Microbiome Use to Stratify Use of Inhaled Corticosteroids: MUSIC Trial

• Status: Completed
• Trial end date: 2019-07-22
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Dundee
• Collaborators: AstraZeneca; NHS Tayside
• Treatments: Bromides; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Fluticasone; Fluticasone Propionate, Salmeterol Xinafoate Drug Combination; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Salmeterol Xinafoate; Xhance

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