Chronic Obstructive Pulmonary Disease (COPD) Biomarker Identification Study

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.

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.

Study Overview

• Status: Completed
• Conditions: COPD

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.

• Study Type: Observational
• Enrollment (Actual): 252

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Heart Lung Centre, Queen Anne Street Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• 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.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Group 1: COPD GOLD Stage 1-2; Subjects with a clinical diagnosis of COPD, according to the GOLD guidelines (Stages 1-2), who are current smokers with at least a 10 pack-year smoking history.
Group 2: Current Cigarette Smokers; Subjects who are current smokers with at least a 10 pack-year smoking history, and matched to the COPD cases by ethnicity, gender and age (within 5 years).
Group 3: Ex-Smokers; Subjects who are ex-smokers with at least a 10 pack-year smoking history who have not smoked for at least one year, and matched to the COPD cases by ethnicity, gender and age (within 5 years).
Group 4: Never Smokers; Subjects who have never smoked (non-smokers), and matched to the COPD cases by ethnicity, gender and age (within 5 years).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impulse Oscillometry (IOS) Measurements: Resonant Frequency (Fres)		Up to 59 days
Spirometry Measurement: Percentage of Predicted Forced Expiratory Volume in 1 Second (FEV1 %Pred)		Up to 59 days
Gas Transfer: Percentage of Predicted Total Diffusing Capacity of the Lungs for Carbon Monoxide (TLCO %Pred)		Up to 59 days
Impulse Oscillometry (IOS) Measurements: Percentage of Predicted Central Airway Resistance at 5Hz (R5 %Pred)		Up to 59 days
Impulse Oscillometry (IOS) Measurements: Percentage of Predicted Reactance at 5 Hz (X5 % Pred)		Up to 59 days
Stethographics Measurements: Non-Weighted Acoustic Chronic Obstructive Pulmonary Disease Scores (ACOPDS)	Stethographics analysis was performed using the 16-channel lung sound analyzer system STG1602 (Stethographics, Boston, MA, USA) following the supplier's recommendations. Lung sound data are obtained from an intermediate deeper-than-normal breath (pattern 2; P2). Each breath pattern is recorded for a minimum of 30 seconds allowing 3 to 6 breaths to be taken, with measurements completed over 3 to 4 minutes. Each of the 16 parameters derived from one measurement are evaluated and a score from 0 to 10 is assigned based on the value of the individual parameter. The total standard Acoustic COPD Score (ACOPDS) is calculated as the sum of the individual score for each parameter, which permits a maximum score of 160. Although this stethographics analysis system was considered experimental, a higher score was associated with poor health outcomes and a lower score with a better health state.	Up to 59 days
Dyspnoea Assessment: Modified Medical Research Council (MMRC) Dyspnoea Scale	The MMRC scale uses a simple grading system to assess a subject's level of dyspnea (shortness of breath). Subjects were asked to grade the degree of breathlessness related to activities by choosing 1 of the following answers: 0: Not troubles by breathlessness except on strenuous exercise; 1: Short of breath when hurrying or walking up a slight hill; 2: Walks slower than contemporaries on the level because of breathlessness, or has to stop for breath when walking at own pace; 3: Stops for breath after about 100 meters or after a few minutes on the level; 4: Too breathless to leave the house, or breathless when dressing or undressing.	Up to 59 days
Prediction of Mortality and Hospitalizations: Modified BODE Index (mBODE)	The BODE Index is a 10-point scale to assess prognostic factors in COPD patients. Body mass index ("B"), airway obstruction ("O"), dyspnea ("D"), and exercise tolerance ("E") are each graded on a 4 point scale (0 to 3), except body mass index (0 or 1) . The final BODE Index value is the sum of the scores for each prognostic factor, where a higher BODE score indicates a higher risk of death. The modified BODE (mBODE) index as defined by Lopez-Campos (2010) was used in this study, and is composed of the following factors: Body mass index: (0 or 1); Degree of airflow obstruction (FEV1% Pred): (0 to 3); Functional dyspnea (MMRC Dyspnoea Scale): (0 to 3); Exercise capacity (VO2max): (0 to 3) Lopez-Campos, José Luis, et al. "Modified BODE indexes: Agreement between multidimensional prognostic systems based on oxygen uptake." International Journal of Chronic Obstructive Pulmonary Disease (2010): 133-140.	Up to 59 days
High-Resolution Computerised Tomography (HRCT) of the Chest	CT scans were assessed by two radiologists. A scoring system from 0 to 4 was applied, depending upon the component: Extent of disease (emphysema): 0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe; Severity of bronchial dilatation: 0=none; 1=mild (1.5x to 2.5x diameter of pulmonary artery); 2=severe (>2.5x diameter of pulmonary artery); Traction bronchiectasis: 0=none; 1=mild (1.5x to 2.5x diameter); 2=severe (>2.5x diameter).; Total bronchiectasis score derived by adding the bronchial dilatation and traction bronchiectasis scores; Bronchial wall thickening: 0=none; 1=0.5x; 2=0.5-1x; 3= >1x the diameter of the adjacent pulmonary artery; Small airways disease: 0=absent, 1=mild, 2=moderate, 3=severe and 4=very severe The total score (higher score indicated a poor outcome) was derived from the mean of all scores. This is described in Chaudhary, Nveed, et al. "Physiological and biological characterization of smokers with and without COPD." F1000Research 6 (2017).	Up to 59 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total leukocytes and differential leukocytes count in sputum	Results are published and available: 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. PMID: 26306861	Up to 59 days
Protein markers as determined by proteomics analysis of induced sputum	Results are published and available: 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. PMID: 26306861	Up to 59 days
mRNA and miRNA (transcriptomics) derived from nasal epithelial cells obtained by nasal scrapes	Results were submitted for publication, reference to be provided upon publication: Marja Talikka*, Florian Martin, Alain Sewer, Gregory Vuillaume, Patrice Leroy, Nveed Chaudhary, Michael J. Peck, Manuel C. Peitsch, and Julia Hoeng. Mechanistic evaluation of the impact of smoking and chronic obstructive pulmonary disease on biological processes in the nasal epithelium.	Up to 59 days
mRNA and miRNA (transcriptomics) derived from leukocytes obtained from blood samples	Results are published and available: 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 PMID: 26614807	Up to 59 days
mRNA and miRNA (transcriptomics) derived from induced sputum	Results are publicly available: 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. PMID: 26306861	Up to 59 days
Lipid markers as determined by lipidomic analysis of blood samples	Results were submitted for publication, reference to be provided upon publication.	Up to 59 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Leukocytes and Differential Leukocytes Count in Sputum	Results are available at: 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. PMID: 26306861	Up to 59 days
Protein Markers as Determined by Proteomics Analysis of Induced Sputum	Results are available at: 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. PMID: 26306861	Up to 59 days
Lipid Markers as Determined by Lipidomic Analysis of Blood Samples	Reference to be provided upon publication.	Up to 59 days
mRNA and miRNA (Transcriptomics) Derived From Induced Sputum	Results are available at: 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. PMID: 26306861	Up to 59 days
mRNA and miRNA (Transcriptomics) Derived From Leukocytes Obtained From Blood Samples	Results are available at: 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 PMID: 26614807	Up to 59 days
mRNA and miRNA (Transcriptomics) Derived From Nasal Epithelial Cells Obtained by Nasal Scrapes	Reference to be provided upon publication.	Up to 59 days

Collaborators and Investigators

• Sponsor: Philip Morris Products S.A.
• Investigators: Principal Investigator: Brian Leaker, MD, Heart Lung Centre, Queen Anne Street Medical Centre

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• Sputum transcriptomics
• Sputum proteomics
• Nasal scrapes transcriptomics

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: January 21, 2013
• First Submitted That Met QC Criteria: January 28, 2013
• First Posted (Estimated): January 31, 2013

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 9, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: COPD; Biomarkers; Sputum; FEV; Cigarette Smoke; Lung Inflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: QASMC 202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data for transcriptomics (sputum and nasal scrapes) and proteomics (sputum) are published and available via the following links:

• Sputum transcriptomics:

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3604/

• Sputum proteomics:

http://www.ebi.ac.uk/pride/archive/projects/PXD001977

• Nasal scrapes transcriptomics:

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-4015/

• Blood transcriptomics:

The link to the Array Express database will be provided upon online publication

• IPD Sharing Time Frame: Immediately following publication. No end date.
• IPD Sharing Access Criteria: Anyone who wishes to access the data.

Study Data/Documents

1. Individual Participant Data Set