Glycopyrronium bromide for chronic obstructive pulmonary disease

  • Protocol
  • Intervention

Authors


Abstract

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

To critically appraise the efficacy and safety of glycopyrronium bromide, in terms of objective and subjective measures, in patients with COPD.

Background

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable lung disease characterised by progressive airflow limitation that is not completely reversible (GOLD 2013). COPD generates high healthcare costs and contributes a significant burden of illness (Halbert 2006) . In the recent Global Burden of Disease Study 2010 (GBD 2010), a large systematic project describing global disease distribution, COPD was ranked the 9th greatest contributor to global burden of disease (Murray 2012). Furthermore, COPD was ranked the 3rd largest cause of death, worldwide (Adair 2012; Lozano 2012). COPD is, therefore, an important disease globally, and effective, safe interventions are vital.

Description of the condition

Chronic airflow limitation is characteristic of COPD (GOLD 2013). Pathologically, chronic airflow limitation can result from processes involving the large airways (chronic bronchitis), small airways (bronchiolitis) and parenchyma (emphysema) (Kim 2013). Chronic bronchitis is defined clinically as daily sputum production for at least three months of two of more consecutive years, while emphysema is a pathological diagnosis characterised by dilation and destruction of alveoli (McKenzie 2012).

In emphysema, destruction of elastic alveolar attachments, connecting small airways to lung parenchyma, decreases the lung's elastic recoil and reduces the radial traction that allows respiratory bronchioles to remain patent during expiration (Hogg 2009; Kim 2008). Destruction of alveolar attachments therefore results in airway collapse during expiration. Alveolar wall destruction and remodelling of pulmonary vessels also reduces the surface area available for gas exchange, causing a mismatch between ventilation and perfusion and resultant hypoxaemia. The pathology of chronic bronchitis involves hypersecretion of mucus in the large airways, associated with the classical findings of submucosal hypertrophy and goblet cell proliferation (Kim 2013).

Description of the intervention

Glycopyrronium bromide, an anticholinergic quaternary ammonium, is a long-acting muscarinic antagonist (Vogelmeier 2011) that has been previously used to decrease pharyngeal and salivary secretion. Autonomic control of airway function is primarily mediated by parasympathetic tone. In lung, glycopyrronium acts by blocking parasympathetic innervation of bronchial smooth muscle, decreasing bronchoconstriction (Haddad 1999). Early pharmacological trials of glycopyrronium demonstrated superior selectivity for muscarinic receptors over the currently used long-acting muscarinic antagonist, tiotropium. Glycopyrronium preferentially binds to excitatory M1 and M3 receptors (Gomez 1995), while tiotropium binds at a greater rate inhibitory M2 receptors (Fuder 1993; Sykes 2012). Inhibitory M2 receptors are found both on pre-synaptic neurons and post-synaptic airway smooth muscle (Belmonte 2005). M2 receptors are also found in cardiac tissue, explaining why glycopyrronium has been found to produce fewer cardiac side-effects, such as tachycardia and arrhythmias (Buhl 2012; Cooper 2006; Trifilieff 2007).

How the intervention might work

The principles of management of COPD according to the Australian COPD-X Guidelines are to confirm the diagnosis of COPD and assess severity, optimise lung function, prevent deterioration and develop support networks and self-management skills (McKenzie 2012). Pharmacological aims include relief of symptoms, reduction in exacerbations, improvement of health status and increasing exercise tolerance. Bronchodilators are central to the management of COPD as they relieve dyspnoeic symptoms and have been shown to improve exercise tolerance and quality of life (Appleton 2006; Chong 2012).

Dyspnoea is the most common symptom of COPD and a common reason for COPD patients initially seeking medical attention (ZuWallack 2004). Long-acting bronchodilators produce significant improvements in lung function, dyspnoea, exercise capacity and quality of life in COPD patients, through a reduction in hyperinflation (Beeh 2002; Wedzicha 2012).

Acetylcholine acts on airway smooth muscle and sub-mucosal glands within lung, acting via M3 receptors, resulting in bronchoconstriction and mucus production (Roffel 1990). However, a local negative feedback pathway for acetylcholine release exists, utilising presynaptic M2 receptors (Beeh 2002; Meurs 2013). Therefore, blocking M1 and M3 receptors reduces bronchoconstriction, while blocking M2 receptors may increase acetylcholine release opposing the bronchodilatory effect. Thus, a drug with M1 and M3 selectivity, such as glycopyrronium, theoretically maximises bronchodilation.

Why it is important to do this review

COPD has significant impacts on morbidity and mortality, particularly in patients with moderate to severe COPD. The use of glycopyrronium bromide as an inhaled medicine has the potential to increase the range of clinically useful pharmacological interventions for patients with COPD. Knowledge about the efficacy and safety of glycopyrronium bromide will guide therapeutic decision-making for physicians treating patients with COPD.

Objectives

To critically appraise the efficacy and safety of glycopyrronium bromide, in terms of objective and subjective measures, in patients with COPD.

Methods

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:

  • a primary diagnosis of asthma;

  • a recent exacerbation of COPD.

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:

  • glycopyrronium bromine versus placebo;

  • glycopyrronium bromide versus tiotropium.

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

Primary outcomes
  1. Health status (as measured by quality of life questionnaires)

  2. Exacerbations - exacerbation rate and total exacerbations

  3. FEV1

Secondary outcomes
  1. Dyspnoea (as measured by dyspnoea score)

  2. Use of rescue bronchodilators

  3. Other lung function test results (e.g. FVC)

  4. 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

Electronic searches

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.

  1. 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.

  2. 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.

  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 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.

  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.

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.

Data synthesis

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:

  1. health status as measured by quality of life questionnaires;

  2. exacerbations - exacerbation rate and total exacerbations;

  3. FEV1;

  4. dyspnoea as measured by dyspnoea score;

  5. use of rescue bronchodilators;

  6. other lung function test results (e.g. FVC);

  7. 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).

  1. COPD severity: divided into patient GOLD Report 2013 stages 1-4 (FEV1 >80%, 50-80%, 30-50%, <30%) prior to intervention.

  2. Smoking status: divided into patients who are smokers and non-smokers.

  3. Concomitant corticosteroid use: divided into patients taking a concomitant inhaled corticosteroid and not taking a concomitant inhaled corticosteroid.

  4. 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.

Sensitivity analysis

We plan to carry out the following sensitivity analyses.

  1. Variation in inclusion criteria: removing studies deemed to vary greatly in inclusion criteria from the rest.

  2. Risk of bias: removing studies at high risk of bias for one or more domains.

  3. Study size: removing studies with a small study size (< 1000 participants).

  4. Analysis using random-effects model: pooling of results using a random-effects model if heterogeneity is suspected.

  5. Analysis by treatment received versus intention-to-treat: including data of non-compliant patients and comparing analysis results to the treatment received method.

Acknowledgements

We thank Emma Welsh and John White from the Cochrane Airways Group for their invaluable advice and support in writing this protocol.

John White was the Editor for this review and commented critically on the review.

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group 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

 

Handsearching: 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

COPD search
  1. Lung Diseases, Obstructive/

  2. exp Pulmonary Disease, Chronic Obstructive/

  3. emphysema$.mp.

  4. (chronic$ adj3 bronchiti$).mp.

  5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

  6. COPD.mp.

  7. COAD.mp.

  8. COBD.mp.

  9. AECB.mp.

  10. or/1-9

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. Search strategy for Cochrane Airways Group Register

#1 MeSH DESCRIPTOR Pulmonary Disease, Chronic Obstructive Explode All

#2 MeSH DESCRIPTOR Bronchitis, Chronic

#3 (obstruct*) near3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)

#4 COPD:MISC1

#5 (COPD OR COAD OR COBD):TI,AB,KW

#6 #1 OR #2 OR #3 OR #4 OR #5

#7 MeSH DESCRIPTOR Glycopyrrolate

#8 glycopyrronium*

#9 glycopyrrolate

#10 NVA237

#11 LAMA

#12 long* NEAR muscarinic* NEAR antagonist*

#13 #7 OR #8 OR #9 OR#10 OR #11 OR #12

#14 #6 and #13

[In search Iine #4, MISC1 denotes the field where the reference has been coded for condition, in this case, COPD]

Contributions of authors

JB wrote and edited the protocol, with guidance from JE, RB, KF and IY, who additionally proof-read and reviewed the protocol.

Declarations of interest

Dr Yang declares that:

  • he has received travel and accommodation sponsorship several times to speak at or participate in educational meetings, which have been organised by an independent organising committee and sponsored by industry;

  • he has accepted hospitality in connection with evening professional educational meetings organised by pharmaceutical companies;

  • he is involved with the National COPD Executive of the Australian Lung Foundation (not-for-profit, public benevolent institution) (http://www.lungfoundation.com.au/) which receives some support from pharmaceutical companies;

  • he has been involved in organising and participating in professional scientific meetings including those organised by the Thoracic Society of Australia and New Zealand, where some sponsorship is usually provided by industry;

  • he has not received consultancy fees or honoraria from pharmaceutical companies, and has not acted as a member of advisory boards for pharmaceutical companies

  • his institutions have received project grants and fellowships from the following sources:

    • National Health and Medical Research (NHMRC) project grants;

    • NHMRC Career Development Fellowship;

    • Cancer Council Queensland project grants;

    • Queensland Government Health and Medical Research project grants;

    • the Prince Charles Hospital Foundation;

    • Australian Research Council (ARC) Discovery Grant;

    • Novartis – one year (2013) unrestricted grant to establish a severe asthma service at The Prince Charles Hospital (to be paid to The Prince Charles Hospital Foundation, for use by the hospital).

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • NHMRC Career Development Fellowship (for IY), Australia.

Ancillary