Microbiome Use to Stratify Use of Inhaled Corticosteroids: MUSIC Trial

NCT02972476 | Completed Phase 4

• 2 other identifiers: 2014RC072016-000734-21
• Study Type: interventional
• Target: 158
• Locations: 1 country
• Sites: 6

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.

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

Chronic Obstructive Pulmonary Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction.

  Baseline, 1, 2, and 3 months

• Change in bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction.

  Baseline, 1, 2, and 3 months

• Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing

  Baseline, 1, 2, and 3 months

• Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing

  Baseline, 1, 2, and 3 months

• Microbiota diversity using the Shannon-Wiener diversity index determined by 16S microbiome sequencing

  Baseline, 1, 2, and 3 months

Other Outcomes (18)

• Comparison of adverse events/serious adverse events between groups on dual bronchodilators and inhaled corticosteroids

  Baseline, 1, 2 and 3 months

• Change in Forced expiratory volume in 1 second

  Baseline, 1, 2 and 3 months

• Change in patient self reported measures

  Baseline, 1, 2 and 3 months

Study Arms (4)

1: Symbicort 400/12 & Eklira Genuair

ACTIVE COMPARATOR

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

2: Seretide 500/50 & Eklira Genuair

ACTIVE COMPARATOR

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

3: Seretide 250/50 & Eklira Genuair

ACTIVE COMPARATOR

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

4: Duaklir Genuair

ACTIVE COMPARATOR

Aclidinium bromide 340mcg \& formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months

Drug: Aclidinium bromide & formoterol fumarate

Interventions

Budesonide & formoterol fumarate and Aclidinium bromide DRUG

Also known as: Symbicort Turbohaler and Eklira Genuair

1: Symbicort 400/12 & Eklira Genuair

Fluticasone 500 & salmeterol and Aclidinium bromide DRUG

Also known as: Seretide Accuhaler 500/50 and Eklira Genuair

2: Seretide 500/50 & Eklira Genuair

Fluticasone 250 & salmeterol and Aclidinium bromide DRUG

Also known as: Seretide Accuhaler 250/50 and Eklira Genuair

3: Seretide 250/50 & Eklira Genuair

Aclidinium bromide & formoterol fumarate DRUG

Also known as: Duaklir Genuair

4: Duaklir Genuair

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Dundee: lead
• AstraZeneca: collaborator
• NHS Tayside: collaborator

Study Sites (6)

NHS Tayside

Dundee, Tayside, DD1 9SY, United Kingdom

Location

Blackpool Teaching Hospital NHS Foundation Trust

Blackpool, FY3 8NR, United Kingdom

Location

NHS Lothian

Edinburgh, EH16 4TJ, United Kingdom

Location

NHS Greater Glasgow and Clyde

Glasgow, United Kingdom

Location

NHS Fife

Kirkcaldy, KY2 5AH, United Kingdom

Location

NHS Lanarkshire

Wishaw, ML2 0DP, United Kingdom

Location

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Budesonide; Formoterol Fumarate; aclidinium bromide; Salmeterol Xinafoate

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Albuterol; Phenethylamines; Ethylamines

Study Officials

• James Chalmers, MBChB, MRCP

  University of Dundee

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 18, 2016
• First Posted: November 23, 2016
• Study Start: December 1, 2016
• Primary Completion: July 22, 2019
• Study Completion: July 22, 2019
• Last Updated: July 20, 2020

Record last verified: 2020-07

Locations

GB (6)