Indacaterol, a once-daily beta 2 -agonist, versus twice-daily beta-agonists or placebo for chronic obstructive pulmonary disease (Protocol) Geake JB, Dabscheck EJ, Wood-Baker R This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 10 http://www.thecochranelibrary.com
T A B L E O F C O N T E N T S HEADER....................................... ABSTRACT...................................... BACKGROUND.................................... OBJECTIVES..................................... METHODS...................................... ACKNOWLEDGEMENTS................................ REFERENCES..................................... APPENDICES..................................... HISTORY....................................... CONTRIBUTIONS OF AUTHORS............................. DECLARATIONS OF INTEREST.............................. SOURCES OF SUPPORT................................. 1 1 2 2 2 5 5 5 7 7 7 7 i
[Intervention Protocol] Indacaterol, a once-daily beta 2 -agonist, versus twice-daily betaagonists or placebo for chronic obstructive pulmonary disease James B Geake 1, Eli J Dabscheck 2, Richard Wood-Baker 3 1 Thoracic and Sleep Medicine, Monash Medical Centre, Clayton, Australia. 2 Allergy Immunology and Respiratory Medicine, Alfred Hospital, Prahan, Australia. 3 Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia Contact address: James B Geake, Thoracic and Sleep Medicine, Monash Medical Centre, Clayton, Victoria, 3168, Australia. james.geake@southernhealth.org.au. bod182au@yahoo.com. Editorial group: Cochrane Airways Group. Publication status and date: New, published in Issue 10, 2012. Citation: Geake JB, Dabscheck EJ, Wood-Baker R. Indacaterol, a once-daily beta 2 -agonist, versus twice-daily beta-agonists or placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD010139. DOI: 10.1002/14651858.CD010139. A B S T R A C T This is the protocol for a review and there is no abstract. The objectives are as follows: To compare the efficacy of indacaterol with placebo and with twice-daily administered long-acting beta 2 -agonists in the treatment of stable COPD. 1
B A C K G R O U N D Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality globally. A number of pharmacotherapeutic interventions have demonstrated efficacy in modifying a variety of long-term clinical outcomes associated with the disease. These include inhaled glucocorticoids, inhaled anticholinergics and inhaled long-acting beta 2 -agonists. The latter class, used either alone or in combination, has an established role in the treatment of COPD, particularly with respect to reducing exacerbations and improving quality of life. Until recently, although these agents have been classed as long-acting, their pharmacokinetic profile has required twice-daily dosing. Indacaterol is a new novel beta 2 -agonist that is administered once-daily and has recently been approved by several regulatory authorities around the world for the treatment of stable COPD. As it requires only once-daily dosing, there are potential benefits in adherence over agents that have been available previously. This agent therefore offers both a new pharmacotherapeutic option for stable COPD, and a potential logical alternative to traditional long-acting beta 2 -agonists that require twice-daily dosing. Description of the condition COPD was the fifth leading cause of death worldwide in 2002, and is projected to become the third leading cause by 2030 (WHO 2008). It carries a considerable financial and social burden to both societies and individuals (Buist 2007; Gershon 2010; Hall 2010).. It is a chronic progressive disease, characterised by airflow limitation that is not fully reversible, occurring as a consequence of exposure to noxious particles or gases. Exposure to cigarette smoke is the most important risk factor for development of the disease in the high-income countries. In low income countries, exposure to smoke from the burning of biomass fuels indoors has been identified as an additional important cause. Although patients may be asymptomatic in the early stages of disease, its clinical course is characterised by progressive dyspnoea, often associated with chronic cough and sputum production. This course if often punctuated by exacerbations, defined as acute deteriorations in the patient s symptoms of dyspnoea, cough or sputum, beyond the day-to-day fluctuations of the disease. Such exacerbations have a major impact on the quality of life of patients, and in developed countries account for the greatest burden on health care systems (GOLD 2010). Description of the intervention Indacaterol is a novel inhaled once-daily beta 2 -agonist that results in smooth muscle relaxation and bronchodilatation. It has been investigated for the treatment of COPD, predominantly in patients with moderate to severe spirometric deficits. It was approved for treatment of COPD by the European Medicines Agency (EMA) in 2009, and more recently by the Food and Drug Administration (FDA) in the United States in 2011. How the intervention might work Similar to both short-acting and twice-daily beta 2 -agonists, indacaterol is thought to work through stimulation of beta 2 -adrenergic receptors present within respiratory smooth muscle, resulting in bronchodilatation. This in turn improves dysfunctional respiratory mechanics present in patients with chronic airflow limitation, possibly resulting in improvement of dyspnoea. Why it is important to do this review COPD is a common disease associated with significant morbidity and mortality. Given the irreversible effects that occur during disease development, the pharmacologic options available for its treatment are relatively limited. Having been recently approved for use in Europe and the United States, the prescription of this medication is likely to escalate in the future. It will therefore, be important that potential prescribers have a keen understanding of this drug s relative efficacy, both in its own right and compared to other treatments available for the disease, in particular twice-daily administered long-acting beta 2 -agonists. O B J E C T I V E S To compare the efficacy of indacaterol with placebo and with twice-daily administered long-acting beta 2 -agonists in the treatment of stable COPD. M E T H O D S Criteria for considering studies for this review Types of studies We will include randomised controlled trials of at least twelve weeks duration. We will not exclude trials on the basis of blinding. Types of participants Adults older than 19 years with a confirmed spirometric diagnosis of COPD. 2
Types of interventions Experimental intervention: once-daily indacaterol at any dose. Comparator interventions: 1. placebo; or 2. twice-daily long-acting beta 2 -agonists. Types of outcome measures Outcome measures will not form part of the eligibility criteria for inclusion of studies in the review. Primary outcomes 1. Exacerbations defined as events requiring the administration of corticosteroids, antibiotics or both (measured as either rates per patient per year, time to first event or patients with one or more events). 2. Exacerbations requiring hospital admission (measured as either rates per patient per year, time to first event or patients with one or more events). 3. Morning trough forced expiratory volume in one second (FEV1) at the end of the dosing interval. 4. Mean difference in quality of life between treatment groups. 5. Number of patients with a clinically significant improvement in quality of life. 6. Number of patients with a clinically significant deterioration in quality of life. Secondary outcomes 1. Peak FEV1. 2. 24-hour area under the curve FEV1. 3. Mean difference in dyspnoea between groups. 4. Number of patients experiencing a clinically significant improvement in dyspnoea. 5. Number of patients experiencing a clinically significant deterioration in dyspnoea. 6. Mortality. 7. Patients experiencing one or more serious adverse events. 8. Peak forced vital capacity (FVC). 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) (The Cochrane Library), 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 coded as COPD using the following terms: (indacaterol or OnBrez or Breezhaler or Arcapta or ultra-long* or ultra long* ). We will also conduct a search of ClinicalTrials.gov (www.clinicaltrials.gov/). We will search all databases from their inception to the present and we will impose no restriction on language of publication. Searching other resources We will search 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. Data collection and analysis Selection of studies Two reviewers (JBG, EJD) will independently assess for inclusion all the potential citations we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, resolution by a third person. We will then assess abstracts and finally full-text papers for inclusion, with any disagreement resolved through discussion or, if required, resolution by a third person. Data extraction and management One reviewer (JBG) will extract data from trials identified in the search strategy and enter this data into Review Manager 5.1 ( RevMan 2011) for statistical analysis. A second reviewer (EJD) will cross-check the extracted data. Assessment of risk of bias in included studies Two reviewers (JBG, EJD) 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 a third assessor. We will assess the risk of bias according to the following domains. 1. Allocation sequence generation. 2. Concealment of allocation. 3. Blinding of participants and investigators. 4. Incomplete outcome data. 5. Selective outcome reporting. We will note other sources of bias. We will grade each potential source of bias as low, high or unclear risk of bias. 3
Measures of treatment effect We will analyse dichotomous data as odds ratios (ORs) using the Mantel-Haenzsel method. We will transform rate ratios into log rate ratios and analyse them using fixed-effect and generic inverse variance (GIV) models in Review Manager 5.1 (RevMan 2011). We will analyse continuous data using the mean difference (MD) when the outcome is measured on the same scale and standardised mean difference (SMD) when on different scales. Where treatment effects are reported as a MD with standard deviations (SDs) or an exact P value, we will calculate the standard error (SE) and enter it with the MD and combine the results using a fixed-effect GIV model in Review Manager 5.1 (RevMan 2011). Unit of analysis issues We will analyse dichotomous data using participants rather than events as the unit of analysis. For repeated observations we will select the longest follow-up from each study. For cluster-randomised trials we will calculate the design effect of the trial, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will then calculate the effective sample size and adjust the number of events in the intervention and control arms accordingly, before entering the data into Review Manager 5.1 (RevMan 2011). If an estimate of an effect measure is presented (rather than summary data for the intervention group) and either a P value or a confidence interval (CI) are provided, we will estimate the SE, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use the GIV method in Review Manager 5.1 to perform a meta-analysis for hazard ratios (HRs) of time-to-event analyses and rate ratios for exacerbation rates. For cross-over trials, we will assess continuous data, wherever possible, using a paired t-test, and we will enter the effect estimate into Review Manager 5.1 using the GIV method. Where dichotomous data are reported, we will conduct analysis in consultation with a statistician. 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. We will analyse data on an intention-to-treat basis. Assessment of heterogeneity We will use the I 2 statistic to measure heterogeneity among the trials in each analysis. An I 2 > 50% will be considered significant; we will explore potential causes of heterogeneity in this situation. Potential sources of heterogeneity are postulated a priori to be due to: 1. differences in methodological quality and risk of bias. Studies will be deemed to be of lower methodological quality if incomplete data have not been adequately addressed for all assessed outcomes, if they are not free from selective reporting, and if they are not free from other sources of bias; 2. differences in uses of concomitant inhaled and systemic medications; and 3. difference in doses of either indacaterol or comparator longacting beta 2 -agonists. Assessment of reporting biases Where we suspect reporting bias, we will attempt to contact study authors asking them to provide missing outcome data. In addition, we will minimise reporting bias of unpublished trials by contacting the manufacturers about additional trials, searching the manufacturer s trials register and ClinicalTrials.gov (http://clinicaltrials.gov/). 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 using a sensitivity analysis. If we identify more than 10 studies for inclusion, we will perform a funnel plot to assess for possible publication bias. Data synthesis We will create a Summary of findings table for primary outcomes using GRADEpro software, with methods described in Chapter 12 of 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. 1. GOLD class 1 and 2 versus GOLD class 3 and 4 for both placebo and long-acting beta 2 -agonist comparisons. 2. Salmeterol versus formoterol/eformoterol for long-acting beta 2 -agonist comparisons. 3. Trials of between 12 and 24 weeks, and trials > 24 weeks. We will use primary outcomes only for subgroup analyses. If we identify substantial heterogeneity we will explore it by performing a sensitivity analysis, systematically excluding studies from the overall analysis based on the potential sources of heterogeneity mentioned above. In addition where there is concern regarding the presence of small study effects inappropriately influencing the results in the setting of between-study heterogeneity (I 2 > 0) we will perform both fixed-effect and random-effects metaanalyses of the data. Sensitivity analysis We will investigate studies at high risk of bias by removing studies of lower methodological quality (e.g. where there is inadequate randomisation, sequence protection and blinding). In addition, if there is significant statistical heterogeneity and there have been different methods used between studies for dealing with missing 4
data, we will perform a sensitivity analysis to assess the effect the different statistical methods have on the overall result. A C K N O W L E D G E M E N T S Ms Liz Stovold, Trials Search Co-ordinator/Information Specialist and Dr Emma Welsh, Managing Editor, both of the Cochrane Airways Group are gratefully acknowledged for their very generous and invaluable assistance. Additional references Buist 2007 Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, et al.international variation in the prevalence of COPD (the BOLD Study): a populationbased prevalence study. Lancet 2007;370(9589):741 50. [PUBMED: 17765523] Gershon 2010 Gershon AS, Wang C, Wilton AS, Raut R, To T. Trends in chronic obstructive pulmonary disease prevalence, incidence, and mortality in Ontario, Canada, 1996 to 2007: a population-based study. Archives of Internal Medicine 2010;170(6):560 5. [PUBMED: 20308643] GOLD 2010 Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. www.goldcopd.org/guidelines-publications-reviewed- 2010.html (accessed 9/3/2012 ) 2010. R E F E R E N C E S Hall 2010 Hall MJ, DeFrances CJ, Williams SN, Golosinskiy A, Schwartzman A. National Hospital Discharge Survey: 2007 summary. National Health Statistics Reports 2010, issue 29:1-20, 24. [PUBMED: 21086860] Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. RevMan 2011 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011. WHO 2008 World Health Organization. World Health Statistics. www.who.int/whosis/whostat/2008/en/index.html (accessed 9/3/2012 ) 2008:30. Indicates the major publication for the study A P P E N D I C E S Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR) Electronic searches: core databases 5
Database MEDLINE (Ovid) EMBASE (Ovid) CENTRAL (the Cochrane Library) PsycINFO (Ovid) CINAHL (Ebsco) AMED (Ebsco) Frequency of search Weekly Weekly Quarterly Monthly Monthly Monthly Handsearches: core respiratory conference abstracts Conference American Academy of Allergy, Asthma and Immunology (AAAAI) American Thoracic Society (ATS) Asia Pacific Society of Respirology (APSR) British Thoracic Society Winter Meeting (BTS) Chest Meeting European Respiratory Society (ERS) International Primary Care Respiratory Group Congress (IPCRG) Thoracic Society of Australia and New Zealand (TSANZ) Years searched 2001 onwards 2001 onwards 2004 onwards 2000 onwards 2003 onwards 1992, 1994, 2000 onwards 2002 onwards 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$.mp. 6
4. (chronic$ 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 H I S T O R Y Protocol first published: Issue 10, 2012 C O N T R I B U T I O N S O F A U T H O R S James Geake (JBG) drafted the protocol in consultation with Eli Dabscheck (EJD) and Richard Wood-Baker (RWB). All authors reviewed the protocol prior to submission for editorial review. D E C L A R A T I O N S O F There are no conflicts of interest. I N T E R E S T S O U R C E S O F S U P P O R T 7
Internal sources Cochrane Airways Group Scholarship, Australia. External sources No sources of support supplied 8
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