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Chronic Obstructive Pulmonary Disease (COPD) Biomarker Identification Study

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Philip Morris Products S.A.
ClinicalTrials.gov Identifier:
NCT01780298
First received: January 21, 2013
Last updated: January 28, 2013
Last verified: January 2013
  Purpose

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. These are called biomarkers.

This study will be conducted in the UK and will (a) identify existing and new biomarkers and (b) compare these amongst the 4 groups of subjects recruited for the study. The groups will consist of 60 COPD subjects, 60 non-smokers (never smoked), 60 ex-smokers and 60 current smokers, all aged 40-70 years. COPD subjects will be matched to the non-COPD subjects by gender, age and ethnicity.

Severe COPD is associated with elevated sputum neutrophil counts therefore sputum samples will be obtained. In order to identify other biomarkers, nasal samples collected by 3 different methods (scraping the inside of the nose with a plastic probe, washing the nostril with salty water and placing strips of filter paper in the nostril for 2 minutes), and blood samples will be also obtained. Other tests to determine the quantity and quality of proteins, a substance called ribonucleic acid (RNA and to extract deoxyribonucleic acid (DNA) will be performed on some of the collected samples. Other tests such as a chest CT scan, full lung function assessment and cardio-pulmonary exercise tolerance test will be also performed.

The study consists of 4 visits in total, plus the follow-up call, and can take a minimum of 14 days to a maximum of 66 days for each subject to fully complete the study.


Condition
COPD

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional
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.

Resource links provided by NLM:


Further study details as provided by Philip Morris Products S.A.:

Primary Outcome Measures:
  • Composite description of lung inflammation as assessed by cellular and molecular biomarkers [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
    • The total leucocyte and differential leucocyte count in sputum.
    • Selected biomarkers of inflammation in blood, sputum and nasal fluid. Biomarkers of inflammation include, but are not limited to, the following: neutrophil elastase, IL1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-9, IL-12, IL-13, IL-17, TNFalpha, TGFbeta, GM-CSF, MCP-1alpha, TIMP-1, MMP8, MMP9, MMP12, IFN gamma and IP-10.
    • Protein markers as determined by proteomics assays from blood, nasal lavage and induced sputum.
    • mRNA and miRNA (transcriptomics) derived from nasal epithelial cells obtained by nasal scrapes .
    • mRNA and miRNA (transcriptomics) derived from leucocytes obtained from blood samples.
    • mRNA and miRNA (transcriptomics) derived from induced sputum.
    • Genomic DNA sequencing from leukocytes obtained from blood samples.
    • Lipid markers as determined by lipidomic assays from blood samples


Secondary Outcome Measures:
  • Composite descriptions of inflammation as assessed by Physiological and Clinical parameters. [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
    1. Full lung function including lung volumes and transfer factor measurements.
    2. IOS measurements.
    3. Multichannel lung sound analysis measurements.
    4. Differential fractional exhaled nitric oxide (differential FENO).
    5. Differential exhaled breath temperature measurements.
    6. The stage of COPD with high resolution CT scan measurements and to compare quantitative CT measurements.
    7. Exercise capacity (VO2 max and SpO2 desaturation) measurements
    8. Demographic details.
    9. Validated QOL measurement (SF36).
    10. Modified Medical Council Dyspnea Scale (MMRC)
    11. General Questionnaire


Biospecimen Retention:   Samples With DNA

Proteomic investigations: Blood serum, Induced Sputum and Nasal Lavage

Transcriptomics investigations (mRNA and micro RNA): Whole Blood, Nasal Scrapes, Induced sputum cell pellet

Genomic DNA sequencing: Whole blood

Lipidomics: Whole blood


Enrollment: 739
Study Start Date: July 2011
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Groups/Cohorts
Group 1: COPD GOLD Stage 1-2
Sixty 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
Sixty 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
Sixty 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
Sixty subjects who have never smoked (non smokers) and matched to the COPD cases by ethnicity, gender and age (within 5 years).

Detailed Description:

A case control study with three matched control groups. 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 which is conducted 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 signs 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 attend the center on up to four further occasions if they meet the inclusion/exclusion criteria at screening. An additional visit (Visit 1a) may be scheduled for subjects who are unable to produce an adequate sputum sample at Visit 1. This will be at the discretion of the Investigator (or suitably qualified designee).

The subject will return for visit 2 (4 to 21 days after screening) once it is determined that the subject is eligible for the study. Visit 3 will be conducted within 3-14 days of the completion of visit 2. Visit 4 will be scheduled 3-14 days post visit 3. A follow up telephone call will be conducted 3-10 days post visit 4.

Subjects will undergo measurements of full lung function including lung volumes and transfer factors, differential exhaled nitric oxide (Differential FENO), impulse oscillatory (IOS), multichannel lung sound analysis, cardio-pulmonary exercise test with measurement of ventilator oxygen capacity (VO2 max) and oxygen saturation levels (SpO2), exhaled breath temperature, nasal sampling and sputum induction. All subjects will complete quality of life questionnaires (SF36 and QOL) and the Modified Medical Council (MMRC) Dyspnea Scale.

All subjects will undergo high resolution CT scan at visit 3 for the quantitative assessment of airway thickness and radiological evidence of emphysema. The staging of COPD will also be determined in subjects with COPD.

Blood samples will be obtained for clinical biochemistry and hematology. The measurement of biomarkers of inflammation will be performed on blood, sputum and nasal fluid samples. Additional biological material (blood and nasal respiratory epithelia obtained from nasal scrapes) will be collected for transcriptomics (mRNA and miRNA gene expression analyses). Proteomic evaluation will be conducted on blood, sputum and nasal fluid samples. Blood samples will be collected for future genome sequencing (genomics) and lipidomics sampling.

  Eligibility

Ages Eligible for Study:   40 Years to 70 Years
Genders Eligible for Study:   Both
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.

Criteria

Inclusion Criteria

  • Provision of written signed 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 to not be 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).
  • Be able 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 FEV1 and FVC of <70 % and FEV1 ≥50 % of predicted normal.

Additional Inclusion Criteria Non-Smoker 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 Smoker 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-Smoker 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 positive drugs of abuse test at visit 1.
  • Subjects, who in the opinion of the Investigator should not, for reasons of the safety or compliance, participate in the study.
  • Use of prohibited medications specified in section 7.4.
  • 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 or 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01780298

Locations
United Kingdom
London, United Kingdom
Sponsors and Collaborators
Philip Morris Products S.A.
  More Information

No publications provided

Responsible Party: Philip Morris Products S.A.
ClinicalTrials.gov Identifier: NCT01780298     History of Changes
Other Study ID Numbers: QASMC 202
Study First Received: January 21, 2013
Last Updated: January 28, 2013
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by Philip Morris Products S.A.:
COPD
Biomarkers
Cigarette Smoke
Lung Inflammation
FEV
Sputum

Additional relevant MeSH terms:
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Lung Diseases
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on November 20, 2014