Aclidinium bromide for stable chronic obstructive pulmonary disease

  • Protocol
  • Intervention



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

To assess the efficacy and safety of aclidinium bromide in stable COPD.


Description of the condition

Chronic obstructive pulmonary disease (COPD) is "a common, preventable and treatable disease, characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases" (GOLD 2013). Tobacco smoke is the major risk factor in the pathogenesis of COPD; chemicals, occupational exposures, indoor and outdoor air pollution are also recognised risk factors (GOLD 2013; Hogg 2009; MacNee 2006; TSANZ 2012; WHO 2012).

COPD is the third leading cause of death after heart diseases and malignancy in the United States (CDC 2011) and accounts for approximately 30,000 deaths each year in the UK (NICE 2010). It was the fourth leading cause of mortality in 2004 with three million deaths worldwide (WHO 2008). Ninety per cent of deaths from COPD occurred in low and middle-income countries in 2008 (WHO 2010). The World Health Organization (WHO) has estimated that COPD will become the third leading cause of death worldwide in 2030 due to a projected increase in smoking and environmental pollution (WHO 2012a). Exacerbations and co-morbidities contribute to the overall severity of COPD in patients (GOLD 2013). Currently available prevalence data do not reflect the actual total burden of COPD because of under reporting and diagnosis being made only when clinically apparent (GOLD 2013).

COPD also has a significant economic impact, mainly due to exacerbations. The total annual cost of COPD to the National Health Service (NHS) in the UK is estimated to be over GBP 800 million for direct healthcare costs (NICE 2011). It accounts for 56% (EUR 38.6 billion) of the total cost of respiratory diseases in the European Union, while the estimated cost in the United States is USD 29.5 billion and USD 20.4 billion, for direct and indirect costs respectively (GOLD 2013).

Acute exacerbations are the main cause of morbidity and mortality in COPD patients and are defined as "an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough, and/or sputum, that is beyond normal day-to-day variations, is acute in onset and may warrant a change in medication in a patient with underlying COPD" (GOLD 2013).

Currently there is no cure for COPD. Apart from smoking cessation and long-term oxygen therapy in severely hypoxic patients, other therapeutic options do not improve survival (GOLD 2013). Thus, the major goal of medication is to relieve symptoms, reduce the frequency and severity of exacerbations, and improve quality of life (ATS/ERS 2011; Chong 2012; GOLD 2013; Sutherland 2004; TSANZ 2012).

Management of stable COPD is multidisciplinary, with options such as smoking cessation (van der Meer 2012), education (Effing 2009), vaccination for influenza (Poole 2010) and pneumococcal infections (Walters 2010), breathing exercises (Holland 2012), pulmonary rehabilitation (Lacasse 2009), pharmacotherapy with inhaled bronchodilators, inhaled corticosteroids for severe COPD or frequent exacerbations (GOLD 2013; TSANZ 2012; Yang 2012), phosphodiesterase-4 inhibitors (Chong 2011), long-term domiciliary oxygen therapy (Cranston 2008) and lung volume reduction surgery (Tiong 2009). Regular long-term use of oral corticosteroids is not recommended for stable COPD and is associated with an increased risk of systemic side effects (GOLD 2013; Walters 2009). Oral theophylline has a modest bronchodilator effect (Ram 2009) but is less effective than inhaled long-acting bronchodilators (GOLD 2013). Mucolytic agents show a slight reduction in exacerbations but have no effect on the overall quality of life (Poole 2012). Neither of these are routinely recommended for stable COPD (GOLD 2013). Long-acting bronchodilators, either long-acting beta2-agonist (LABA) (Nannini 2012; Welsh 2011) or long-acting muscarinic antagonist (LAMA) (Karner 2012), are the first-line maintenance therapy for moderate to severe, stable COPD (GOLD 2013; NICE 2010).

Description of the intervention

Aclidinium bromide is a new long-acting antimuscarinic agent that blocks the action of the neurotransmitter acetylcholine. It was approved by the US Food and Drug Administration (FDA) on 23 July 2012 for use in moderate to severe, stable COPD patients (FDA 2012). It is marketed as Tudorza Pressair by Forest Laboratories and Almirall in the US. It is a dry powder formulation (Sims 2011) and the FDA approved dosage is 400 µg inhaled twice daily. In Europe and the UK it has been launched as Eklira Genuair by Almirall.

It is delivered by a state-of-the-art multidose dry powder inhaler (MDPI), termed Genuair or Pressair, which is preloaded with a one-month supply of medication. The MDPI is specially designed with a visible dose level indicator with anti-double dosing mechanism, multiple feedback mechanisms to indicate successful inhalation such as audible click and a slightly sweet taste, as well as an end-of-dose lock-out system to prevent further use after the final dose (Maltais 2012; Sims 2011).

How the intervention might work

Airway obstruction mediated by vagal cholinergic tone is the major reversible contributor to COPD (Jones 2011). Currently there are five known subtypes of muscarinic cholinergic receptors (M1 to M5), of which three (M1, M2 and M3) are present in the bronchial airway smooth muscle (Karakiulakis 2012; Maltais 2012).

Acetylcholine acts on M1 receptors to facilitate further neurotransmission from parasympathetic ganglia, which then binds to M3 receptors located on the airway smooth muscle cells to induce bronchoconstriction. M2 receptors mediate feedback inhibition of acetylcholine release at the cholinergic nerve endings (Karakiulakis 2012; Sims 2011; Vogelmeier 2011).

Aclidinium bromide is a LAMA which inhibits the action of acetylcholine at the muscarinic receptors with approximately six-fold kinetic selectivity for M3 receptors compared to the M2 subtype, causing more effective bronchodilator action with fewer M2 mediated cardiac side effects (Maltais 2012; Sims 2011). The onset of action of aclidinium bromide (30 minutes) is similar to ipratropium (30 minutes) but faster than tiotropium (80 minutes). The duration of action of aclidinium (t1/2 = 29 hours) is shorter than tiotropium (t1/2 = 64 hours) but longer than ipratropium (t1/2 = 8 hours) (Maltais 2012).

These muscarinic receptors are also present in other parts of the body, such as M1 receptors in the central nervous system (CNS), M2 in the heart, M3 in the gastrointestinal tract (GIT), iris and sphincter and M4 in the neostriatum, whereas the functional role of M5 is not clear (Gavaldà 2010). Thus, the non-selective blockade of muscarinic receptors can have the potential for systemic side effects.

Aclidinium has been shown in preclinical and clinical studies to rapidly hydrolyse into two inactive metabolites in the plasma, with a very short plasma half life of 2.4 minutes, while that of ipratropium is 96 minutes and tiotropium is more than six hours (Maltais 2012). This low and transient level in the plasma leads to less drug-drug interaction and contributes to a more favourable safety profile.

Why it is important to do this review

Although a long-lasting bronchodilator effect and favourable safety profile of aclidinium bromide has been shown in a number of clinical trials (Jones 2011; Jones 2012), the summarised safety and efficacy profile of this agent compared to placebo, or currently established treatment options such as LABAs or LAMAs, is lacking. We aim to fill this gap by performing a systematic review of the findings of all available randomised controlled trials (RCTs), to help clinicians provide evidence-based long-term management of stable COPD.


To assess the efficacy and safety of aclidinium bromide in stable COPD.


Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) with a parallel-group design comparing aclidinium bromide with placebo or LABA or LAMA, both open-label and blinded studies. Since COPD is a progressive disorder which deteriorates with time, we will exclude cross-over trials. We will also exclude cluster-randomised trials to avoid bias.

Types of participants

We will include studies involving adults (over 18 years of age) diagnosed with moderate to severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2013), American Thoracic Society (ATS), European Respiratory Society (ERS) (ATS/ERS 2011), Thoracic Society of Australia and New Zealand (TSANZ 2012), UK National Institute for Health and Clinical Excellence (NICE 2010) or the WHO. Participants in the studies will have evidence of airway obstruction (post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio of < 70% and FEV1 < 80% of predicted value) with clinical presentation of dyspnoea, chronic cough or sputum production and/or a history of smoking. We will exclude studies which enrolled patients with bronchial asthma, bronchiectasis, cystic fibrosis or other lung diseases.

Types of interventions

  1. Aclidinium bromide versus placebo

  2. Aclidinium bromide versus LABA

  3. Aclidinium bromide versus LAMA

Types of outcome measures

Primary outcomes
  1. Mortality (all-cause and respiratory)

  2. Exacerbations requiring a short course of oral steroids, antibiotics or both

  3. Quality of life measured by a validated scale, St George's Respiratory Questionnaire (SGRQ) or Chronic Respiratory Disease Questionnaire (CRQ)

Secondary outcomes
  1. Change in lung function (FEV1, FEV1/FVC)

  2. Functional capacity by six-minute walk distance

  3. Hospital admissions due to exacerbations or all-cause

  4. Improvement in symptoms measured by Transitional Dyspnoea Index (TDI)

  5. Adverse events

  6. Non-fatal serious adverse events

  7. Withdrawals due to lack of efficacy or adverse events

We will assess mortality and exacerbations as primary outcomes since exacerbations are the main cause of morbidity and mortality in COPD patients. We will also include quality of life as primary outcome since it is one of the most important parameters that can measure both subjective and objective well-being of COPD patients who have to live with this chronic disease. We will record change in lung function from the baseline, exercise capacity, hospital admissions and symptom improvement as secondary outcomes, as these may not directly reflect mortality and morbidity in COPD. For the safety profile of this new intervention (aclidinium bromide), we will study adverse events, non-fatal serious adverse events and withdrawals from studies as secondary outcome measures.

Search methods for identification of studies

Electronic searches

We will identify trials from 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 'COPD' will be searched using the following terms:

Aclidinium* or "LAS34273" or "Tudorza" or "Eklira" or "Genuair" or "Pressair" or "LAMA" or "Muscarinic Antagonists"

We will also conduct a search of (Appendix 2) and the WHO International Clinical Trials Registry Platform (ICTRP) (WHO ICTRP). All databases will be searched from their inception to the present and there will be no restriction on language of publication.

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references. We will contact authors of identified trials and ask them to identify other published and unpublished studies. We will also contact manufacturers and experts in the field. We will search the US FDA website (FDA 2012) for details of the clinical trials. We will also search the manufacturers' websites (Forest Pharmaceuticals and Almirall) for additional information on studies identified through the electronic searches. Studies published in a language other than English will be translated.

Data collection and analysis

Selection of studies

Two review authors (HN and SM) will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third review author (ZS), who is an expert in the field. We will include the trials meeting the criteria regardless of language or publication status (published, unpublished, in press and in progress). We will record excluded studies together with the reasons for exclusion.

Data extraction and management

Two review authors (HN and SM) will independently extract and record the data from included studies using standard data extraction forms, which will be cross-checked. The data extraction will include study characteristics: mainly study design, participants, interventions, primary and secondary outcome measures and the analysis performed in original studies. If there are discrepancies, we will consult a third review author (ZS) to resolve the inconsistencies. In cases of insufficient or missing data, we will contact corresponding authors of the studies for additional information. One of the review authors (HN) will enter data into Review Manager 5 software for analysis and this will be checked by another review author (SM).

Assessment of risk of bias in included studies

Two review authors (HN and SM) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved by discussion or by involving a third assessor (ZS). 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. We will record these judgements in the 'Risk of bias' tables accompanying the characteristics of each included study and summarise them in the 'Risk of bias' summary figure. If needed, we will contact the investigators of the RCTs for the details of procedures involved in the conduct of trials and will keep the recorded replies for evidence. We will exclude those trials with high risk of bias. We will use the information from the assessment of risk of bias to carry out stratified analysis.

Measures of treatment effect

Dichotomous data

We will analyse dichotomous outcome data (such as mortality, exacerbations and withdrawals) using Mantel-Haenszel odds ratio (OR) with 95% confidence intervals (CI). If events are rare, we will apply the Peto odds ratio.

We will also calculate the number needed to treat (NNT) for dichotomous outcomes to reflect the number of patients necessary to obtain a beneficial or harmful outcome with the intervention.

Continuous data

We will assess continuous data variables (such as quality of life, symptoms, lung function and exercise capacity) as fixed-effect mean differences (MD) with 95% CI when the same scale is used to measure the outcome in all the included studies. We will use the standardised mean difference (SMD) when all studies assess the same outcome but measure it in different ways. MD based on change from baseline will be preferred over MD based on absolute values.

Unit of analysis issues

We will analyse participants as the unit of analysis for dichotomous data. For continuous data, we will use MD which is the average change from baseline and not the absolute mean. For outcomes that may occur more than once, such as exacerbations, hospital admissions and adverse events, we will analyse the count data as continuous to prevent unit of analysis error.

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. In cases where missing data are not available despite attempts to obtain this, we will record it in our review. We will perform sensitivity analysis to assess the impact of unknown status or assumptions made about missing data on participants who withdrew from trials on the overall pooled result of the meta-analysis. We will follow an intention-to-treat (ITT) principle in the analysis of outcomes from randomised trials, if appropriate.

Assessment of heterogeneity

We will assess heterogeneity between the trials by checking for poor overlap of horizontal lines representing each trial on the forest plot and with the Chi2 test, with a 10% level of significance. We will use the I² statistic to measure the percentage of inconsistency in results due to inter-trial variability in each analysis. If we identify substantial heterogeneity, we will explore it by pre-specified subgroup analysis. We will regard the level of statistical variation among the trials as high if the I² value is more than 50%.

Assessment of reporting biases

We will use funnel plots for assessing reporting biases, if the meta-analysis includes 10 or more studies. Where we suspect reporting bias by asymmetrical appearance of the funnel plot after exclusion of other reasons for funnel plot asymmetry, 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 a sensitivity analysis.

Data synthesis

We will analyse the data using Review Manager 5. For pooling of outcomes of studies, we will use a fixed-effect model if the I2 statistic is homogeneous. We will use a random-effects model for data synthesis when heterogeneity is identified as significant (I2 > 50%) and cannot be explained by subgroup analyses. We will combine dichotomous outcome variables using a Mantel-Haenszel OR with 95% CI. For continuous outcome data, we will analyse as MD with 95% CI. Where treatment effects are reported as MD with 95% CI or exact P value, we will calculate the standard error, enter it with the MD and combine the results using a fixed-effect model generic inverse variance (GIV) analysis in Review Manager 5. We will also calculate the NNT from the pooled OR and its CI.

We will create a 'Summary of findings' table using the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and using GRADEpro software for overall grading of the quality of the evidence. We will include the following outcomes.

  1. Mortality (all-cause and respiratory)

  2. Exacerbations requiring a short course of oral steroids, antibiotics or both

  3. Quality of life

  4. Functional capacity by six-minute walk distance

  5. Hospital admissions due to exacerbations or all-cause

  6. Non-fatal serious adverse events

Subgroup analysis and investigation of heterogeneity

If there is significant heterogeneity, we will perform subgroup analysis in order to explain it. We will carry out the following subgroup analyses.

  1. Dose of aclidinium bromide (e.g. 200 μg; 400 μg)

  2. Frequency of aclidinium bromide (once daily; twice daily)

  3. Duration of treatment periods (short-term (12 weeks or less); long-term (more than 12 weeks))

  4. Disease severity at baseline (FEV1 < 50% predicted; FEV1 ≥ 50% predicted)

  5. Concurrent therapy with theophylline (dichotomised as yes/no)

The following outcomes will be used in subgroup analysis.

  1. Exacerbations

  2. Quality of life

  3. Change in lung function

Sensitivity analysis

We will assess the robustness of our analyses by repeating the meta-analysis after exclusion of studies with high risk of bias and those with unclear methodological data from the overall analysis in sensitivity analysis.


We would like to thank the staff of the Cochrane Airways Group and The Cochrane Collaboration for their utmost help and support, especially Dr Emma J Welsh and Ms Elizabeth Stovold for their feedback, suggestions and advice for this protocol. Special thanks go to Dr Aung Win Thein, Associate Professor, Melaka-Manipal Medical College for his critical comments on this protocol. Furthermore, we would like to acknowledge Professor Datuk Dr. Abdul Razzak M.S, Pro Vice Chancellor & Chief Executive of Manipal University, Dr Jaspal Singh Sahota and Dr Adinegara Bin Lutfi Abas, Dean and Deputy Dean of Melaka-Manipal Medical College, Malaysia for their continuous support, guidance and encouragement on the Cochrane systematic review.


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

Electronic searches: core databases

DatabaseFrequency of search
CENTRAL (The Cochrane Library)Monthly
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
PsycINFO (Ovid)Monthly

Handsearches: core respiratory conference abstracts

ConferenceYears 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.





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

Search terms: "aclidinium" OR "aclidinium bromide" OR "LAMA" OR "muscarinic antagonists" OR "LAS34273"

Condition: COPD or Chronic Obstructive Pulmonary Disease

Study type: interventional studies

Contributions of authors

HN and ZS wrote the protocol with suggestions and input on the methods from SM. All authors reviewed the protocol prior to submission for editorial review.

Declarations of interest

The authors have no connection with any organisations which could have conflict of interest. We are doing this systematic review for academic purposes.