acute asthma setting.
Mosnaim 2002	Control intervention was not inhaled corticosteroid
Mosnaim 2008	Intervention was not anti‐leukotriene
Murphy 2006	Intervention was not anti‐leukotriene
Najberg 2008	Intervention was not anti‐leukotriene
Nakagawa 1992	Not a randomised controlled trial
Nakajima 2001	Participants received additional non‐permitted co‐interventions (beclomethazone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Nakazono 2004	Control intervention was not inhaled corticosteroid
Nathan 1998	Control intervention was not inhaled corticosteroid
Nathan 2000	Participantsreceived additional non‐permitted co‐interventions (salmeterol with ICS and ICS with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Nathan 2004	Duplication of paper in Chest 2005;128(4):1910‐1920
Nathan 2005	Participants received additional non‐permitted co‐interventions (fluticasone+salmeterol with montelukast) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Nayak 1998	Control intervention was not inhaled corticosteroid
NCT00096954	Test group is not anti‐leukotrienes. Control group is not ICS.
NCT00140881	Ongoing and results are not available
NCT00196547	Ongoing and results are not available
NCT00213252	Ongoing and results are not available
NCT00299065	Ongoing and results are not available
NCT00319488	Ongoing and results are not available
NCT00395408	Ongoing and results are not available
NCT00421018	Ongoing and results are not available
NCT00462592	Ongoing and results are not available
NCT00471809	Terminated and results are not available
NCT00486343	Terminated and results are not available
NCT00504946	Ongoing and results are not available
NCT00545324	Ongoing and results are not available
NCT00545844	Control group received non‐permitted drugs (Montelukast and long‐acting beta 2 agonist)
NCT00575861	Ongoing and results are not available
NCT00666679	Test group received non‐permitted drug (Mometasone)
NCT00699062	Ongoing and results are not available
NCT00755794	Ongoing and results are not available
NCT00756418	Ongoing and results are not available
NCT00913328	Ongoing and results are not available
NCT00943397	Control group is not ICS
NCT01055041	Ongoing and results are not available
NCT01241084	Ongoing and results are not available. Test group is not anti‐leukotrienes.
Negro 1997	Not a randomised controlled trial
Neki 2006	Not a randomised controlled trial
Nelson 2001	Control intervention were not placebo
Nelson 2004	Participants received additional non‐permitted co‐interventions (fluticasone+salmeterol with montelukast) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Nelson 2004a	Participants received additional non‐permitted co‐interventions (fluticasone+salmeterol with montelukast) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid. Participants were not people with asthma.
Nelson 2006	Intervention was not anti‐leukotriene
Nishima 2005	Control intervention was not inhaled corticosteroid
Nishimura 1999	Control intervention were not placebo
Nishiyama 2006	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Nishizawa 2002	Intervention was not anti‐leukotriene
Noonan 1998	Control intervention was not inhaled corticosteroid
Noonan 1999	Not a randomised controlled trial
Nsouli 2000	Control intervention was not placebo
Nsouli 2001	Control intervention was not placebo
O'Byrne 1997	Not a randomised controlled trial
O'Byrne 1997a	Not a randomised controlled trial
O'Byrne 1997b	Not a randomised controlled trial
O'Connor 1994	Not a randomised controlled trial
O'Connor 2004	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
O'Connor 2006	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
O'Shaughnessy 1996	Participants were not people with asthma Outcomes were solely the result of provocation
O'Sullivan 2002	Duplicate of published abstract in European Respiratory Journal 2002;20(Suppl 38):388s
O'Sullivan 2002a	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
O'Sullivan 2003	Control intervention was not placebo
Obase 2001	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Obata 1992	Not a randomised controlled trial
Odjakova 2000	Not a randomised controlled trial
Ohbayashi 2007	Intervention was not anti‐leukotriene
Ohbayashi 2009	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone+salmeterold) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Ohbayashi 2009a	Participants received additional non‐permitted co‐interventions (pranlukast with fluticasone) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Ohkura 2009	Participants received additional non‐permitted co‐interventions (pranlukast with inhaled corticosteroids+long acting beta2 agonists) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Ohta 2009	Intervention was not anti‐leukotriene; Control intervention was not inhaled corticosteroid
Okudaira 1997	Not a randomised controlled trial
Oosaki 1997	Not a randomised controlled trial
Oosaki 1997a	Not a randomised controlled trial
Oppenheimer 2008	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone+salmeterold) other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Ostrom 2003	Duplicate of published abstract in Journal of Pediatrics 2005;147(2):213‐220
Overbeek 2002	Outcomes measures did not reflect asthma control
Palmqvist 2003	Intervention administered for < 4 weeks
Palmqvist 2005	Intervention administered for < 4 weeks
Panettieri 1997	Not a randomised controlled trial
Papadopoulos 2009	Control intervention was not inhaled corticosteroid
Pasaoglu 2008	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Patel 2010	Participants received additional non‐permitted co‐interventions (budesonide+formoterol with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Paterson 1999	Intervention administered for < 4 weeks
Pavord 2007	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Pearlman 1999	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Pearlman 2002	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Pedersen 2007	Intervention administered for < 4 weeks
Pereira 1989	Participants were not people with asthma
Perng 2004	Participants received additional non‐permitted co‐interventions (zafirlukast with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Peroni 2005a	Participants received additional non‐permitted co‐interventions (budesonide with montelukast and formoterol with budesonide) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Philip 2005	Control intervention was not inhaled corticosteroid
Phipatanakul 2003	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroid) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Phipatanakul 2003a	Duplication of paper published in Annals of Allergy Asthma & Immunology 2003;91(1):49‐54
Pieters 2005	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Pizzichini 1999	Control intervention was not inhaled corticosteroid
Plaza 2005	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Pogson 2008	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Pohl 2006	Intervention was not anti‐leukotriene
Polos 2003	Participants received additional non‐permitted co‐interventions (fluticasone with montelukast and salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Polos 2004	Duplication of paper published in Pediatrics 2005;116(2):360‐369
Ponce 2009	Participants received additional non‐permitted co‐interventions (budesonide+salmeterol with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Price 1999	Control intervention was not inhaled corticosteroid
Price 2002	Control intervention were not placebo
Price 2003	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Price 2004	Duplication; Participants received additional non‐permitted co‐interventions (eg. montelukast with budesonide)
Price 2006	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Pullerits 1999	Participants were not people with asthma (allergic rhinitis)
Pullerits 2001	Participants were not people with asthma
Pullerits 2002	Participants were not people with asthma
Qaqundah 2006	Intervention was not anti‐leukotriene;
Rachelefsky 1997	Not a randomised controlled trial
Ragab 2001	Not a randomised controlled trial
Ramsay 1997	Control intervention was not inhaled corticosteroid
Ramsay 1998	Control intervention was not inhaled corticosteroid
Rand 2004	Duplication of full paper in Journal of Allergy & Clinical Immunology 2007;119(4):916‐923
Ratner 2003	Participants were not people with asthma
Reiss 1996	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid. Intervention administered for < 4 weeks.
Reiss 1997	Control intervention was not inhaled corticosteroid. Duplication of full paper in Clin Exp Allergy 2001;31:1‐10.
Reiss 1997b	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Reiss 1997c	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid. Intervention administered for < 4 weeks.
Reiss 1998	Control intervention was not inhaled corticosteroid
Reiss 2008	Duplication of paper published in Journal of Asthma 2009;46(5):465‐469
Riccioni 2001a	Duplication of International Journal of Immunopathology and Pharmacology 2001:14(2):87‐92
Riccioni 2002	Not a randomised controlled trial
Riccioni 2003a	Not a randomised controlled trial
Riccioni 2005	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Rickard 1999	Control intervention was not placebo
Rickard 2001	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Ringdal 1997	Outcomes did not reflect control of chronic or acute asthma
Ringdal 2003	Participants received additional non‐permitted co‐interventions (fluticasone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Robinson 2001	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid. Intervention administered for < 4 weeks.
Rosenhall 2003	Intervention was not anti‐leukotriene
Rowe 2007	Intervention was not anti‐leukotriene
Ruggins 2003	Participants received additional non‐permitted co‐interventions (inhaled corticosteroids with montelukast and salmeterol with inhaled corticosteroids) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Sahn 1997	Control intervention was not inhaled corticosteroid
Sano 2006	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Schneider 2008	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Schuh 2009	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Schwartz 1995	Control intervention was not inhaled corticosteroid
SD‐004‐0216	Participants received additional non‐permitted co‐interventions (budesonide with zafirlukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Shah 2003	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Shah 2004	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Shah 2006	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Sheth 2002	Participants received additional non‐permitted co‐interventions other than short‐acting ß2‐agonists and/or short course of oral corticosteroid
Shimoda 2005	Duplication
Shingo 2001	Control intervention was not inhaled corticosteroid
Shoji 1999	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Simons 2001	Control intervention was not inhaled corticosteroid
Simpson 2004	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Sims 2003	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroids) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid. Intervention administered for < 4 weeks.
Sims 2008	Duplication
Smith 1993	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks.
Smith 1997	Treatments were administered for <4 weeks
Smith 1998	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Smugar 2009	Participants received additional non‐permitted co‐interventions (montelukast with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Smugar 2009a	Duplication of full paper in Annals of Allergy Asthma & Immunology 2010;104(6):511‐517
Spahn 1996a	Not a randomised controlled trial
Spector 1992	Control intervention was not inhaled corticosteroid
Spector 1994	Control intervention was not inhaled corticosteroid
Spector 1995	Control intervention was not inhaled corticosteroid
Spector 1996	Not a randomised controlled trial
Stanford 2002	Non‐permitted drugs
Stensrud 2006	Not a randomised controlled trial
Stevenson 2005	Intervention was not anti‐leukotriene
Sthoeger 2007	Intervention was not anti‐leukotriene
Storms 2001	Not a randomised controlled trial. Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Storms 2004	Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroids) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Strauch 2003	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Strunk 2003	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Strunk 2008	Participants received additional non‐permitted co‐interventions (budesonide+salmeterol with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Sugihara 2010	Intervention was given < 4 weeks
Suguro 1997	Not a randomised controlled trial
Suissa 1997	Control intervention was not inhaled corticosteroid
Sutherland 2010	Not a randomised controlled trial‐retrospective analysis
Suzuki 1997	Not a randomised controlled trial
Svensson 1994	Control intervention was not inhaled corticosteroid
Swern 2008	Not a randomised controlled trial. Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Swernson 2003	Participants received additional non‐permitted co‐interventions (ICS with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Tamaoki 1997	Control intervention was not inhaled corticosteroid
Tan 2006	Intervention was not anti‐leukotriene
Tashkin 1998	Control intervention was not inhaled corticosteroid
Teper 2009	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Terzano 2001	Intervention was not anti‐leukotriene
Thoma 2002	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Todi 2010	Participants received additional non‐permitted co‐interventions (antiasthmatic drugs with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Tognella 2004	Participants received additional non‐permitted co‐interventions (fluticasone with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Tohda 2002	Control intervention was not placebo
Tomari 2001	Control intervention was not placebo
Tomita 1999	Participants received additional non‐permitted co‐interventions (inhaled and oral corticosteroids) other than short‐acting beta2‐agonists
Tonelli 2003	Not a randomised controlled trial; Participants received additional non‐permitted co‐interventions (antihistaminic drugs) other than short‐acting beta2‐agonists
Townley 1995	Control intervention was not inhaled corticosteroid
Trofor 2002	Not a randomised controlled trial. Control intervention was not inhaled corticosteroid.
Tsai 2010	Intervention was not anti‐leukotriene. Control intervention was not inhaled corticosteroid.
Tsuchida 2005	Participants received additional non‐permitted co‐interventions (beclomethasone with pranlukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Tug 2007	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Tukiainen 2002	Intervention was not anti‐leukotriene
Uh 2007	Participants received additional non‐permitted co‐interventions (salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Ulrik 2009	Duplication of work presented in Am J Respir Crit Care Med 2009;179:A2416
Ulrik 2009a	Control intervention was not inhaled corticosteroid
Ulrik 2010	Control intervention was not inhaled corticosteroid. Participants received additional non‐permitted co‐interventions (montelukast with inhaled corticosteroids) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid.
Van Adelsberg 2005	Control intervention was not inhaled corticosteroid
Van Der Meer 2009	Intervention was not anti‐leukotriene; Control intervention was not inhaled corticosteroid
Vaquerizo 2003	Control intervention was not placebo
Vastagh 2003	Intervention was not anti‐leukotriene
Verhoeven 2001	Participants were not asthmatics (COPD)
Verini 2007	Participants received additional non‐permitted co‐interventions (fluticasone with montelukast and salmeterol with fluticasone) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid. Intervention administered for < 4 weeks.
Vermeulen 2007	Intervention was not anti‐leukotriene
Vethanayagam 2002	Intervention administered for < 4 weeks
Vidal 2001	Intervention administered for < 4 weeks
Vidal 2001a	Intervention administered for < 4 weeks
Virchow 1997	Control intervention was not inhaled corticosteroid
Virchow 1997a	Duplication
Virchow 1997b	Control intervention was not inhaled corticosteroid
Virnig 2008	Participants received additional non‐permitted co‐interventions (other antiasthmatic drugs with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Volovitz 1999	Duplication of full paper in Curr Med Res Opin 2001;17(2):96‐104
Von Berg 2002	Intervention was not anti‐leukotriene
Wada 2000	Participants received additional non‐permitted co‐interventions (inhaled steroids) other than short‐acting beta2‐agonists
Wada 2009	Control intervention was not inhaled corticosteroid
Wahedna 1999	Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Warren 2003	Ongoing clinical trial.
Wasserman 2006	Intervention was not anti‐leukotriene
Wechsler 1998	Not a randomised controlled trial
Weinberg 1998	Outcomes did not reflect control of chronic or acute asthma
Weiss 2010	Control intervention was not inhaled corticosteroids
Welch 1994	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks.
Wen 2008	Intervention was not anti‐leukotriene
Wenzel 1994	Control intervention was not inhaled corticosteroid
Wenzel 1995	Control participants were not people with asthma. Intervention administered for < 4 weeks.
Wenzel 1997	Duplication of data published in American Journal of Respiratory & Critical Care Medicine 1998;157:A411
Westbroek 1997	Intervention was not anti‐leukotriene
Westbroek 1998	Intervention administered for < 4 weeks
Westbroek 2000	Intervention administered for < 4 weeks
Williams 2001	Duplication of three studies
Wilson 1999	Control intervention was not placebo
Wilson 2000	Control intervention was not inhaled corticosteroid; Intervention administered for < 4 weeks
Wilson 2001	Intervention administered for < 4 weeks
Wilson 2001a	Participants were not prople with asthma
Wilson 2001b	Intervention administered for < 4 weeks
Wilson 2001c	Outcome measures did not reflect asthma control
Wilson 2004	Not a randomised controlled trial
Wilson 2010	Not a randomised controlled trial
Wilson 2010a	Participants received additional non‐permitted co‐interventions (ICS with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Wise 2009	Control intervention was not inhaled corticosteroid
Xiang 2001	Control intervention was not placebo
Yaldiz 2000	Participants received additional non‐permitted co‐intervention (ICS with montelukast)
Yamamoto 1994	Control intervention was not inhaled corticosteroid. Intervention administered for < 4 weeks. Outcomes were solely the result of provocation.
Yildirim 2001	Control intervention was not placebo
Yildirim 2004	Participants received additional non‐permitted co‐interventions (budesonide with montelukast) other than short‐acting beta2‐agonists and/or short course of oral corticosteroid
Yoo 2001	Participants received additional non‐permitted co‐interventions (inhaled corticosteroids) other than short‐acting beta2‐agonists
Yoshida 2000	Intervention administered for < 4 weeks
Yoshida 2002	Intervention administered for < 4 weeks
Zeiger 2004	Not a randomised controlled trial
Zeiger 2005a	Duplication of full paper published in American Journal of Medicine 2005;118(6):649‐657
Zeneca Accolate 1998	Not a randomised controlled trial (product monograph)
Zhang 1999	Control intervention was not inhaled corticosteroid
Zorc 2003	Intervention was not anti‐leukotriene

Differences between protocol and review

We revised the protocol to take account of the new methods in the Cochrane Handbook for Systematic Reviews of Interventions.

• Updated the Cochrane Collaboration's 'Risk of bias' tool to include six domains

Contributions of authors

Dr Bhupendrasinh Chauhan reviewed the literature search from 2003 to December 2010, identified and reviewed all citations for relevance, reviewed all included trials for methodology and data extraction, verified all references, description of studies and data entry, analysed and interpreted results of the meta‐analysis, manuscript writing.

Prof Francine Ducharme conceived the protocol, requested the literature search, identified and contacted the corresponding authors and/or the pharmaceutical companies to solicit their collaboration in this review and in the identification of other possibly relevant trials, created the methodology and data extraction forms, reviewed all citations for relevance with research assistants, reviewed all included trials for methodology and data extraction, corresponded with authors or pharmaceutical companies to verify methodology and data extraction, verified all references, description of studies and data entry, analysed and interpreted results of the meta‐analysis.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Francine Ducharme is supported by a National Researcher Award from the Fonds de la Santé du Québec, Canada.

• Bhupendrasinh Chauhan, Canada.

  received a postdoctoral scholarship from Canadian Institute of Health Research, Canada

Declarations of interest

Bhupendrasinh Chauhan ‐ none known.

Prof. Francine Ducharme has received travel support, research funds and fees for speaking from Glaxo SmithKline, Novartis, Nycomed, and Merck Frosst Inc.

Edited (no change to conclusions), comment added to review