Criteria for considering studies for this review
Types of studies
We will include only randomised controlled trials with a parallel group design conducted for at least 12 weeks duration. We will not exclude studies on the basis of blinding. Cross-over trials will not be included. We will include studies reported as full-text, those published as abstract only, and unpublished data.
Types of participants
We will include children aged one to 18 years and adults with persistent asthma symptoms, including preschool children with suspected, or at risk of developing, persistent asthma.
Types of interventions
In each trial, participants will have been randomised to patient-initiated intermittent ICS therapy used at the onset of an exacerbation (recognised as separate or combined treatment with a short acting beta2-agonist reliever) and be compared with placebo. ICS will be allowed in any formulation. No co-interventions are permitted other than rescue relievers and oral corticosteroids used during exacerbations.
Types of outcome measures
Asthma exacerbations: patients experience one or more exacerbations requiring rescue oral corticosteroids
Serious adverse events.
Exacerbations requiring hospital admissions
Quality of life (validated questionnaires only)
Measures of lung function (forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR))
Adverse events/side effects.
Reporting one of more of the outcomes listed here in the trial is not an inclusion criterion for the review.
Search methods for identification of studies
We will identify trials from the Cochrane Airways Group's Specialised Register (CAGR), which is maintained by the Trials Search Co-ordinator for the Group. The Register contains trial reports identified through 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). We will search all records in the CAGR using the search strategy in Appendix 2.
We will also conduct a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the WHO trials portal (www.who.int/ictrp/en/). We will search all databases from their inception to the present, and we will impose no restriction on language or type of publication.
Searching other resources
We will check reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for trial information.
We will search for errata or retractions from included studies published in full-text on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was done within the review.
Data collection and analysis
Selection of studies
Two review authors (JC, CH) will independently screen titles and abstracts for inclusion of all the potential studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full-text study reports/publication and the same two review authors will independently screen the full-text and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person (IA). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.
Data extraction and management
We will use a data collection form for study characteristics and outcome data which has been piloted on at least one study in the review. Two review authors will extract study characteristics from included studies (JC, CH). We will extract the following study characteristics.
Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, and date of study.
Participants: N, mean age, age range, gender, severity of condition, asthma diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria.
Interventions: intervention, comparison, concomitant medications, and excluded medications.
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
Notes: funding for trial, and notable conflicts of interest of trial authors.
Two review authors will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data was not reported in a usable way. We will resolve disagreements by consensus or by involving a third person (IA). One review author (JC) will transfer data into the Review Manager (RevMan 2012) file. We will double-check that data is entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (CH) will spot-check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (IA). We will assess the risk of bias according to the following domains.
Random sequence generation.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective outcome reporting.
We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all-cause mortality may be very different than for a patient reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assesment of bias in conducting the systematic review
We will conduct the review according to this published protocol and report any deviations form it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will analyse dichotomous data as odds ratios and continuous data as mean difference or standardised mean difference. We will enter data presented as a scale with a consistent direction of effect.
We will undertake meta-analyses only where this is meaningful i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
We will narratively describe skewed data reported as medians and interquartile ranges.
Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta-analysis, we will halve the control group to avoid double-counting.
For continuous outcomes, we will halve the number of participants in the group that served twice as comparator to avoid over-representation. For dichotomous outcomes, we will halve both the numerator and denominator of the group that served twice as comparator.
Unit of analysis issues
We will analyse dichotomous data using participants as the unit of analysis (rather than events) to avoid counting the same participant more than once. This is a specific issue with repeated events such as exacerbations. For continuous data, the mean difference based on change from baseline will be preferred over mean difference based on absolute values.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity (considered to be an I² statistic>50%) we will report it and explore possible causes by prespecified subgroup analysis.
Assessment of reporting biases
If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study and publication biases.
We will use a fixed-effect model and perform a sensitivity analysis with random-effects model especially in the presence of heterogeneity, because in this situation, a random-effects meta-analysis weights the studies relatively more equally than a fixed-effect analysis.
Summary of findings table
We will create a 'Summary of findings' table including outcomes for exacerbations, serious adverse events, quality of life, symptom scores and adverse events. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta-analyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We will justify all decisions to down- or up-grade the quality of studies using footnotes and we will make comments to aid reader's understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses.
Type of inhaled corticosteroid used and dose
Single versus separate inhaled corticosteroid steroid and short acting beta2-agonist devices
Severity of disease at baseline
Adults versus school aged children versus pre-school children
Type of device used or spacer
We will use only primary outcomes in subgroup analyses and will use the formal test for subgroup interactions in Review Manager (RevMan 2012).
We will assess the sensitivity of our primary outcomes to degree of bias by comparing the overall results with those exclusively from trials assessed as being at low risk of bias. This will be performed by excluding studies at high risk of bias for blinding, randomisation/allocation concealment and then a second analysis to exclude studies that may have inadequate reporting of outcomes.