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INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol (INCOGNITO)

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ClinicalTrials.gov Identifier: NCT03152149
Recruitment Status : Recruiting
First Posted : May 12, 2017
Last Update Posted : April 8, 2019
Sponsor:
Collaborators:
Boehringer Ingelheim
NHS Tayside
Information provided by (Responsible Party):
James Chalmers, University of Dundee

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Drug: Tiotropium & olodaterol Drug: fluticasone furoate & vilanterol Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Arm Intervention/treatment
Active Comparator: 1. Spiolto Respimat
Spiolto Respimat (Tiotropium 2.5 micrograms,olodaterol 2.5 micrograms) 2 puffs once daily for 6 months
Drug: Tiotropium & olodaterol
Spiolto Respimat (Tiotropium 2.5 micrograms,olodaterol 2.5 micrograms) 2 puffs once daily for 6 months
Other Name: Spiolto Respimat

Active Comparator: 2. Relvar Ellipta
Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once per day for 6 months
Drug: fluticasone furoate & vilanterol
Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once per day for 6 months
Other Name: Relvar Ellipta




Primary Outcome Measures :
  1. Change in bacterial load of total bacteria determined by quantitative polymerase chain reaction [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on airway bacterial load from sputum


Secondary Outcome Measures :
  1. Change in bacterial community composition determined by 16S microbiome sequencing as measured by the Shannon Diversity index. [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    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

  2. Sputum neutrophil elastase activity determined using an activity based immunoassay [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on sputum neutrophil elastase activity

  3. Change in sputum neutrophil extracellular traps determined using a validated ELISA [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on concentration sputum neutrophil extracellular traps

  4. Change in sputum cytokines and inflammatory markers including but not limited to CXCL-8, IL17, IL-1beta, resistin, IL13 [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on sputum cytokines and inflammatory markers


Other Outcome Measures:
  1. Relative abundance of Haemophilus Operational Taxonomic Units at genus level or relative abundance of proteobacteria at phylum level. [ Time Frame: Baseline, 1, 2, 3 and 6 months ]
    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

  2. Proportion of patients with dysbiosis as defined by >40% relative Operational Taxonomic Units of a single organism. [ Time Frame: Baseline, 1, 2, 3 and 6 months ]
    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

  3. Comparison of adverse events/serious adverse events between groups on dual bronchodilators and inhaled corticosteroids [ Time Frame: Baseline, 1, 2, 3 and 6 months ]
    To evaluate the safety and tolerability of Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol in patients previously treated with inhaled corticosteroids

  4. Bacterial community composition determined by 16s microbiome sequencing. [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To provide a longitudinal characterisation of the upper and lower airway microbiota in oropharyngeal/nasopharyngeal swabs and sputum in COPD

  5. Mean fluorescence intensity by flow cytometry [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    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

  6. Change in ex-vivo phagocytosis of Haemophilus tested by incubating sputum cells with FITC-labelled H. influenzae [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To determine the effects of the Tiotropium and olodaterol combination vs fluticasone furoate and vilanterol on sputum neutrophil phagocytosis of Haemophilus influenzae

  7. Quality of life [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    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)

  8. Quality of life [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To evaluate patient reported outcome measures between the groups treated with Tiotropium and olodaterol combination vs fluticasone furoate and vilantero using MRC dyspnoea score

  9. Quality of life [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    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)

  10. Quality of life [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    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

  11. Comparison of time to first exacerbation of Chronic Obstructive Pulmonary Disease [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To evaluate if changes in the airway microbiota or airway inflammatory profiles are associated with time to first exacerbation of Chronic Obstructive Pulmonary Disease

  12. Number of exacerbations of Chronic Obstructive Pulmonary Disease [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To evaluate if changes in the airway microbiota or airway inflammatory profiles are associated with number of exacerbations of Chronic Obstructive Pulmonary Disease

  13. Change in FEV1 [ Time Frame: From baseline to 1, 2, 3 and 6 months ]
    To evaluate if changes in the airway microbiota or airway inflammatory profiles are associated with change in FEV1



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03152149


Contacts
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Contact: James Chalmers, MBChB, MRCP 01382 386131 j.chalmers@dundee.ac.uk
Contact: Clare Clarke 01382 383108 c.z.clarke@dundee.ac.uk

Locations
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United Kingdom
NHS Tayside Recruiting
Dundee, United Kingdom, DD1 9SY
Contact: James Chalmers, MBChB, MRCP    01382 386131    j.chalmers@dundee.ac.uk   
NHS Greater Glasgow and Clyde Recruiting
Glasgow, United Kingdom
Contact: John Haughney         
Northumbria Healthcare NHS Foundation Trust Recruiting
North Shields, United Kingdom, NE29 8NH
Contact: Stephen Bourke         
Nottingham University Hospitals NHS Trust Recruiting
Nottingham, United Kingdom, NG7 2UH
Contact: Dominick Shaw         
Sponsors and Collaborators
University of Dundee
Boehringer Ingelheim
NHS Tayside
Investigators
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Principal Investigator: James Chalmers, MBChB, MRCP University of Dundee

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Responsible Party: James Chalmers, Dr., University of Dundee
ClinicalTrials.gov Identifier: NCT03152149    
Other Study ID Numbers: 2016RC22
2016-004473-41 ( EudraCT Number )
First Posted: May 12, 2017    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by James Chalmers, University of Dundee:
Chronic Obstructive Pulmonary Disease
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Inflammation
Pathologic Processes
Respiratory Tract Diseases
Fluticasone
Tiotropium Bromide
Olodaterol
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action