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Microbiome Use to Stratify Use of Inhaled Corticosteroids: MUSIC Trial (MUSIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02972476
Recruitment Status : Completed
First Posted : November 23, 2016
Last Update Posted : July 20, 2020
Sponsor:
Collaborators:
AstraZeneca
NHS Tayside
Information provided by (Responsible Party):
University of Dundee

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease 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 Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 158 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Investigating the Mechanism of Inhaled Corticosteroids Associated Pneumonia by Longitudinal Characterisation of the Airway Microbiome in Patients With Severe COPD
Study Start Date : December 2016
Actual Primary Completion Date : July 22, 2019
Actual Study Completion Date : July 22, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 1: Symbicort 400/12 & Eklira Genuair
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
Other Name: Symbicort Turbohaler and Eklira Genuair

Active Comparator: 2: Seretide 500/50 & Eklira Genuair
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
Other Name: Seretide Accuhaler 500/50 and Eklira Genuair

Active Comparator: 3: Seretide 250/50 & Eklira Genuair
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
Other Name: Seretide Accuhaler 250/50 and Eklira Genuair

Active Comparator: 4: Duaklir Genuair
Aclidinium bromide 340mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months
Drug: Aclidinium bromide & formoterol fumarate
Other Name: Duaklir Genuair




Primary Outcome Measures :
  1. Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction [ Time Frame: Baseline, 1, 2, and 3 months ]
    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.


Secondary Outcome Measures :
  1. Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction. [ Time Frame: Baseline, 1, 2, and 3 months ]
    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.

  2. Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction. [ Time Frame: Baseline, 1, 2, and 3 months ]
    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.

  3. Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing [ Time Frame: Baseline, 1, 2, and 3 months ]
    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.

  4. Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing [ Time Frame: Baseline, 1, 2, and 3 months ]
    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.

  5. Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing [ Time Frame: Baseline, 1, 2, and 3 months ]
    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

  6. Change in number of Operational Taxonomic Units of protocol defined respiratory pathogens. [ Time Frame: Baseline, 1, 2 and 3 months ]
    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

  7. Change in number of Operational Taxonomic Units of protocol defined respiratory pathogens. [ Time Frame: Baseline, 1, 2 and 3 months ]
    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.

  8. Change in number of Operational Taxonomic Units of protocol defined respiratory pathogens. [ Time Frame: Baseline, 1, 2 and 3 months ]
    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

  9. Change in airway microbiota bacterial species diversity measured using the Shannon Wiener diversity indexand beta diversity indices. [ Time Frame: Baseline, 1, 2 and 3 months ]
    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.

  10. Change in bacterial load of respiratory pathogens determined by quantitative polymerase chain reaction Microbiome characterisation [ Time Frame: Baseline, 1, 2 and 3 months ]
    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

  11. Change in bacterial load of respiratory pathogens determined by quantitative polymerase chain reaction [ Time Frame: Baseline, 1, 2 and 3 months ]
    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

  12. Changes in inflammatory markers in the sputum. [ Time Frame: Baseline, 1, 2 and 3 months ]
    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.

  13. Changes in inflammatory markers in the blood. [ Time Frame: Baseline, 1, 2 and 3 months ]
    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.


Other Outcome Measures:
  1. Comparison of adverse events/serious adverse events between groups on dual bronchodilators and inhaled corticosteroids [ Time Frame: Baseline, 1, 2 and 3 months ]
    To evaluate the safety and tolerability of withdrawal of inhaled corticosteroids in severe Chronic Obstructive Pulmonary Disease

  2. Change in Forced expiratory volume in 1 second [ Time Frame: Baseline, 1, 2 and 3 months ]
    To evaluate the safety and tolerability of withdrawal of inhaled corticosteroids in severe Chronic Obstructive Pulmonary Disease

  3. Change in patient self reported measures [ Time Frame: Baseline, 1, 2 and 3 months ]
    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

  4. Correlation between change in alpha and beta diversity indices and the frequency of adverse events [ Time Frame: Baseline, 3 months ]
    To evaluate if changes in the airway microbiota are associated with AEs

  5. Comparison of inflammatory markers before and after one month washout period. [ Time Frame: -1 months and baseline ]
    To determine the impact of inhaled corticosteroids withdrawal on airway inflammation.

  6. Comparison of bacterial load before and after one month washout period. [ Time Frame: -1 months and baseline ]
    To determine the impact of inhaled corticosteroids withdrawal on airway bacterial load

  7. Comparison of microbiome characterisation before and after one month washout period. [ Time Frame: -1 months and baseline ]
    To determine the impact of inhaled corticosteroids withdrawal on airway microbiome.

  8. Microbiota diversity determined by 16s microbiome sequencing using the Shannon Diversity index. [ Time Frame: Baseline, 1, 2 and 3 months ]
    To provide a longitudinal characterisation of the upper and lower airway microbiome in oropharyngeal/nasopharyngeal swabs and sputum in Chronic Obstructive Pulmonary Disease

  9. Bacterial community composition determined by 16s microbiome sequencing using number of reads of protocol defined respiratory pathogens. [ Time Frame: Baseline, 1, 2 and 3 months ]
    To provide a longitudinal characterisation of the upper and lower airway microbiome in oropharyngeal/nasopharyngeal swabs and sputum in Chronic Obstructive Pulmonary Disease

  10. Total bacterial load using qPCR [ Time Frame: Start of decontamination period (washout) to end of decontamination period (baseline) ]
    To assess the effectiveness of chlorhexidine decontamination on lower airway microbiology in sputum in Chronic Obstructive Pulmonary Disease

  11. Bacterial community composition determined by 16s microbiome sequencing [ Time Frame: Start of decontamination period (washout) to end of decontamination period (baseline) ]
    To assess the effectiveness of chlorhexidine decontamination on upper and lower airway microbiology in Chronic Obstructive Pulmonary Disease

  12. Bacterial community composition determined by 16s microbiome sequencing [ Time Frame: Start of decontamination period (washout) to end of decontamination period (baseline) ]
    To assess the effectiveness of chlorhexidine decontamination on upper airway microbiome in sputum in Chronic Obstructive Pulmonary Disease

  13. Quality of life- St Georges Respiratory Questionnaire [ Time Frame: Baseline, 1 and 3 months ]
    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

  14. Comparison of oropharyngeal swabs with quantitative PCR, and 16s sequencing to measure validity, responsiveness and reliability comparing inhaled corticosteroids to dual bronchodilator regimes alone [ Time Frame: Baseline, 1, 2 and 3 months ]
    To compare different microbiological methods for the assessment of changes in the upper and lower airway microbiome in COPD

  15. Change in FEV1 [ Time Frame: From baseline to 3 months follow-up. ]
    To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points

  16. Comparison of time to first exacerbation of Chronic Obstructive Pulmonary Disease [ Time Frame: From Baseline to 3 months ]
    To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points

  17. Number of exacerbations of Chronic Obstructive Pulmonary Disease [ Time Frame: Baseline, 3 months and as required, for example when an exacerbation occurs. ]
    To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points

  18. Time to next exacerbation of Chronic Obstructive Pulmonary Disease [ Time Frame: Baseline, 3 months and as required, for example when an exacerbation occurs. ]
    To evaluate if changes in the airway microbiome or airway inflammatory profiles are associated with efficacy or safety end-points



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02972476


Locations
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United Kingdom
NHS Tayside
Dundee, Tayside, United Kingdom, DD1 9SY
Blackpool Teaching Hospital NHS Foundation Trust
Blackpool, United Kingdom, FY3 8NR
NHS Lothian
Edinburgh, United Kingdom, EH16 4TJ
NHS Greater Glasgow and Clyde
Glasgow, United Kingdom
NHS Fife
Kirkcaldy, United Kingdom, KY2 5AH
NHS Lanarkshire
Wishaw, United Kingdom, ML2 0DP
Sponsors and Collaborators
University of Dundee
AstraZeneca
NHS Tayside
Investigators
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Principal Investigator: James Chalmers, MBChB, MRCP University of Dundee
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Responsible Party: University of Dundee
ClinicalTrials.gov Identifier: NCT02972476    
Other Study ID Numbers: 2014RC07
2016-000734-21 ( EudraCT Number )
First Posted: November 23, 2016    Key Record Dates
Last Update Posted: July 20, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by University of Dundee:
Chronic Obstructive Pulmonary Disease
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Fluticasone
Budesonide
Bromides
Formoterol Fumarate
Salmeterol Xinafoate
Fluticasone-Salmeterol Drug Combination
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticonvulsants
Sympathomimetics