Vilanterol and fluticasone for asthma

  • Protocol
  • Intervention

Authors


Abstract

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

To examine the effects of vilanterol and fluticasone furorate on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma compared to placebo.

Background

Description of the condition

There are periods where asthma, a chronic respiratory disease, may be relatively well controlled, and then abruptly followed by a marked deterioration (referred to as an exacerbation). Currently, the number of people with asthma is estimated at 300 million, and forecasts suggest that by 2025 the total will be closer to 400 million (WHO 2007). Between 2001 and 2009 there was an increase from 20 million to 25 million in the US, where there are slightly lower prevalence rates among adults (8%) than children (10%) (CDC 2012; CDCP 2011). There are also considerable differences in asthma prevalence among different ethnic groups. Between 2008 and 2010 the US rates were: Multiple-race (14.1%), Alaskan Native (9.4%), American Indian (also 9.4%), black (11.2%), white (7.7%) and Asian (5.2%) populations (CDCP 2011). The prevalence of wheezing symptoms in children varies geographically with the UK having the highest recorded prevalence of current wheezing at 32.3% and Ethiopia the lowest at 1.7% (Patel 2008).

Asthma is associated with impaired quality of life (Clayton 2005); in particular, it is also noted that there are financial implications associated with the condition (Wu 2007). Each year, asthma exacerbations impact on approximately 10 million people with asthma in the US (Krishnan 2006). Elsewhere, there are similarly high incidence rates; in the UK there were over 65,000 hospital admissions for asthma in the period 2005 to 2006 (NHS 2011). There are well recognised factors that can be addressed to prevent hospital admissions in children with acute asthma (Ordonez 1998). In recent years a number of evidence-based clinical guidelines have emerged, at both national (e.g. BTS/SIGN 2012; NIH 2007) and international (e.g. GINA 2011) levels, to provide guidance for the management of asthma. Asthma is a consequence of airways inflammation, however, with appropriate clinical management it is possible to maintain health-related quality of life for considerable periods (WHO 2011). Mortality specifically associated with asthma and asthma morbidity is a major health concern (Braman 2006).

Description of the intervention

Asthma is a chronic inflammatory disorder of the airways that is characterised by reversible airways obstruction. A combination of inhaled corticosteroid (ICS) and long-acting ß2 agonist (LABA) is recommended for patients at step three of the British Thoracic Society guidelines; that is, patients not controlled on inhaled corticosteroids alone. There is evidence that addition of a LABA in patients who have uncontrolled symptoms on ICS alone can lead to improved lung function, improved symptoms, reduced use of rescue medications and a reduction in asthma exacerbations (BTS/SIGN 2012). Although generally less effective, the combination of ICS and leukotriene antagonist (LTRA) is a valid alternative to ICS and LABA (Montuschi 2008; Montuschi 2010)

Inhaled corticosteroids are fundamental in the treatment of asthma and fluticasone furoate belongs to this class of drugs. Inhaled corticosteroids work by reducing inflammation and airway hyper-responsiveness (Barnes 1998), thus improving the symptoms of asthma and the patient's lung function (Montuschi 2011). The majority of ICS are administered twice daily and studies have shown that using most of the presently available ICS once daily is less effective and leads to an increase in the requirement for rescue medication (BTS/SIGN 2012; Weiner 1995).

Vilanterol (VI) is a new drug that belongs to the LABA class. It is an ultra-LABA with rapid onset action in experimental models and has a 24-hour duration of bronchodilating effect in patients with asthma (Fuso 2013). The addition of LABA therapy to ICS treatment in asthma has been shown to improve lung function and reduce asthma symptoms and exacerbation rates (Remington 2005). Presently, the available LABAs require twice-daily administration apart from indacterol, approved for chronic obstructive pulmonary disease (COPD),which requires once-daily administration. 

At the present time, there are several combination inhalers available for the treatment of asthma in adults, that is containing both ICS and LABA. However, these all involve twice-daily dosing, which is less convenient for patients and leads to a reduction in compliance with long-term therapy. Therefore, a once-daily combination inhaler would hopefully lead to increased compliance with treatment long term in people with asthma. 

There are few data on once-daily combination treatments other than vilanterol and fluticasone furorate for asthma. A 12-week randomised controlled double blind study of 531 children aged six to 15 years, showed taking a single inhaler containing budesonide and formoterol once daily maintained pulmonary function but taking the same inhaler twice daily resulted in improved pulmonary function, fewer discontinuations for worsening asthma, and less daytime rescue medication (Eid 2010). Once-daily budesonide/formoterol has shown improved asthma control variable compared to once-daily budesonide alone (at a four times higher dose) in four to 11 years olds (Bisgaard 2006).

How the intervention might work

Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment and are initiated when patients require the use of short-acting ‘reliever’ medications on a regular basis.  As well as the benefits mentioned previously, patients who are compliant with ICS therapy demonstrate a reduction in asthma exacerbations and mortality related to asthma (Powell 2003). It is well recognised that poor compliance is a major issue in patients with poorly controlled symptoms (BTS/SIGN 2012). One of the issues that may contribute to this is the twice-daily dosing regimen of most ICS.

Fluticasone furoate is a relatively new long-acting inhaled corticosteroid. It remains active for at least 24 hours after administration. Early studies have shown an improvement in lung function tests and a favourable safety and tolerability profile (Bleecker 2011; Woodcock 2011).

In recent years, there has been increasing evidence for the addition LABAs to ICS in the treatment of asthma and the benefit appears to be more than bronchodilatation alone. The action of corticosteroids is mediated by cytoplasmic glucocorticoid receptors (GRs) and after binding with the corticosteroids, the GR translocates to the nucleus where it is able to regulate gene expression (Montuschi 2011). LABAs have also been shown to induce GR nuclear translocation, although not as effectively as glucocorticoids. By studying the sputum epithelial cells and macrophages of people with asthma, it has been shown that the LABA, salmeterol, in combination with fluticasone propionate, was more effective at enhancing GR nuclear translocation than low-dose fluticasone propionate alone (Usmani 2005).

Interleukin-8 (IL-8) is a chemokine that has been implicated in the abnormal airway inflammation seen in asthma and it has been demonstrated that patients with clinically stable asthma have higher levels of IL-8 in broncho-alveolar lavage samples compared with normal healthy control particIpants (Nocker 1996). In a study looking at IL-8 production from neutrophils stimulated by cigarette smoke, it was shown that salmeterol and fluticasone propionate additively suppressed IL-8 release from neutrophils when compared with either agent alone. Interestingly, this effect is not seen in all human cell types and appears to be cell-specific. The mechanism of action is not yet clear but is has been suggested that increased translocation of the GR receptor to the nucleus may be involved (Mortaz 2008).

In patients who are uncontrolled on regular ICS, current BTS guidelines recommend the addition of a LABA, such as salmeterol or formoterol (BTS/SIGN 2012). Both these medications have a twice-daily dosing regimen that affects compliance and therefore, asthma control. LABAs are of benefit due to their bronchodilation effect and vilanterol (VI) is a new selective ß2 agonist within this class (Cazzola 2011). It has been shown that vilanterol is well tolerated with no significant adverse effects (Kempsford 2013) and also leads to an increase in symptom-free periods and a reduction in the use of rescue medication (Lotvall 2012).

In summary, limited studies suggest that there are effective once-daily ICS and LABAs that would allow a once-daily dosing regimen. This would hopefully lead to increased adherence and improved asthma control in adults and in children

Why it is important to do this review

There are published randomised trials on vilanterol and fluticasone furorate. This review will aim to establish whether vilanterol and fluticasone furorate may have a positive role in the management of chronic asthma in children and adults.

Objectives

To examine the effects of vilanterol and fluticasone furorate on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma compared to placebo.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs). We will include studies reported as full-text, those published as abstract only, and unpublished data.

Types of participants

We will include trials involving adults and children with a diagnosis of asthma. We will exclude participants with the following co-morbidities: co-existing chronic diseases such as smoking-related COPD, congenital heart diease and other chronic diseases such as cystic fibrosis and chronic renal failure. We will also exclude people who are current smokers and pregnant women.

Types of interventions

We will include trials comparing the following interventions.

  • Vilanterol and fluticasone furorate versus placebo

  • Vilanterol and fluticasone furorate versus ICS and as required SABA

  • Vilanterol and fluticasone furorate versus other combination inhalers

  • Vilanterol  and fluticasone furorate versus ICS and LABA in separate inhalers

We will include the following co-interventions provided they are not part of the randomised treatment: bronchodilators, systemic or inhaled steroids, leukotriene antagonists, oral aminophylline and macrolide antibiotics.

Types of outcome measures

Primary outcomes
  1. Health-related quality of life.

  2. Severe asthma exacerbation as defined by hospital admissions or treatment with a course of oral corticosteroids.

  3. Serious adverse events.

Secondary outcomes
  1. Measures of lung function: forced expiratory flow in one second (FEV1), peak expiratory flow (PEF).

  2. Asthma symptoms.

  3. 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 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' web sites 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 [SM, CP] will independently screen the titles and abstracts 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/publications and the same two review authors [SM, CP] 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 [NW]. 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. One review author [CP] will extract study characteristics from included studies. 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: number (N), mean age, age range, gender, severity of condition, 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 [KD, CP] will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person [NW]. One review author [KD] will transfer data into the Review Manager (RevMan 2012) file. We will double-check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author [SM] will spot-check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors [KD, 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). We will resolve any disagreements by discussion or by involving another author [CP]. 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 and present them with 95% confidence intervals. 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.

Unit of analysis issues

If cross-over 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 intra cluster correlation coefficient. If this is not reported in the trial, 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). 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

Statistical heterogeneity between studies will be assessed visually by inspection of the forest plots and using the Chi2 test (P < 0.1 will be considered significant due to the low power of the test). The I2 statistic will also be calculated; this describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). Values of I2 range from 0 to 100, with 0 representing no heterogeneity and 100 representing considerable heterogeneity.

For this review:

  • 0% to 40% heterogeneity might not be important;

  • 30% to 60% may represent moderate heterogeneity;

  • 50% to 90% may represent substantial heterogeneity; and

  • 75% to 100% considerable heterogeneity.

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 biases and publication bias.

Data synthesis

We will use a fixed-effect model and perform a sensitivity analysis with a random-effects model if there is substantial heterogeneity.

Data on outcomes will be combined at six months and 12 months. Other time points will be described if data are available.

'Summary of findings' table

We will create a 'Summary of findings' table using the following outcomes.

  1. Health-related quality of life.

  2. Asthma exacerbation as defined by hospital admissions or treatment with a course of oral corticosteroids.

  3. Serious adverse events.

  4. Adverse events/side effects.

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 that 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 the reader's understanding of the review where necessary.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses.

  1. Age (nought to five years, six to 16 years, 16 plus).

We will use the following outcomes in subgroup analyses.

  1. Health-related quality of life.

  2. Asthma symptoms.

We will use the formal test for subgroup interactions in Review Manager (Review Manager 2012).

Sensitivity analysis

We plan to carry out the following sensitivity analyses.

  1. Excluding studies with an overall high risk of bias.

  2. Excluding cross-over trials and cluster randomised trials.

  3. Random-effects model.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.

Acknowledgements

We would particularly like to acknowledge the excellent support and assistance from Emma Welsh, Liz Stovold and Emma Jackson of the Cochrane Airways Review group, together with the greatly appreciated guidance from Chris Cates (Cochrane Airways Review Group Co-ordinating Editor). The support provided by librarians Judith Scammel, Jane Appleton and Hilary Garrett at St Georges University London is also greatly appreciated.

Haydn Walters 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

 

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. (randomized 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 AST:MISC1

#2 MeSH DESCRIPTOR Asthma Explode All

#3 asthma*:ti,ab

#4 #1 or #2 or #3

#5 fluticasone*

#6 GW685698

#7 FF:TI,AB

#8 #5 OR #6 OR #7

#9 vilanterol*

#10 GW642444

#11 VI:TI,AB

#12 #9 OR #10 OR #11

#13 #8 AND #12

#14 FF/VI:TI,AB

#15 #13 or #14

#16 #4 and #15

[In search line #1, MISC1 denotes the field in which the reference has been coded for condition, in this case, asthma]

Contributions of authors

All review authors contributed to the writing of the protocol.

Declarations of interest

There are no declarations of interest.

Sources of support

Internal sources

  • National Institute for Health Research (SJM), UK.

External sources

  • No sources of support supplied

Ancillary