Clinical trial NCT01780298: Chronic Obstructive Pulmonary Disease (COPD) Biomarker Identification Study
Official title: A Biomarker Study to Compare Gene and Protein Expression Profiles in Four Separate Groups of Subjects Including COPD Cases (GOLD Stage 1-2 and Current Smokers With a ≥ 10 Pack Year Smoking History) and Three Control Groups of Matched Non-smoking Subjects (Never Smoked), Ex-smokers and Current Smokers, to Identify Novel Biomarkers, to Assess Standard Biomarkers of Inflammation and to Compare Inflammatory Cell Responses and Selected Markers of Inflammation in Blood, Induced Sputum and Nasal Samples.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: COPD
Keywords: COPD
Biomarkers
Cigarette Smoke
Lung Inflammation
FEV
Sputum
Lead sponsor: Philip Morris Products S.A.
Sponsor class: INDUSTRY
First posted: 2013-01-31
Enrollment: 252
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: In this study, male and female subjects aged between 40-70 years will be included. All subjects must be matched by ethnicity, gender and age (within 5 years) of the subjects with COPD recruited in the study.

Brief summary: Chronic obstructive pulmonary disease (COPD) is a common inflammatory disease of the airway affecting approximately 10% of individuals aged 40 years or more with a smoking history. The disease is characterized by an increase in numbers of airway white blood cells (neutrophils, lymphocytes and monocytes). Stimulation of white blood cells results in the release of different agents of inflammation. Some of these agents give an indication of the presence or severity of a disease when measured.

This case control study will be conducted at The Heart Lung Centre, London, UK. The study aims to determine biomarkers for the differentiation of subjects with COPD (GOLD Stage 1-2 and who are current smokers with a ≥ 10 pack year smoking history) and three matched control groups: one of non-smoking subjects (never smoked), one of ex-smokers and one of current smokers. COPD subjects will be matched to the non-COPD subjects by gender, age and ethnicity.

The study will include a range of physiological measurements including lung function, computerized tomography scans (CT scans), cardio pulmonary exercise test and computerized multichannel lung sounds analysis (Stethographics). In addition, lung inflammation will be assessed by cellular and molecular biomarkers using e.g. transcriptomics and proteomics technologies.

Detailed description: At the screening visit, subject consent will be obtained prior to conducting any study related procedures. Informed consent may be obtained on registration/review visit at the Centre where it is conducted and thus prior to visit 1.

The screening visit will involve obtaining demographic data and medical history information as well as performing safety assessments such as vital sign measurements, electrocardiogram (ECG), and clinical laboratory tests. An induced sputum sample will be obtained to ensure that subjects can produce an adequate sputum sample. Smokers will receive information on smoking cessation at the screening visit and follow-up telephone call.

Subjects will come back to the center on up to four further occasions if they meet the inclusion/exclusion criteria at screening:

* visit 2: 4 to 21 days after screening,
* visit 3: 3-14 days post visit 2, and
* visit 4: 3-14 days post visit 3.

A follow-up telephone call will be conducted 3-10 days post visit 4.

Eligibility criteria: Inclusion Criteria

* Provision of signed written informed consent which includes genetic consent.
* Ability to comply with study procedures.
* Males and females aged 40-70 years inclusive.
* Have a body mass index (BMI) between 18 and 35 kg/m2 inclusive and minimum body weights of 50 kg.
* Have a normal physical examination, and have normal laboratory values, 12-lead ECG and vital signs (blood pressure, heart rate and respiratory rate), unless the Investigator considers an abnormality as not clinically significant.
* Ability to perform reproducible spirometry according to the American Thoracic Society and the European Respiratory Society (ATS/ERS) guidelines (American Thoracic Society, 2005).
* Ability to produce a minimum 0.1 gram sputum sample after induction with inhaled hypertonic saline.

Additional Inclusion Criteria COPD Group

* A clinical diagnosis of COPD according to the GOLD guidelines (stage 1-2).
* Current smokers with ≥10 pack-year smoking history.
* Demonstrate a post-bronchodilator ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) of \<70 % and FEV1 ≥50 % of predicted normal.

Additional Inclusion Criteria Non-Smokers Group

* Have never smoked tobacco products.
* Demonstrate normal lung function by post bronchodilator FEV1 ≥80 % of predicted normal, with no evidence of airway obstruction FEV1/FVC ratio ≥70 %.
* Have a sputum eosinophilia \<2 % and a sputum neutrophilia \<80 % from the sample collected at visit 1 (Belda et al., 2000).

Additional Inclusion Criteria Smokers Group

* Be current smokers with defined smoking history of ≥10 pack years.
* Have normal lung function by post bronchodilator FEV1 ≥80 % of predicted normal, with no evidence of airway obstruction FEV1/FVC ratio ≥70 %.

Additional Inclusion Criteria Ex-Smokers Group

* Be ex-smokers, with defined smoking history of ≥10 pack years and to have quit smoking at least 1 year before entering the study.
* Have normal lung function by post bronchodilator FEV1 ≥80 % of predicted normal, with no evidence of airway obstruction FEV1/FVC ratio ≥70 %.

Exclusion Criteria:

* Current evidence or recent history of any clinically significant disease or abnormality (other than COPD in the subjects with COPD group), which in the opinion of the Investigator, would put the subject at risk, or which would compromise the quality of the study data, including but not limited, to cardiovascular disease, myocardial infarction, cardiac failure, uncontrolled hypertension, life-threatening arrhythmias, uncontrolled diabetes, neurologic or neuromuscular disease, liver disease, gastrointestinal disease or electrolyte abnormalities.
* Females with a positive pregnancy test at visit 1 or 3.
* Females currently breastfeeding.
* Involvement in the planning and conduct of the study.
* Surgery or significant trauma within 3 months of visit 1.
* History of tuberculosis or other non-specific pulmonary diseases such as asthma.
* Symptoms, signs or laboratory findings suggestive of an ongoing infective illness as judged by the Investigator at visit 1 or 2.
* Participation in any clinical study with an investigational drug in the 4 months prior to visit 1, or participation in a study with a new formulation of a marketed drug in the 3 months prior to visit 1, or participation in a methodology study in the month prior to visit 1.
* Symptoms of any clinically significant illness within 2 weeks prior to visit 1.
* A significant history of alcohol abuse or consumption of more than the recommended units of alcohol per week (28 units for males and 21 units for females).
* A significant history of drug abuse (including benzodiazepines) or a positive test of drug abuse test at visit 1.
* Subjects, who in the opinion of the Investigator should not, for safety or compliance reasons, participate in the study.
* Use of prohibited medications.
* Subjects who have a first degree relative (parents, sibling or child) already enrolled in the study.

Additional Exclusion Criteria - subjects with COPD

* Recent history of hospitalization due to an exacerbation of airway disease within 3 months of the screening visit or subjects with need for increased treatments for COPD within 6 weeks prior to the screening visit.
* Prior lung volume reduction surgery or history of chest/lung irradiation.
* Regular use of daily oxygen therapy.
* Long standing history and primary diagnosis of asthma.
* Use of systemic steroids within 3 months prior to the screening visit.
* Respiratory tract infection within 6 weeks prior to the screening visit.

Primary outcomes:
measure: Spirometry Measurement: Percentage of Predicted Forced Expiratory Volume in 1 Second (FEV1 %Pred)
timeFrame: Up to 59 days
measure: Gas Transfer: Percentage of Predicted Total Diffusing Capacity of the Lungs for Carbon Monoxide (TLCO %Pred)
timeFrame: Up to 59 days
measure: Impulse Oscillometry (IOS) Measurements: Percentage of Predicted Central Airway Resistance at 5Hz (R5 %Pred)
timeFrame: Up to 59 days
measure: Impulse Oscillometry (IOS) Measurements: Percentage of Predicted Reactance at 5 Hz (X5 % Pred)
timeFrame: Up to 59 days
measure: Impulse Oscillometry (IOS) Measurements: Resonant Frequency (Fres)
timeFrame: Up to 59 days
measure: Stethographics Measurements: Non-Weighted Acoustic Chronic Obstructive Pulmonary Disease Scores (ACOPDS)
timeFrame: Up to 59 days
measure: Dyspnoea Assessment: Modified Medical Research Council (MMRC) Dyspnoea Scale
timeFrame: Up to 59 days
measure: Prediction of Mortality and Hospitalizations: Modified BODE Index (mBODE)
timeFrame: Up to 59 days
measure: High-Resolution Computerised Tomography (HRCT) of the Chest
timeFrame: Up to 59 days
Secondary outcomes:
Other outcomes:
measure: Total Leukocytes and Differential Leukocytes Count in Sputum
timeFrame: Up to 59 days
measure: Protein Markers as Determined by Proteomics Analysis of Induced Sputum
timeFrame: Up to 59 days
measure: Lipid Markers as Determined by Lipidomic Analysis of Blood Samples
timeFrame: Up to 59 days
measure: mRNA and miRNA (Transcriptomics) Derived From Induced Sputum
timeFrame: Up to 59 days
measure: mRNA and miRNA (Transcriptomics) Derived From Leukocytes Obtained From Blood Samples
timeFrame: Up to 59 days
measure: mRNA and miRNA (Transcriptomics) Derived From Nasal Epithelial Cells Obtained by Nasal Scrapes
timeFrame: Up to 59 days
Locations:
city: London
country: United Kingdom
facility: Heart Lung Centre, Queen Anne Street Medical Centre
Study officials:
affiliation: Heart Lung Centre, Queen Anne Street Medical Centre
name: Brian Leaker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Titz B, Sewer A, Schneider T, Elamin A, Martin F, Dijon S, Luettich K, Guedj E, Vuillaume G, Ivanov NV, Peck MJ, Chaudhary NI, Hoeng J, Peitsch MC. Alterations in the sputum proteome and transcriptome in smokers and early-stage COPD subjects. J Proteomics. 2015 Oct 14;128:306-20. doi: 10.1016/j.jprot.2015.08.009. Epub 2015 Aug 22.
citation: Martin F, Talikka M, Hoeng J, Peitsch MC. Identification of gene expression signature for cigarette smoke exposure response--from man to mouse. Hum Exp Toxicol. 2015 Dec;34(12):1200-11. doi: 10.1177/0960327115600364.
citation: Chaudhary N, Luettich K, Peck MJ, Pierri E, Felber-Medlin L, Vuillaume G, Leroy P, Hoeng J, Peitsch MC. Physiological and biological characterization of smokers with and without COPD. F1000Res. 2017 Jun 13;6:877. doi: 10.12688/f1000research.11698.2. eCollection 2017.
citation: Titz B, Luettich K, Leroy P, Boue S, Vuillaume G, Vihervaara T, Ekroos K, Martin F, Peitsch MC, Hoeng J. Alterations in Serum Polyunsaturated Fatty Acids and Eicosanoids in Patients with Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD). Int J Mol Sci. 2016 Sep 20;17(9):1583. doi: 10.3390/ijms17091583.