A Phase 4 interventional study of Budesonide & formoterol fumarate and Aclidinium bromide and Fluticasone 500 & salmeterol and Aclidinium bromide in Chronic Obstructive Pulmonary Disease, sponsored by University of Dundee. Completed at 6 sites in United Kingdom. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2020-07-20.
Sponsored by University of Dundee · Phase 4, Interventional, and Basic science
A randomised controlled trial to test the hypothesis that inhaled therapies for chronic obstructive pulmonary disease (COPD) have differential effects on the upper airway microbiome.
COPD is the third leading cause of death worldwide. Exacerbations drive disease progression and worsening quality of life and therefore prevention of exacerbations has been a major goal of treatment.
Patients with COPD are frequently prescribed inhaled corticosteroids (ICS) which have been shown to reduce exacerbations in combination with long acting beta2-adrenoceptor agonists (LABA). In recent years, all ICS preparations have been associated with a significant increased risk of pneumonia in either randomised trials or observational studies leading to warnings from national regulatory authorities and leading experts. This has led to a re-evaluation of the role of ICS in COPD treatments. It is likely that the risk of pneumonia is not equal across all ICS doses and molecules.
There is a compelling rationale for ICS having a strong effect on the upper airway microbiome, and that this may be one mechanism of increased pneumonia risk with these drugs. The existing literature regarding ICS and pneumonia risk are lacking; 1) there are no head to head trials comparing different ICS preparations and 2) the comparator in these studies to date have been long acting beta2-adrenoceptor agonists alone, whereas the most appropriate comparator in current management would be combined LABA and long-acting muscarinic antagonist (LAMA).
The MUSIC TRIAL is a multi-centre randomised open label controlled parallel group study with four treatment arms and a total of 120 participants. Severe COPD patients currently treated with inhaled corticosteroid therapy will be randomised to treatment with one of three preparations of ICS in combination with LABA or the control arm of dual bronchodilator therapy following a four week washout period. Participants will return monthly to determine if there are changes in the microbiome in their upper airway.
This study will establish one potential mechanism for the increased susceptibility to pneumonia in ICS users and assess intraclass differences in ICS molecules and the effect of ICS dose on the microbiome. Demonstrating that different COPD treatments can have different effects on the lung microbiome is an important step in understanding clinical differences in the safety and effectiveness of different treatments for severe COPD.
Inhaled corticosteroids (ICS) are commonly prescribed for patients with chronic obstructive pulmonary disease (COPD), but their role in the management of COPD is currently being re-evaluated in light of new evidence and the emergence of alternative treatments. Studies have shown that the use of ICS and particularly ICS combined with long acting beta2-adrenoceptor agonists (LABA) in individuals with COPD reduces the frequency of COPD exacerbations and improves health status and lung function compared to LABA alone or placebo. The current National Institute for Care Excellence (NICE) guidelines for COPD recommend ICS for patients with a forced expiratory volume in 1 second below 50% predicted, or for patients with higher lung function who have persisting symptoms or exacerbations despite treatment with long acting bronchodilators. Data suggests that up to 75% of patients with COPD in the United Kingdom (UK) are subsequently prescribed ICS.
The daily dose of ICS utilised in COPD treatments are much higher than those used in asthma treatments, with licensed daily doses being 1000 mcg fluticasone propionate (2000 mcg beclomethasone dipropionate (BDP) equivalents) or 800 mcg budesonide (800 mcg BDP equivalents).
Recent concerns have been expressed about the safety of ICS in COPD following several randomised controlled trials of fluticasone propionate and fluticasone furoate, among others, demonstrating an increase in rates of pneumonia as an adverse event. Several systematic reviews and observational studies confirm an association between ICS use and risk of pneumonia.
All ICS preparations have been associated with an increased risk of pneumonia in either randomised trials or observational studies leading to warnings from national regulatory authorities and leading experts.
It is likely however, that the risk of pneumonia is not equal across all ICS doses and molecules. Research into this area is greatly limited by the lack of head to head comparisons between different ICS preparations in COPD.
It is hypothesised that the anti-inflammatory and immunosuppressive effects of ICS lead to increase susceptibility to colonisation of the upper respiratory tract with pathogenic bacteria associated with pneumonia such as S. pneumoniae and Haemophilus influenzae. This study will establish one potential mechanism for the increased susceptibility to pneumonia in ICS users and assess intraclass differences in ICS molecules used in COPD and the effect of ICS dose. It is known that changes in the microbiome in COPD are associated with disease severity and with lung inflammation. Demonstrating that different COPD treatments can have different effects on the lung microbiome is an important step in understanding clinical differences in the safety and effectiveness of different treatments for severe COPD. The longer term clinical objective of this study is therefore to determine whether a proportion of patients with COPD might be more safely managed with either lower dose, pharmacologically different ICS preparations or with LABA/LAMA therapies to reduce the risk of pneumonia.
Hypothesis Fluticasone propionate will facilitate a higher level of bacterial airway colonisation by pathogens associated with pneumonia compared to budesonide or treatment exclusively with bronchodilators, therefore providing a mechanistic explanation for increased pneumonia risk associated with ICS.
STUDY OBJECTIVES To determine a potential mechanism of inhaled corticosteroid associated pneumonia in COPD by demonstrating ICS effects on the upper (throat and nasal swabs) and lower airway (sputum) microbiome.
To determine the mechanism of observed differences in pneumonia risk between fluticasone propionate, and budesonide by demonstrating differential effects on the airway microbiome.
3,303 studies on the registry are indexed under Lung Diseases; 355 are open to participants now.
This study's enrollment of 158 is above the median of 72 across 2,118 interventional studies indexed under Lung Diseases.
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Exclusion Criteria:
Acceptable forms of contraception:
Budesonide 400mcg \& formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months
Drug: Budesonide & formoterol fumarate and Aclidinium bromide
Fluticasone propionate 500mcg \& salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months
Drug: Fluticasone 500 & salmeterol and Aclidinium bromide
Fluticasone propionate 250mcg \& salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months
Drug: Fluticasone 250 & salmeterol and Aclidinium bromide
Aclidinium bromide 340mcg \& formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months
Drug: Aclidinium bromide & formoterol fumarate
Also known as: Symbicort Turbohaler and Eklira Genuair
Also known as: Seretide Accuhaler 500/50 and Eklira Genuair
Also known as: Seretide Accuhaler 250/50 and Eklira Genuair
Also known as: Duaklir Genuair
Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction
To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on upper airway bacterial load from oropharyngeal swabs.
Time frame: Baseline, 1, 2, and 3 months
Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction.
To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on lower airway bacterial load and microbiome from sputum and on upper airway in nasophyarengeal swab.
Time frame: Baseline, 1, 2, and 3 months
Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction.
To compare the effects of fluticasone/salmeterol 250/50mcg vs budesonide/formoterol 400/12 mcg on upper and lower airway microbiome in oropharyngeal/nasopharyngeal and sputum samples.
Time frame: Baseline, 1, 2, and 3 months
Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing
To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on lower airway microbiome from sputum and on upper airway in nasopharyngeal swab. To compare the effects of fluticasone/salmeterol 250/50mcg vs budesonide/formoterol 400/12 mcg on upper and lower airway microbiome in oropharyngeal/nasopharyngeal and sputum samples.
Time frame: Baseline, 1, 2, and 3 months
Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing
To compare the effects of fluticasone/salmeterol 250/50mcg vs budesonide/formoterol 400/12 mcg on upper and lower airway microbiome in oropharyngeal/nasopharyngeal and sputum samples.
Time frame: Baseline, 1, 2, and 3 months
Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing
To compare the effects on the upper and lower airway microbiome in oropharyngeal, nasopharyngeal swabs and sputum of individual inhaled corticosteroids (ICS) fluticasone propionate and budesonide (pooled ICS group) compared to a dual bronchodilator based regime without ICS
Time frame: Baseline, 1, 2, and 3 months
Change in number of Operational Taxonomic Units of protocol defined respiratory pathogens.
To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on lower airway microbiome from sputum and on upper airway in nasopharyngeal swab
Time frame: Baseline, 1, 2 and 3 months
Change in number of Operational Taxonomic Units of protocol defined respiratory pathogens.
To compare the effects of fluticasone/salmeterol 250/50mcg vs budesonide/formoterol 400/12 mcg on upper and lower airway microbiome in oropharyngeal/nasopharyngeal and sputum samples.
Time frame: Baseline, 1, 2 and 3 months
Change in number of Operational Taxonomic Units of protocol defined respiratory pathogens.
To compare the effects on the upper and lower airway microbiome in oropharyngeal, nasopharyngeal swabs and sputum of individual inhaled corticosteroids (ICS) fluticasone propionate and budesonide (pooled ICS) compared to a dual bronchodilator based regime without ICS
Time frame: Baseline, 1, 2 and 3 months
Change in airway microbiota bacterial species diversity measured using the Shannon Wiener diversity indexand beta diversity indices.
To compare the effects of fluticasone/salmeterol 250/50mcg vs budesonide/formoterol 400/12 mcg on upper and lower airway microbiome in oropharyngeal/nasopharyngeal and sputum samples.
Time frame: Baseline, 1, 2 and 3 months
Change in bacterial load of respiratory pathogens determined by quantitative polymerase chain reaction Microbiome characterisation
To compare the impact of high and low dose inhaled corticosteroid fluticasone propionate on the upper and lower airway microbiome in oropharyngeal, nasopharyngeal swabs and sputum
Time frame: Baseline, 1, 2 and 3 months
Change in bacterial load of respiratory pathogens determined by quantitative polymerase chain reaction
To compare the impact of high and low dose inhaled corticosteroid fluticasone propionate on the upper and lower airway microbiome in oropharyngeal, nasopharyngeal swabs and sputum
Time frame: Baseline, 1, 2 and 3 months
Changes in inflammatory markers in the sputum.
To evaluate the impact of inhaled corticosteroids on airway inflammation. Comparing inhaled corticosteroids to dual bronchodilator regimes alone. Measured with neutrophil elastase, myeloperoxidase, IL-8, IL-1beta.
Time frame: Baseline, 1, 2 and 3 months
Changes in inflammatory markers in the blood.
To evaluate the impact of inhaled corticosteroids on airway and systemic inflammation. Comparing inhaled corticosteroids to dual bronchodilator regimes alone. Measued with eosinophils \& neutrophils, C-reactive protein, serum resistin, specific IgG antibody to bacterial pathogens.
Time frame: Baseline, 1, 2 and 3 months
Comparison of adverse events/serious adverse events between groups on dual bronchodilators and inhaled corticosteroids
To evaluate the safety and tolerability of withdrawal of inhaled corticosteroids in severe Chronic Obstructive Pulmonary Disease
Time frame: Baseline, 1, 2 and 3 months
Change in Forced expiratory volume in 1 second
To evaluate the safety and tolerability of withdrawal of inhaled corticosteroids in severe Chronic Obstructive Pulmonary Disease
Time frame: Baseline, 1, 2 and 3 months
Change in patient self reported measures
To evaluate the safety and tolerability of withdrawal of inhaled corticosteroids in severe Chronic Obstructive Pulmonary Disease using St. George's Respiratory Questionnaire and Chronic Obstructive Pulmonary Disease Assessment Test score
Time frame: Baseline, 1, 2 and 3 months
Correlation between change in alpha and beta diversity indices and the frequency of adverse events
To evaluate if changes in the airway microbiota are associated with AEs
Time frame: Baseline, 3 months
Comparison of inflammatory markers before and after one month washout period.
To determine the impact of inhaled corticosteroids withdrawal on airway inflammation.
Time frame: -1 months and baseline
Comparison of bacterial load before and after one month washout period.
To determine the impact of inhaled corticosteroids withdrawal on airway bacterial load
Time frame: -1 months and baseline
Comparison of microbiome characterisation before and after one month washout period.
To determine the impact of inhaled corticosteroids withdrawal on airway microbiome.
Time frame: -1 months and baseline
Microbiota diversity determined by 16s microbiome sequencing using the Shannon Diversity index.
To provide a longitudinal characterisation of the upper and lower airway microbiome in oropharyngeal/nasopharyngeal swabs and sputum in Chronic Obstructive Pulmonary Disease
Time frame: Baseline, 1, 2 and 3 months
Bacterial community composition determined by 16s microbiome sequencing using number of reads of protocol defined respiratory pathogens.
To provide a longitudinal characterisation of the upper and lower airway microbiome in oropharyngeal/nasopharyngeal swabs and sputum in Chronic Obstructive Pulmonary Disease
Time frame: Baseline, 1, 2 and 3 months
Total bacterial load using qPCR
To assess the effectiveness of chlorhexidine decontamination on lower airway microbiology in sputum in Chronic Obstructive Pulmonary Disease
Time frame: Start of decontamination period (washout) to end of decontamination period (baseline)
Bacterial community composition determined by 16s microbiome sequencing
To assess the effectiveness of chlorhexidine decontamination on upper and lower airway microbiology in Chronic Obstructive Pulmonary Disease
Time frame: Start of decontamination period (washout) to end of decontamination period (baseline)
Bacterial community composition determined by 16s microbiome sequencing
To assess the effectiveness of chlorhexidine decontamination on upper airway microbiome in sputum in Chronic Obstructive Pulmonary Disease
Time frame: Start of decontamination period (washout) to end of decontamination period (baseline)
Quality of life- St Georges Respiratory Questionnaire
To evaluate patient reported outcome measures on three different inhaled corticosteroids regimes compared to dual bronchodilator regimes using St. George's Respiratory Questionnaire and Chronic Obstructive Pulmonary Disease assessment test score
Time frame: Baseline, 1 and 3 months
Comparison of oropharyngeal swabs with quantitative PCR, and 16s sequencing to measure validity, responsiveness and reliability comparing inhaled corticosteroids to dual bronchodilator regimes alone
To compare different microbiological methods for the assessment of changes in the upper and lower airway microbiome in COPD
Time frame: Baseline, 1, 2 and 3 months
Change in FEV1
To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points
Time frame: From baseline to 3 months follow-up.
Comparison of time to first exacerbation of Chronic Obstructive Pulmonary Disease
To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points
Time frame: From Baseline to 3 months
Number of exacerbations of Chronic Obstructive Pulmonary Disease
To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points
Time frame: Baseline, 3 months and as required, for example when an exacerbation occurs.
Time to next exacerbation of Chronic Obstructive Pulmonary Disease
To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points
Time frame: Baseline, 3 months and as required, for example when an exacerbation occurs.
Plan to share: Undecided
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University of Dundee