Chronic Obstructive Pulmonary Disease Clinical Trial
Official title:
Investigating the Mechanism of Inhaled Corticosteroids Associated Pneumonia by Longitudinal Characterisation of the Airway Microbiome in Patients With Severe COPD
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.
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.
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