Microbiome Use to Stratify Use of Inhaled Corticosteroids: MUSIC Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Investigating the Mechanism of Inhaled Corticosteroids Associated Pneumonia by Longitudinal Characterisation of the Airway Microbiome in Patients With Severe COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Budesonide & formoterol fumarate and Aclidinium bromide
* Drug: Fluticasone 500 & salmeterol and Aclidinium bromide
* Drug: Fluticasone 250 & salmeterol and Aclidinium bromide
* Drug: Aclidinium bromide & formoterol fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged greater than or equal to 40 years Current or ex smokers having at least a 10 pack year smoking history A clinical diagnosis of Chronic Obstructive Pulmonary Disease (COPD) made by a physician with a post-bronchodilator forced expiratory volume 1 (FEV1)/ forced vital capacity (FVC) ratio at screening of <70% Severe COPD according to consensus guidelines consisting of a post-bronchodilator FEV1 <50% predicted at screening and/or a history of 2 or more exacerbations in the previous year OR one hospital admission for an exacerbation of COPD in the previous year (equivalent to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 grade C and D) Able to perform all study procedures including spirometry and questionnaires with minimal assistance. Exclusion Criteria: Inability to give informed consent Asthma (defined according to Scottish Intercollegiate Guidelines Network) A primary diagnosis of bronchiectasis confirmed on high-resolution computed tomography.(it is not necessary to perform a computerised tomography (CT) scan to exclude this if the patient has not previously had one. Only known bronchiectasis with a previous CT scan should be excluded). • Antibiotics within the past 28 days, apart from oral macrolides which are permitted if they have been used for at least 3 months prior to randomization Oral/ nasal corticosteroids of any kind in the 28 days prior to screening visit Current use of the following: roflumilast, ritonavir, itraconazole, telithromycin, or ketoconazole (or other CYP3A4 inhibitors). Active, or within 28 days of screening visit, oral candidiasis, actively receiving dental treatment for oral infection or poor dentition. Immunosuppression including current oral corticosteroids at a dose >5mg for >28 days. Glomerular filtration rate (eGFR) below 30ml/min/1.73meter squared or requiring dialysis. Last known eGFR result will be used . Use of any investigational drugs within five times of the elimination half-life after the last study dose or within 30 days, whichever is longer. Known allergy, intolerance or contraindication to any of the study drugs Galactose intolerance Unstable co-morbidities (cardiovascular disease, active malignancy) which in the opinion of the Investigator would make the patient unsuitable to be enrolled in the study. This includes any abnormality identified on screening bloods or screening electrocardiograph which in the opinion of the Investigator would make the patient unsuitable for the study. An exacerbation of COPD occurring during the screening to randomisation period. If this occurs the patient should be withdrawn from the study and may be rescreened once they have been free from corticosteroid and antibiotic treatment for 28 days. In these cases patients would receive the current Participant Information Sheet and be consented prior to starting the study from Visit 1. Documented that the patient has never received pneumococcal polysaccharide vaccination Receipt of Pneumococcal conjugate vaccine (e.g PCV-13) Pregnancy or breast feeding Women of child bearing potential (WOCBP) who are not practicing an acceptable method of contraception (see below) Acceptable forms of contraception: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable intrauterine device (IUD) intrauterine hormone-releasing system ( IUS) bilateral tubal occlusion vasectomised partner sexual abstinence

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1: Symbicort 400/12 & Eklira Genuair<br>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<br> <br> * Other names: Symbicort Turbohaler and Eklira Genuair;|
| Active Comparator: 2: Seretide 500/50 & Eklira Genuair<br>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<br> <br> * Other names: Seretide Accuhaler 500/50 and Eklira Genuair;|
| Active Comparator: 3: Seretide 250/50 & Eklira Genuair<br>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<br> <br> * Other names: Seretide Accuhaler 250/50 and Eklira Genuair;|
| Active Comparator: 4: Duaklir Genuair<br>Aclidinium bromide 340mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months | Drug: Aclidinium bromide & formoterol fumarate<br> <br> * Other names: Duaklir Genuair;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 1, 2, and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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 | 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 | 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. | 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 | 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. | 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 | 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 | 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. | 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. | Baseline, 1, 2 and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease