INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol

NCT03152149 | Completed Phase 4

• 2 other identifiers: 2016RC222016-004473-41
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 4

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.

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

Chronic Obstructive Pulmonary Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Change in bacterial community composition determined by 16S microbiome sequencing as measured by the Shannon Diversity index.

  From baseline to 1, 2, 3 and 6 months

• Sputum neutrophil elastase activity determined using an activity based immunoassay

  From baseline to 1, 2, 3 and 6 months

• Change in sputum neutrophil extracellular traps determined using a validated ELISA

  From baseline to 1, 2, 3 and 6 months

• Change in sputum cytokines and inflammatory markers including but not limited to CXCL-8, IL17, IL-1beta, resistin, IL13

  From baseline to 1, 2, 3 and 6 months

Other Outcomes (13)

• Relative abundance of Haemophilus Operational Taxonomic Units at genus level or relative abundance of proteobacteria at phylum level.

  Baseline, 1, 2, 3 and 6 months

• Proportion of patients with dysbiosis as defined by >40% relative Operational Taxonomic Units of a single organism.

  Baseline, 1, 2, 3 and 6 months

• Comparison of adverse events/serious adverse events between groups on dual bronchodilators and inhaled corticosteroids

  Baseline, 1, 2, 3 and 6 months

Study Arms (2)

1. Spiolto Respimat

ACTIVE COMPARATOR

Spiolto Respimat (Tiotropium 2.5 micrograms,olodaterol 2.5 micrograms) 2 puffs once daily for 6 months

Drug: Tiotropium & olodaterol

2. Relvar Ellipta

ACTIVE COMPARATOR

Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once per day for 6 months

Drug: fluticasone furoate & vilanterol

Interventions

Tiotropium & olodaterol DRUG

Spiolto Respimat (Tiotropium 2.5 micrograms,olodaterol 2.5 micrograms) 2 puffs once daily for 6 months

Also known as: Spiolto Respimat

1. Spiolto Respimat

fluticasone furoate & vilanterol DRUG

Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once per day for 6 months

Also known as: Relvar Ellipta

2. Relvar Ellipta

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Dundee: lead
• Boehringer Ingelheim: collaborator
• NHS Tayside: collaborator

Study Sites (4)

NHS Tayside

Dundee, DD1 9SY, United Kingdom

Location

NHS Greater Glasgow and Clyde

Glasgow, United Kingdom

Location

Northumbria Healthcare NHS Foundation Trust

North Shields, NE29 8NH, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, NG7 2UH, United Kingdom

Location

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

tiotropium-olodaterol; fluticasone furoate; vilanterol

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• James Chalmers, MBChB, MRCP

  University of Dundee

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2017
• First Posted: May 12, 2017
• Study Start: June 1, 2017
• Primary Completion: November 26, 2019
• Study Completion: November 26, 2019
• Last Updated: July 20, 2020

Record last verified: 2020-07

Locations

GB (4)