Chronic Obstructive Pulmonary Disease Clinical Trial
Official title:
INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol
This protocol describes a randomised controlled trial to test the hypothesis that 6 months of
treatment with tiotropium and olodaterol will result in a reduction in bacterial load, an
improvement in neutrophilic inflammation and clinical benefits compared with treatment with
inhaled fluticasone furoate and vilanterol in patients with neutrophilic Chronic obstructive
pulmonary disease (COPD).
COPD is the third leading cause of death worldwide and a major cause of morbidity in the UK.
Exacerbations drive disease progression and worsening quality of life and therefore
prevention of exacerbations has been a major goal of treatment.
In recent years, attempts have been made to phenotype COPD patients in order to target
therapies to the correct groups of patients that will benefit. Inhaled corticosteroids (ICS)
are primarily effective for patients with eosinophilic inflammation, while there are few
established therapies for patients with neutrophilic disease. In recent years, all ICS
preparations have been associated with a significant increased risk of pneumonia and this
risk appears to be greatest in patients with non-eosinophilic inflammation. Combined
treatment with long acting beta-agonists (LABA) and long acting muscarinic antagonists (LAMA)
combinations appears to be a safer and more effective alternative for patients with
non-eosinophilic disease. The combination of tiotropium and olodaterol in particular, has
strong preclinical data supporting beneficial effects on neutrophilic inflammation.
The trial is a multi-centre randomised open label controlled parallel group study with two
treatment arms in 80 participants. Moderate to very severe COPD patients and currently
treated with inhaled corticosteroid therapy will be randomised to treatment with either the
combination of tiotropium and olodaterol (LABA/LAMA) or fluticasone furoate and vilanterol
(ICS/LABA). Participants will return at 1 month, 2 months, 3 months and 6 months for sampling
of the lower airway by sputum samples and the upper airway using oropharyngeal and
nasopharyngeal swabs. Sputum will be used to test for airway neutrophilic inflammation.
This study will make an important contribution to understanding "phenotyping" in COPD by
identifying whether the combination of tiotropium and olodaterol improves airway bacterial
load and restores neutrophil function in patients with neutrophilic COPD.
BACKGROUND 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.
Recent concerns have been expressed about the safety of ICS in COPD following several
randomized controlled trials of fluticasone propionate and fluticasone furoate 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.
A series of post-hoc analyses of large randomized controlled trials of ICS/ long acting
beta-agonists (LABA) or ICS alone have suggested that benefits of ICS in terms of
exacerbation reduction and preventing lung function decline are limited to a subgroup of
patients with eosinophilic airway inflammation. Eosinophils are highly sensitive to ICS, and
so there is a compelling rationale for this association, and therefore an emerging consensus
that ICS should be reserved for those patients with eosinophilic disease. This can be
identified on the basis of blood eosinophil count although the precise cut-off is yet to be
determined. This is strongly supported by a post-hoc analysis of the WISDOM randomized
controlled trial of ICS withdrawal in which ICS withdrawal was only associated with an
increase in exacerbations above blood eosinophil counts of 300 cells per ul. Furthermore in
the FLAME study which excluded patients with very high eosinophils counts, LABA/long acting
muscarinic antagonists (LAMA) was superior to ICS/LABA in terms of reducing exacerbations.
If there is an emerging consensus regarding the treatment of "eosinophilic COPD", then the
unmet need in the management of COPD is for the majority of patients that have neutrophilic
airway inflammation. Neutrophilic inflammation does not respond to inhaled corticosteroids
and indeed there is in-vitro evidence that inhaled corticosteroids may exacerbate
neutrophilic inflammation by delaying neutrophil apoptosis. Neutrophilic inflammation is
associated with disordering of the lung microbiome with overgrowth of Proteobacteria, a
process that may be exacerbated by ICS. Release of proteolytic enzymes such as elastase and
matrix metalloproteinase from neutrophils are associated with disease progression and lung
function decline in COPD.
RATIONALE FOR STUDY It is hypothesised that the combination of tiotropium and olodaterol may
be an ideal treatment option for patients with neutrophilic COPD because
- Tiotropium and olodaterol have both been shown to have potentially beneficial effects in
suppressing neutrophilic inflammation without impairing bacterial killing
- These effects may reverse the detrimental impact of inhaled corticosteroids on airway
neutrophil function and the microbiome.
In particular olodaterol was evaluated in cigarette smoke- and Lipolpolysaccharide - induced-
models of neutrophil lung inflammation in mice and guinea pigs. The results showed Olodaterol
to suppress neutrophil recruitment to the lung (by up to 90%) while preserving chemotactic
function (which is required for effective phagocytosis of pathogens). Tiotropium has also
been extensively investigated and is known to suppress neutrophil recruitment and neutrophil
dependent remodelling in a number of in-vivo models and may work synergistically with
olodaterol in reducing neutrophil retention in the lung.
This extensive preclinical work justifies a study of olodaterol/tiotropium in human subjects
evaluating its impact on neutrophilic inflammation. This could establish the combination of
olodaterol/tiotropium as the first line therapy for patients with neutrophilic COPD.
This trial will compare treatment of patients with COPD previously treated with ICS
randomized to either tiotropium/olodaterol combination or fluticasone furoate/vilanterol
combination. The objective of the trial is to evaluate in-vivo effects of these drugs on the
lung microbiota and airway neutrophil function. In particular, we expect that 6 months
treatment with olodaterol/tiotropium will result in a reduced airway bacterial load (through
restored neutrophil function allowing neutrophils to kill airway bacteria), an increase in
microbiota diversity, an enhanced ex-vivo killing of Haemophilus influenzae and reduced
markers of neutrophilic airway inflammation.
HYPOTHESIS Tiotropium and olodaterol combination treatment will result in a reduced airway
bacterial load at 6 months compared to fluticasone furoate and vilanterol. The reduced
bacterial load will be associated with improvements in the airway microbiota and reduced
markers of neutrophilic inflammation and restored neutrophil function.
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