Clinical trial NCT03924843: mRNA and miRNA Airway Inflammatory Markers
Official title: Responsivity and Reproducibility of Messenger and Micro RNA Airway Inflammatory Markers - a Pilot Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: COPD
COPD Exacerbation
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2019-04-23
Enrollment: 21
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Twenty COPD patients with an initial COPD exacerbation will be followed for a period of seven weeks for three consecutive visits

Brief summary: This study investigates cytokine Messenger (mRNA) and microRNA (miRNA) level expression of interleukin (IL) -6, IL-8, IL-17, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 beta and transforming growth factor (TGF)-beta regarding their reproducibility and responsivity in induced sputum and nasal mucosa of patients with chronic obstructive pulmonary disease (COPD) in order to assess their potential as a biomarker outcome measure.

Detailed description: Rationale:There is an increased interest to identify sensitive airway biomarkers in order to evaluate the potential and efficacy of anti-inflammatory and -remodelling therapeutic interventions. Biomarkers should be easily obtainable, reliable and valid. In COPD, easily obtainable would suggest use of blood, or more directly associated with the airways: sputum or epithelial brushes. Sputum is an obvious opportunity. It has been shown that gene expression changes in the nasal mucosa might be used as suitable surrogate for epithelial cells of the lower airways in patients with airway inflammatory diseases. However, further studies are needed to validate these assumptions. Measurement of messenger RNA, and of micro RNA derived from sputum samples and nasal brushes would fulfil the ease of use required of a biomarker. Messenger RNA would allow for easier quantification in variable dilution samples (sputum). The Groningen Research Institute for Asthma and COPD (GRIAC research group) has experience with sputum and nasal brushes, mRNA and miRNA, but more information is needed on especially reproducibility of the measurements, as well as on responsivity. Both are a prerequisite when designing new intervention trials with such biomarkers.

Therefore, the aim of this study is to investigate cytokine messenger and microRNA level expression of IL-6, IL-8, IL-17, TNF-alpha, MCP-1, MIP-1 beta and TGF-beta regarding their reproducibility and responsivity in induced sputum and nasal mucosa of COPD patients in order to assess their potential as an objective outcome measure.

The primary objectives of this prospective pilot study are the determination of the reproducibility and responsivity of mRNA level expression of IL-6, IL-8, TNF-alpha, MCP-1, MIP-1 beta, ECP and TGF-beta as airway inflammatory markers in induced sputum as well as mRNA and miRNA expression levels of IL-6, IL-8, IL-17, TNF-alpha, MCP-1, MIP-1 beta and TGF-beta as airway inflammatory markers in nasal mucosa. The secondary objective includes the analyses of the measurement characteristics of inflammation cell profiles, LTB4 and protein levels of IL-6, IL-8, TNF-alpha, MCP-1, MIP-1 beta, ECP and TGF-beta.

Twenty COPD patients with an initial COPD exacerbation will be followed for a period of seven weeks for three consecutive visits

The main parameters of induced sputum samples will be mRNA level expression of IL-6, IL-8, TNF-alpha, MCP-1, MIP-1 beta and TGF-beta. The main parameters of nasal mucosa samples will be mRNA and miRNA level expression of IL-6, IL-8, IL-17, TNF-alpha, MCP-1, MIP-1 beta and TGF-beta.

To allow for full perspective on the outcomes, inflammatory cell profiles, Leukotriene B4 (LTB4) and protein levels of IL-6, IL-8, TNF-alpha, MCP-1, MIP-1 beta, eosinophilic cationic protein (ECP) and TGF-beta in sputum will be assessed.

Eligibility criteria: Inclusion Criteria:

* Men/Women age \>40 years.
* Diagnoses of COPD according to criteria of the American Thoracic Society (ATS), a disease state characterized by the presence of chronic airway obstruction due to chronic bronchitis (cough/sputum on most days a week for 3 months in a year for at least two successive years) and/or emphysema
* Diagnosis of moderate or severe COPD exacerbation (see "Definitions")
* FEV1 \> 0.8 L and ability to produce sputum after hypertonic saline production
* Post bronchodilator FEV1/Forced Vital Capacity (FVC) ratio \<70 % and post bronchodilator FEV1\< 80% pred.
* A smoking history of \>10 pack years

Exclusion Criteria:

* Pneumonia as determined by X-ray
* \> 48 h intake of prednisolon/antibiotics
* Need for mechanical ventilation (either invasive or non-invasive)
* Treatment with immune-modulating agents for any disease
* Experimental interventions for COPD last half year
* Former/concomitant diagnosis of asthma
* Any significant other pulmonary disease or disorder
* Other significant disease or disorder (like alpha-1-antitrypsine deficiency, significant bronchiectasis, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic (including diagnosed diabetes), malignant, psychiatric, major physical impairment), which, in the opinion of the investigators may either put the patient at risk because of participation in the study, or may influence the results of the study, or the patient's ability to participate in the study.
* Existing pregnancy/ current willingness for becoming pregnant

Primary outcomes:
measure: Change of mRNA cytokine expression measured in induced sputum samples
timeFrame: Change of outcome measures will be assessed during one COPD exacerbation phase, after 42 days and after 44-51 days
measure: Change of miRNA and mRNA cytokine expression measured in nose mucosa samples
timeFrame: Change of outcome measures will be assessed during one COPD exacerbation phase, after 42 days and after 44-51 days
Secondary outcomes:
measure: Change of inflammatory cell profiles, LTB4 levels and protein cytokine levels measured in induced sputum samples
timeFrame: Change of outcome measures will be assessed during one COPD exacerbation phase, after 42 days and after 44-51 days
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center; Department of Pulmonary Diseases
Study officials:
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