Chronic Obstructive Pulmonary Disease Clinical Trial
— INCOGNITOOfficial title:
INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol
Verified date | July 2020 |
Source | University of Dundee |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 80 |
Est. completion date | November 26, 2019 |
Est. primary completion date | November 26, 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 40 Years and older |
Eligibility |
Inclusion Criteria: - Male and female patients aged > 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 - Post-bronchodilator Forced Expiratory Volume 1 (FEV1)/Forced Vital Capacity ratio at screening of <70% - Moderate to Very Severe COPD (GOLD II-IV) according to consensus guidelines consisting of a post-bronchodilator FEV1 <80% predicted at screening. - Currently treated with inhaled corticosteroids (with or without long acting bronchodilators) for at least 12 months prior to screening. - Able to perform all study procedures including spirometry and questionnaires with minimal assistance - Blood eosinophil count less than 300 eosinophil cells per microlitre on bloods taken at screening. - Able to produce a sputum sample at the baseline visit (either spontaneously or with nebulised saline induction) Exclusion Criteria: - Inability to give informed consent - Asthma - Acute Antibiotics within 28 days prior to screening - Long term macrolide therapy if newly commenced in the past 3 months - Current use of the following: roflumilast, ritonavir, itraconazole, telithromycin, or ketoconazole (or other strong CYP3A4 inhibitors). - Systemic Immunosuppressive medication including current oral corticosteroids at a dose >5mg for >28 days. - Glomerular filtration rate (eGFR) below 30ml/min/1.73m2 or requiring dialysis. This will be determined at screening. - 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 - 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 - An exacerbation of COPD occurring during the 28 days prior to screening requiring treatment with either oral corticosteroids or antibiotics. - An exacerbation requiring treatment with antibiotics or corticosteroids between the screening and randomization visit - Pregnancy or breast feeding - Women of child bearing potential who are not practicing an acceptable method of contraception - Long term oxygen therapy - Lapp lactase deficiency, glucose-galactose malabsorption or another inherited disorder of galactose metabolism. |
Country | Name | City | State |
---|---|---|---|
United Kingdom | NHS Tayside | Dundee | |
United Kingdom | NHS Greater Glasgow and Clyde | Glasgow | |
United Kingdom | Northumbria Healthcare NHS Foundation Trust | North Shields | |
United Kingdom | Nottingham University Hospitals NHS Trust | Nottingham |
Lead Sponsor | Collaborator |
---|---|
University of Dundee | Boehringer Ingelheim, NHS Tayside |
United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Relative abundance of Haemophilus Operational Taxonomic Units at genus level or relative abundance of proteobacteria at phylum level. | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on the airway microbiota. Microbiota will be characterised in sputum, oropharyngeal swabs and nasopharyngeal swabs | Baseline, 1, 2, 3 and 6 months | |
Other | Proportion of patients with dysbiosis as defined by >40% relative Operational Taxonomic Units of a single organism. | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on the airway microbiota. Microbiota will be characterised in sputum, oropharyngeal swabs and nasopharyngeal swabs | Baseline, 1, 2, 3 and 6 months | |
Other | Comparison of adverse events/serious adverse events between groups on dual bronchodilators and inhaled corticosteroids | To evaluate the safety and tolerability of Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol in patients previously treated with inhaled corticosteroids | Baseline, 1, 2, 3 and 6 months | |
Other | Bacterial community composition determined by 16s microbiome sequencing. | To provide a longitudinal characterisation of the upper and lower airway microbiota in oropharyngeal/nasopharyngeal swabs and sputum in COPD | From baseline to 1, 2, 3 and 6 months | |
Other | Mean fluorescence intensity by flow cytometry | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on neutrophil receptor expression - specifically expression of CD88, CD35, CD11b and CD41a in COPD patients | From baseline to 1, 2, 3 and 6 months | |
Other | Change in ex-vivo phagocytosis of Haemophilus tested by incubating sputum cells with FITC-labelled H. influenzae | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on sputum neutrophil phagocytosis of Haemophilus influenzae | From baseline to 1, 2, 3 and 6 months | |
Other | Quality of life St. George's Respiratory Questionnaire(SGRQ) | To evaluate patient reported outcome measures between the groups treated with Tiotropium and olodaterol combination vs fluticasone furoate and vilantero using COPD assessment test (CAT) | From baseline to 1, 2, 3 and 6 months | |
Other | Quality of life COPD assessment test (CAT) | To evaluate patient reported outcome measures between the groups treated with Tiotropium and olodaterol combination vs fluticasone furoate and vilantero using MRC dyspnoea score | From baseline to 1, 2, 3 and 6 months | |
Other | Quality of life MRC dyspnoea score | To evaluate patient reported outcome measures between the groups treated with Tiotropium and olodaterol combination vs fluticasone furoate and vilantero using St. George's Respiratory Questionnaire(SGRQ) | From baseline to 1, 2, 3 and 6 months | |
Other | Quality of life transitional dyspnoea index | To evaluate patient reported outcome measures between the groups treated with Tiotropium and olodaterol combination vs fluticasone furoate and vilantero using the transitional dyspnoea index | From baseline to 1, 2, 3 and 6 months | |
Other | Comparison of time to first exacerbation of Chronic Obstructive Pulmonary Disease | To evaluate if changes in the airway microbiota or airway inflammatory profiles are associated with time to first exacerbation of Chronic Obstructive Pulmonary Disease | From baseline to 1, 2, 3 and 6 months | |
Other | Number of exacerbations of Chronic Obstructive Pulmonary Disease | To evaluate if changes in the airway microbiota or airway inflammatory profiles are associated with number of exacerbations of Chronic Obstructive Pulmonary Disease | From baseline to 1, 2, 3 and 6 months | |
Other | Change in FEV1 | To evaluate if changes in the airway microbiota or airway inflammatory profiles are associated with change in FEV1 | From baseline to 1, 2, 3 and 6 months | |
Primary | Change in bacterial load of total bacteria determined by quantitative polymerase chain reaction | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on airway bacterial load from sputum | From baseline to 1, 2, 3 and 6 months | |
Secondary | Change in bacterial community composition determined by 16S microbiome sequencing as measured by the Shannon Diversity index. | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on the airway microbiota. Microbiota will be characterised in sputum, oropharyngeal swabs and nasopharyngeal swabs | From baseline to 1, 2, 3 and 6 months | |
Secondary | Sputum neutrophil elastase activity determined using an activity based immunoassay | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on sputum neutrophil elastase activity | From baseline to 1, 2, 3 and 6 months | |
Secondary | Change in sputum neutrophil extracellular traps determined using a validated ELISA | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on concentration sputum neutrophil extracellular traps | From baseline to 1, 2, 3 and 6 months | |
Secondary | Change in sputum cytokines and inflammatory markers including but not limited to CXCL-8, IL17, IL-1beta, resistin, IL13 | To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on sputum cytokines and inflammatory markers | From baseline to 1, 2, 3 and 6 months |
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