Chronic Obstructive Pulmonary Disease Clinical Trial
— MUSICOfficial title:
Investigating the Mechanism of Inhaled Corticosteroids Associated Pneumonia by Longitudinal Characterisation of the Airway Microbiome in Patients With Severe COPD
Verified date | July 2020 |
Source | University of Dundee |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 158 |
Est. completion date | July 22, 2019 |
Est. primary completion date | July 22, 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 40 Years and older |
Eligibility |
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 |
Country | Name | City | State |
---|---|---|---|
United Kingdom | Blackpool Teaching Hospital NHS Foundation Trust | Blackpool | |
United Kingdom | NHS Tayside | Dundee | Tayside |
United Kingdom | NHS Lothian | Edinburgh | |
United Kingdom | NHS Greater Glasgow and Clyde | Glasgow | |
United Kingdom | NHS Fife | Kirkcaldy | |
United Kingdom | NHS Lanarkshire | Wishaw |
Lead Sponsor | Collaborator |
---|---|
University of Dundee | AstraZeneca, NHS Tayside |
United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | 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 | Baseline, 1, 2 and 3 months | |
Other | 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 | Baseline, 1, 2 and 3 months | |
Other | 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 | Baseline, 1, 2 and 3 months | |
Other | 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 | Baseline, 3 months | |
Other | Comparison of inflammatory markers before and after one month washout period. | To determine the impact of inhaled corticosteroids withdrawal on airway inflammation. | -1 months and baseline | |
Other | Comparison of bacterial load before and after one month washout period. | To determine the impact of inhaled corticosteroids withdrawal on airway bacterial load | -1 months and baseline | |
Other | Comparison of microbiome characterisation before and after one month washout period. | To determine the impact of inhaled corticosteroids withdrawal on airway microbiome. | -1 months and baseline | |
Other | 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 | Baseline, 1, 2 and 3 months | |
Other | 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 | Baseline, 1, 2 and 3 months | |
Other | Total bacterial load using qPCR | To assess the effectiveness of chlorhexidine decontamination on lower airway microbiology in sputum in Chronic Obstructive Pulmonary Disease | Start of decontamination period (washout) to end of decontamination period (baseline) | |
Other | 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 | Start of decontamination period (washout) to end of decontamination period (baseline) | |
Other | 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 | Start of decontamination period (washout) to end of decontamination period (baseline) | |
Other | 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 | Baseline, 1 and 3 months | |
Other | 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 | Baseline, 1, 2 and 3 months | |
Other | Change in FEV1 | To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points | From baseline to 3 months follow-up. | |
Other | 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 | From Baseline to 3 months | |
Other | 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 | Baseline, 3 months and as required, for example when an exacerbation occurs. | |
Other | 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 | Baseline, 3 months and as required, for example when an exacerbation occurs. | |
Primary | 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 | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 |
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