Longitudinal Follow up to Assess Biomarkers Predictive of Emphysema Progression in Patients With COPD (Chronic Obstructive Pulmonary Disease)

Completed

• Conditions: Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema

• Registration Number: NCT02719184
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

The study will include 60 healthy subjects (ex-smoker without any airflow limitation), 125 COPD GOLD (global initiative for chronic obstructive lung disease) I , 125 COPD GOLD II, 125 COPD GOLD III and up to 20 patients with COPD and A1AT (Alpha1-Antitrypsin) deficiency (ZZ genotype). Soluble and imaging biomarkers will be investigated addressing different aspects of disease pathways postulated to be relevant for COPD progression.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-03-18
• Study First Submitted QC: 2016-03-21
• Study First Posted: 2016-03-25
• Study Start: 2016-04-13
• Primary Completion: 2021-06-14
• Study Completion: 2021-06-14
• Results First Submitted: 2023-06-12
• Status Verified: 2024-03
• Results First Submitted QC: 2024-03-19
• Last Update Submitted: 2024-03-19
• Results First Posted: 2024-08-16
• Last Update Posted: 2024-08-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 463

Inclusion Criteria

General Inclusion Criteria

• Male or female healthy subjects or COPD (GOLD I to III) outpatients with or without A1AT deficiency
• Ex-smokers for at least 9 months with a smoking history of >=20 pack years
• Signed informed consent consistent with ICH-GCP (International Conference on Harmonisation - Good Clinical Practice) guidelines prior to participation in the study, which includes the application of study restrictions
• Age >= 40 and <=70 years
• Body mass index (BMI) of >= 18 and <= 35 kg/m2 (<= 30 kg/m2 in the MRI subset)
• Ability to perform all study related procedures including technically acceptable pulmonary function tests, body plethysmography, DLCO ( Diffusing Capacity of the lungs for Carbon Monoxide) , sputum induction (if applicable), chest CT (Computed Tomography) and MRI (if applicable)

Inclusion Criteria Specific for Patients with COPD - Patients must have a current diagnosis of COPD made by a physician prior to or during Visit 1 and a mMRC (Modified Medical Research Council Dyspnea Scale) score of 1 or more. The diagnosis of COPD must be in accordance with GOLD Guidelines and must be documented by the following criteria: Known relatively stable airway obstruction with a post-bronchodilator FEV1 (Forced Expiratory Volume in first second)/FVC (Forced Vital Capacity) < 70 %

• The current COPD must be mild, moderate or severe based on lung functions and symptoms and the clinical situation must have stabilized for at least 4 weeks prior to Visit 1. The following definitions adapted from the GOLD Guidelines apply:

  1. mild: post-broncho-dilator FEV1 >=80% of predicted normal (GLI 2012 and JRS 2014) at Visit 1
  2. moderate: 50%<= post-broncho-dilator FEV1 < 80% of predicted normal (GLI 2012 and JRS 2014) without chronic respiratory failure at Visit 1
  3. severe: 30%<= post-bronchodilator FEV1 <50% of predicted normal (GLI 2012 and JRS 2014) without chronic respiratory failure at Visit 1

• Patients must be on stable therapy (not limited to respiratory medication) for the last 4 weeks prior to Visit 1

Inclusion Criteria Specific Patients with COPD and A1AT Deficiency

• Documented A1AT deficiency of ZZ genotype

Inclusion Criteria Specific Healthy Subjects

• Normal lung function values at Visit 1 with a documented post-bronchodilator FEV1 >=80% of predicted normal (GLI 2012 and JRS 2014) and a post-bronchodilator FEV1/FVC >= lower limit of normal
• Mean post DLCO over all acceptable measurements at Visit 1 of >= 70% of predicted normal
• Further inclusion criteria apply

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Exclusion Criteria

General Exclusion Criteria

• Previous participation in this study or participation in another trial with an investigational drug within 6 weeks prior to Visit 1 or during the study

• Significant pulmonary disease or other significant medical conditions* (as determined by medical history, examination and clinical investigations at screening) that may in the opinion of the investigator result in any of the following:

  1. Put the subject at risk because of participation in the study
  2. Cause concern regarding the subject's ability to participate in this study *e.g. rheumatoid arthritis, inflammatory bowel disease, severe liver disease, psoriasis, hematological, infectious and psychiatric diseases

• Documented history of asthma. For allergic rhinitis or atopy, source documentation to verify that the subject does not have asthma

• Planned surgery during the study expected to interfere with study procedures and outcome

• Blood withdrawal of more than 100 mL within the past 6 weeks prior to Visit 1 and between Visit 1 and 2

• Significant alcohol or drug abuse within past 2 years prior to Visit 1

• Women who are pregnant, nursing or plan to become pregnant while in the study

• Place of permanent residence of less than 3 months prior to Visit 1

• For the MRI subset: subject who do not meet the following criteria for the MRI assessment at Visit 2: systolic blood pressure between 90 and 180 mmHg (SBP), diastolic blood pressure between 50 and 110 mmHg (DBP), pulse rate between 40 and 110 bpm, ear temperature between 35 - 37.5 C, and a glomerular filtration rate (GFR) >= 30 mL/min (GFR must not be older than 14 days from the MRI assessment)

Exclusion Criteria Specific for Patients with COPD

• Respiratory tract infection or COPD exacerbation in the 4 weeks prior to Visit 1 or during the screening period prior to Visit 2, if rescheduling rules cannot be met

Exclusion Criteria Specific Patients with COPD and A1AT Deficiency

• Newly added anti-inflammatory treatment within 4 weeks prior to Visit 1
• Patients on treatment with PDE (Phosphodiesterase)-5 inhibitors (e.g. Roflumilast) and maintenance treatment Methylxanthines (e.g. Theophylline)
• Hospitalisation for respiratory failure during the year prior to Visit 1
• A history of cystic fibrosis
• Clinical diagnosis of bronchiectasis requiring specific treatment
• Clinically relevant abnormal baseline hematology and blood chemistry
• Known active tuberculosis
• Patients with change in any therapy within 4 weeks prior to Visit 1
• Current and planned A1AT augmentation therapy
• A malignancy for which the patient has undergone resection, radiation or chemotherapy within past 5 years. Patients with treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed
• Inability to comply with restrictions regarding diet, life style and medication
• Further exclusion criteria apply

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Duration of Exacerbations During Study (Per Year)	Up to 156 weeks	The duration of exacerbations for each subject was calculated as: sum of duration of episodes during study (days)\*(365.25/ number of days in study).
Number of Participants With at Least Moderate Exacerbation During Study by the Category of Number of Moderate Exacerbations	Up to 156 weeks	Number of participants with at least moderate exacerbation during study by the category of number of moderate exacerbation (no moderate exacerbation, 1 moderate exacerbation, or \>= 2 moderate exacerbations) was reported.
Absolute Change From Baseline at Week 156 in Adjusted Lung Density (ALD) Based on Percentile Density at 15% (PD15) Adjusted for Lung Volume	Up to Week 156. Change from baseline value at Week 156 was reported.	The absolute change from baseline at Week 156 in adjusted lung density (ALD) based on Percentile Density at 15% (PD15) adjusted for lung volume was reported. The ALD was calculated as: Percentile Density at 15% (PD15) \[gram/Liter (L)\] \* (Inspiratory volume \[L\]/predicted total lung volume \[L\]). The absolute change from baseline in ALD gram/Liter (g/L) was analyzed by Mixed Model for Repeated Measures (MMRM).
Number of Participants by the Category of Number of Exacerbations During Study	Up to Week 156	Number of participants by the category of number of exacerbations (no exacerbation, 1 exacerbation, or \>= 2 exacerbations) during study was reported.
Annual Rate of Lung Function Decline Based on Forced Expiratory Volume in 1 Second (FEV1)	Up to Week 156	The annual rate of lung function decline based on Forced Expiratory Volume in 1 second (FEV1) was reported. The annual rate was estimated from a random slope and intercept model with fixed categorical effects of diagnosis group, fixed continuous effects of time \[Year\], and including diagnosis group-by-time interaction. Random effect was included for subject specific intercept and time. Within-subject errors are modelled by an unstructured variance-covariance matrix.
Number of Participants With Severe Exacerbations During Study by the Category of Number of Severe Exacerbations	Up to 156 weeks	Number of participants with severe exacerbations during study by the category of number of severe exacerbations (no severe exacerbation, 1 severe exacerbation, or \>= 2 severe exacerbations) was reported.

Trial Locations

Locations (51)

McGill University Health Centre (MUHC); 🇨🇦 Montreal, Quebec, Canada

Fraunhofer ITEM; 🇩🇪 Hannover, Germany

Kagoshima University Hospital; 🇯🇵 Kagoshima, Kagoshima, Japan

Medicines Evaluation Unit; 🇬🇧 Manchester, United Kingdom

Hospital Son Espases; 🇪🇸 Palma de Mallorca, Spain

Hospital Quirónsalud Madrid; 🇪🇸 Pozuelo de Alarcón, Spain

The Catholic University of Korea, Eunpyeong St. Mary's Hospital; 🇰🇷 Seoul, Korea, Republic of

National Jewish Health; 🇺🇸 Denver, Colorado, United States

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

University of Utah Health Sciences Center; 🇺🇸 Salt Lake City, Utah, United States

SMG-SNU Boramae Medical Center; 🇰🇷 Seoul, Korea, Republic of

Aarhus University Hospital; 🇩🇰 Aarhus N, Denmark

IKF Pneumologie GmbH & Co. KG; 🇩🇪 Frankfurt, Germany

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States

Brussels - UNIV St-Pierre; 🇧🇪 Brussels, Belgium

McMaster University Medical Centre; 🇨🇦 Hamilton, Ontario, Canada

University of California San Diego; 🇺🇸 San Diego, California, United States

Diagnostics Research Group; 🇺🇸 San Antonio, Texas, United States

KLB Gesundheitsforschung Lübeck GmbH; 🇩🇪 Lübeck, Germany

Royal University Hospital; 🇨🇦 Saskatoon, Saskatchewan, Canada

Kishiwada City Hospital; 🇯🇵 Osaka, Kishiwada, Japan

The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center; 🇺🇸 Torrance, California, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

IUCPQ (Laval University); 🇨🇦 Quebec, Canada

Hvidovre Hospital; 🇩🇰 Hvidovre, Denmark

Showa University Fujigaoka Hospital; 🇯🇵 Kanagawa, Yokohama, Japan

University of Iowa Hospitals and Clinics; 🇺🇸 Iowa City, Iowa, United States

Temple University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

UZ Leuven; 🇧🇪 Leuven, Belgium

Showa University Hospital; 🇯🇵 Tokyo, Shinagawa-ku, Japan

University Clinical Center, Gdansk; 🇵🇱 Gdansk, Poland

Royal Free Hospital; 🇬🇧 London, United Kingdom

Osaka City University Hospital; 🇯🇵 Osaka, Osaka, Japan

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Gentofte Hospital; 🇩🇰 Hellerup, Denmark

HYKS Keuhkosairauksien tutkimusyksikkö; 🇫🇮 Helsinki, Finland

TYKS; 🇫🇮 Turku, Finland

Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH; 🇩🇪 Großhansdorf, Germany

Respiratory Medicine Centre, private prac., Bialystok; 🇵🇱 Bialystok, Poland

Glenfield Hospital; 🇬🇧 Leicester, United Kingdom

University of Alberta Hospital (University of Alberta); 🇨🇦 Edmonton, Alberta, Canada

Hospital del Mar; 🇪🇸 Barcelona, Spain

Hospital Vall d'Hebron; 🇪🇸 Barcelona, Spain

Institute of Tuberculosis & Lung Disease, Warsaw; 🇵🇱 Warsaw, Poland

Skånes universitetssjukhus, Lund; 🇸🇪 Lund, Sweden

Queen Elizabeth Hospital; 🇬🇧 Birmingham, United Kingdom

Konkuk University Medical Center; 🇰🇷 Seoul, Korea, Republic of

Korea University Guro Hospital; 🇰🇷 Seoul, Korea, Republic of

Hospital de Bellvitge; 🇪🇸 L'Hospitalet de Llobregat, Spain

Hospital Clínic de Barcelona; 🇪🇸 Barcelona, Spain

St. Joseph's Healthcare Hamilton; 🇨🇦 Hamilton, Ontario, Canada