Criteria for considering studies for this review
Types of studies
We will include double-blind, randomised controlled trials (RCTs). We will include full-text studies, as well as studies published as abstract only, and unpublished studies. We will include both parallel-group and cross-over designs.
Types of participants
We will include studies of adults with COPD, defined as post-bronchodilator ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) < 0.70, or according to defined international or national guidelines for COPD (e.g. the Global initiative for chronic Obstructive Lung Disease (GOLD), the American Thoracic Society/European Respiratory Society (ATS/ERS)). We will exclude studies of participants with the following co-morbidities/characteristics:
We will not exclude participants on the basis of presence of bronchodilator reversibility (improvement in FEV1 post-bronchodilator of 12% or 200mL improvement if baseline FEV1 ≤ 1.7L), provided that the patients were considered to have predominant COPD (not predominant asthma).
Types of interventions
We will include the following interventions and comparators:
Additionally, we will also consider the related drug, glycopyrrolate (EP-101), once it has been approved for clinical use by the US Food and Drug Administration (FDA). No other co-interventions or combination therapies will be studied.
A minimum of four weeks duration of intervention will be required for each included study.
Types of outcome measures
Health status (as measured by quality of life questionnaires)
Exacerbations - exacerbation rate and total exacerbations
Dyspnoea (as measured by dyspnoea score)
Use of rescue bronchodilators
Other lung function test results (e.g. FVC)
Mortality, adverse events and serious adverse events
The primary objective of this review is to assess the efficacy of glycopyrronium, hence health status and exacerbations will be the primary measures of this review. Secondary outcomes include other measures of efficacy, as well as safety parameters.
Search methods for identification of studies
We will identify trials from the Cochrane Airways Group Specialised Register (CAGR). The CAGR contains trial reports found via systematic search 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 (Appendix 1). We will search the CAGR using the strategy illustrated in Appendix 2. We will search the database from inception to the present, and we will impose no restriction on language 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 identify errata or retractions from included studies published in full-text on PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) and report the date this was performed.
We will also conduct a search of ClinicalTrials.gov (http://clinicaltrials.gov/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/), to identify trials yet to be published.
Data collection and analysis
Selection of studies
Two authors (JB, JE) 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 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 author (IY). 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 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (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. One author (JB) will extract study characteristics from included studies. We will extract the following study characteristics.
Design and methodology: study design, randomisation, blinding, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, date of study and source of funding.
Participants: number eligible, number enrolled, number in treatment, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking status, 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 authors (JB, JE) 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 author (IY). Oneauthor (JB) will transfer data into the Cochrane Coillaboration's statistical software, Review Manager 2013. We will double-check that data is entered correctly by comparing the data presented in the systematic review with the study reports. A second author (JE) will spot-check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two authors (JB, JE) 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 (IY). 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.
Each potential source of bias will be graded as high, low or unclear and a quote from the study report together with a justification for our judgment will be provided in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
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. Where studies use different measurement scales, the standardised mean difference will be calculated.
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.
Unit of analysis issues
The unit of analysis will be the patient. If crossover trials are identified, data from a paired analysis will be sought from the trial report or authors in order to appropriately include data in the review using the inverse variance method. If cluster randomised trials are identified then analysis will be at the level of the individual while allowing for the clustering in the data by using the intracluster correlation coefficient (ICC). If this is not reported in the trial then it will be imputed from similar studies.
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).
Assessment of heterogeneity
We will use the I2 statistic to measure heterogeneity among the trials in each analysis (Higgins 2011). If we identify substantial heterogeneity we will report it and explore possible causes by prespecified subgroup analysis.
Assessment of reporting biases
We will assess selective reporting within each trial by comparing the protocol and final published study or otherwise the methods and results sections. Where reporting bias is suspected, we will attempt to contact study authors asking them to provide missing outcome data. 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 conducting a sensitivity analysis.
We will test for publication bias using a funnel plot if meta-analysis with at least five studies is possible.
We will use a fixed-effect model to calculate the summary odds ratios (ORs) and mean differences (MDs). However if there are concerns about statistical heterogeneity of data, we will use a random-effects model to account for a distribution intervention effects across studies. If meta-analysis is not possible or appropriate, we will undertake a narrative review of the findings.
'Summary of findings' table
We will create a 'Summary of findings' table using the following outcomes:
health status as measured by quality of life questionnaires;
exacerbations - exacerbation rate and total exacerbations;
dyspnoea as measured by dyspnoea score;
use of rescue bronchodilators;
other lung function test results (e.g. FVC);
mortality, adverse events and serious adverse events.
We will use the five Grading of Recommendations Assessment, Development and Evaluation (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 the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses of the primary outcome (FEV1).
COPD severity: divided into patient GOLD Report 2013 stages 1-4 (FEV1 >80%, 50-80%, 30-50%, <30%) prior to intervention.
Smoking status: divided into patients who are smokers and non-smokers.
Concomitant corticosteroid use: divided into patients taking a concomitant inhaled corticosteroid and not taking a concomitant inhaled corticosteroid.
Bronchodilator reversibility: divided into patients with bronchodilator reversibility (improvement in FEV1 post-bronchodilator of 12% or 200 mL improvement if baseline FEV1 ≤ 1.7L) and without reversibility.
We will use the formal test for subgroup interactions in Review Manager 2013.
We plan to carry out the following sensitivity analyses.
Variation in inclusion criteria: removing studies deemed to vary greatly in inclusion criteria from the rest.
Risk of bias: removing studies at high risk of bias for one or more domains.
Study size: removing studies with a small study size (< 1000 participants).
Analysis using random-effects model: pooling of results using a random-effects model if heterogeneity is suspected.
Analysis by treatment received versus intention-to-treat: including data of non-compliant patients and comparing analysis results to the treatment received method.