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.

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.

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.