Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and adults

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To compare the efficacy and safety of intermittent ICS versus placebo in the management of children and adults in patients with persistent asthma upon measures of exacerbations, hospitalisations, lung function, symptoms and serious adverse events.

Background

Description of the condition

Asthma is estimated to affect approximately 334 million people around the world and is a leading cause of respiratory-related morbidity and mortality (Vos 2013). This is a significant health problem where the prevalence has been increasing in both developing and developed countries (Global Asthma Report 2011; Lai 2009; Pearce 2007). The condition has been defined by the Global Initiative for Asthma (GINA) as ‘a chronic inflammatory disorder of the airways in which many cell and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particular at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment’. Clinicians will be guided by the typical symptoms. There may be no abnormal signs on physical examination in the interval phase, or, if the asthma is persistent and not optimally controlled there may be features of chronic airway limitation. Other supportive features may include a personal history of atopy or a family history of atopy or asthma, as well as information provided from lung function or provocation tests. Classification of severity can then be assessed according to symptom pattern, which helps to determine the need for a controller medication (GINA 2012).

Description of the intervention

International guidelines recommend daily inhaled corticosteroids (ICS) in adults and children who have persistent asthma (BTS 2012; GINA 2012). In this setting, chronic disease management has been markedly improved over the past 30 years due to the introduction of ICS therapy. This class of medication has been found to improve control over asthma symptoms by suppressing airway inflammation and reducing exacerbations, with demonstrated efficacy in promoting overall quality of life and clinical measures of lung function (Barnes 1998; Pauwels 2003; The Childhood Asthma Program Research Group 2000).

How the intervention might work

Introduction and appropriate titration of the dose of ICS has been associated with a reduction in the rates of mild and severe asthma exacerbations (Pauwels 1997). However, in patients with mild persistent symptoms (once per day) with few if any exacerbations, the optimal approach has not been fully studied. People may be inclined to discontinue their recommended daily ICS treatment when they are asymptomatic and therefore the benefits of a preventer inhaler are less well perceived (Rand 2005).

There are established adverse effects associated with prolonged ICS therapy (Zhang 2011). In children, recent reports have shown an impact on growth trajectory and final adult height (Kelly 2012; Sharek 1999).

Recent evidence may suggest that inhaled corticosteroids, used intermittently at the onset of exacerbations and continued for a short duration in combination with a short acting beta2-agonist, could be an effective step-down regimen in adults (Papi 2007) and children (Martinez 2011) with mild, persistent asthma. A recent Cochrane systematic review found low quality evidence that intermittent and daily ICS strategies were similarly effective in terms of requirements for the use rescue oral corticosteroids and the rate of severe adverse health events (Chauhan 2013). However, the strength of this evidence limited conclusions that these two regimes were equivalent. Furthermore, there is evidence to suggest that short courses of high-dose inhaled corticosteroid administered at the onset of symptoms, compared to regular lower-dose use, provide similar results in terms of the number of exacerbations in studies of adults (Foresi 2000). Thus, timely use of inhaled corticosteroids may help to prevent people from experiencing exacerbations.

Why it is important to do this review

While there is a strong dose related relationship between regular ICS adherence and treatment outcomes, many reports suggest that less than 50% of adults and children are receiving the full extent of therapy that has been prescribed for them (Bender 2002; Burgess 2008; Rand 2007). On the one hand this may result in less than adequate individual outcomes with excessive symptomatology, as well as health care costs associated with hospital utilisation to manage exacerbations. On the other hand this could reflect how health professionals beliefs towards medication taking behaviour differ from the general population and misrepresent the response to therapy (Bender 2003).

A number of trials have compared intermittent ICS use versus placebo, but our understanding is that this question about benefits on exacerbations and patient outcomes has yet to be formally analysed as part of a systematic review. There may also be a dose dependent level for clinical response more apparent as well as differences when distinguishing episodic wheeze versus persistent asthma in younger children (Ducharme 2009; McKean 2000). These results will be relevant to patients and policy makers as an approach that may be better tolerated, involve less medication costs and potentially be more closely adhered to.

Objectives

To compare the efficacy and safety of intermittent ICS versus placebo in the management of children and adults in patients with persistent asthma upon measures of exacerbations, hospitalisations, lung function, symptoms and serious adverse events.

Methods

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

Primary outcomes
  1. Asthma exacerbations: patients experience one or more exacerbations requiring rescue oral corticosteroids

  2. Serious adverse events.

Secondary outcomes
  1. Exacerbations requiring hospital admissions

  2. Quality of life (validated questionnaires only)

  3. Symptom scores

  4. Study withdrawals

  5. Measures of lung function (forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR))

  6. 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

Electronic searches

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.

  1. 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.

  2. Participants: N, mean age, age range, gender, severity of condition, asthma diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria.

  3. Interventions: intervention, comparison, concomitant medications, and excluded medications.

  4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

  5. 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.

  1. Random sequence generation.

  2. Allocation concealment.

  3. Blinding of participants and personnel.

  4. Blinding of outcome assessment.

  5. Incomplete outcome data.

  6. Selective outcome reporting.

  7. Other bias.

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.

Data synthesis

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.

  1. Type of inhaled corticosteroid used and dose

  2. Single versus separate inhaled corticosteroid steroid and short acting beta2-agonist devices

  3. Severity of disease at baseline

  4. Adults versus school aged children versus pre-school children

  5. Type of device used or spacer

  6. Concomitant medication

  7. Study duration

We will use only primary outcomes in subgroup analyses and will use the formal test for subgroup interactions in Review Manager (RevMan 2012).

Sensitivity analysis

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.

Acknowledgements

We acknowledge Dr Emma Welsh and Mrs Elizabeth Stovold of the Cochrane Airways Group for their advice and support.

[full name] was the Editor for this review and commented critically on the review.

Appendices

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

Electronic searches: core databases

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

 

Handsearches: 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 Meeting2003 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

 

MEDLINE search strategy used to identify trials for the CAGR

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

Appendix 2. Cochrane Register of Studies (CRS) search

#1 AST:MISC1

#2 MeSH DESCRIPTOR Asthma Explode All

#3 asthma*:ti,ab

#4 #1 or #2 or #3

#5 intermittent*

#6 as-needed*

#7 "as needed"

#8 prn

#9 irregular*

#10 occasional*

#11 sporadic*

#12 short-course*

#13 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12

#14 #4 and #13

[Note: in search line #1 MISC1 refers to the field in which the record has been coded for condition, in this case, asthma]

Contributions of authors

Jimmy Chong: protocol initiation and development.

Innes Asher: protocol initiation and development.

Declarations of interest

None to declare.

Sources of support

Internal sources

  • Nil, Not specified.

External sources

  • No sources of support supplied

Ancillary