Ignite Creation Date:
2024-05-06 @ 12:53 AM
Last Modification Date:
2024-10-26 @ 10:56 AM
Study NCT ID:
NCT01687946
Status:
COMPLETED
Last Update Posted:
2016-03-16
First Post:
2012-08-23
Brief Title:
Explorative Study on the Molecular Pathology of Lung Fibrosis by Combination of Clinical Assessment and System Biology
Sponsor:
Medical University of Vienna
Organization:
Medical University of Vienna
Study Overview
Official Title:
Pilot Investigation on the Combined Use of Established Clinical Criteria and Systems Biology for Progressive Pulmonary Fibrosis
Status:
COMPLETED
Status Verified Date:
2016-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
RESOLVEs objective is to identify and characterize validated molecular targets capable of shifting primary organ repair towards fibroproliferative wound healing
Work package 2 WP2 of RESOLVE includes the clinical study protocols within the RESOLVE system evaluating different forms of pulmonary repair in humans ranging from normal repair over mainly inflammatory to predominantly fibroproliferative repair
Hypothesis
Fibrosis of the lung is an aberrant and intensified form of wound healing It is the result of an unresolved disturbance of both initiation and control of repair which is partly age-related As a result of the relentlessly activated wound healing reaction mechanisms of inflammation largely representing the condition of chronic inflammation within the peripheral bronchial tree will aggravate this abnormal form of repair
A systematic comparison of the molecular pathology of fibrotic repair representing
Varying intensity of fibrosis related to the pathology of usual interstitial pneumonia UIP
Varying inflammatory mechanisms UIP vs Hypersensitivity pneumonitis HP acute and chronic and
Varying stages of age Normal pulmonary repair in young and old individuals vs acutechronic HP vs UIP will be able to
identify molecules capable of shifting regular repair towards fibroproliferative repair and
elucidate their interrelationship with other molecules forming coordinated yet misdirected metabolic responses characteristic for fibroproliferative repair
Work package 2 WP2 of RESOLVE includes the clinical study protocols within the RESOLVE system evaluating different forms of pulmonary repair in humans ranging from normal repair over mainly inflammatory to predominantly fibroproliferative repair
Hypothesis
Fibrosis of the lung is an aberrant and intensified form of wound healing It is the result of an unresolved disturbance of both initiation and control of repair which is partly age-related As a result of the relentlessly activated wound healing reaction mechanisms of inflammation largely representing the condition of chronic inflammation within the peripheral bronchial tree will aggravate this abnormal form of repair
A systematic comparison of the molecular pathology of fibrotic repair representing
Varying intensity of fibrosis related to the pathology of usual interstitial pneumonia UIP
Varying inflammatory mechanisms UIP vs Hypersensitivity pneumonitis HP acute and chronic and
Varying stages of age Normal pulmonary repair in young and old individuals vs acutechronic HP vs UIP will be able to
identify molecules capable of shifting regular repair towards fibroproliferative repair and
elucidate their interrelationship with other molecules forming coordinated yet misdirected metabolic responses characteristic for fibroproliferative repair
Detailed Description:
Background
After reaching adulthood the organs of the human body preserve their shape and function over a long period making directed repair one of the most important mechanisms throughout lifetime Regular wound healing after an injury consists of a well-ordered sequence of overlapping phases inflammation formation of supportive new tissue re-epithelization and final regeneration of epithelial and endothelial lining cells and essentially repeats the complex process of organ development In young adults damage to an organ is frequently answered by fully regenerative wound healing repeating mechanisms of embryonic organ growth called primary wound healing Repeated damage in younger individuals may cause secondary wound healing in form of scar formation serving as a rescue program to maintain surface integrity once epithelial andor endothelial reorganization has failed
Organ failure in the ageing organism however is different and essentially represents the loss of its capacity to achieve an orderly reactivation of organ development This different quality of wound healing consists of a combination of chronic inflammation and fibroproliferative non-regenerative repair Its pathology refers to a large group of diseases involving every organ of the human body
In the lung its most prominent form is characterized by a well-defined histopathology named usual interstitial pneumonia UIP Unfortunately this histopathology while identifying a particularly aggressive phenotype of the fibroproliferative repair response itself does not allow for an unambiguous clinical diagnosis as the UIP pattern may be found in different fibrotic diseases of the lung such as hypersensitivity pneumonitis HP especially in its chronic form
In addition various mechanisms of inflammation which are partly related to the wound healing response itself may profoundly intensify the aberrant wound healing response As a result the mechanisms leading to this condition and maintaining its characteristic clinical appearance are unknown
The current investigation belongs to the work package 2 of the RESOLVE study system FP7-HEALTH-F4-2008 Contract no 202047 which contains the clinical study protocol evaluating different forms of fibrotic repair in the human lung RESOLVEs main objective is to identify and characterize clinically validated molecular targets capable of shifting primary organ repair towards fibroproliferative wound healing In this pilot study different forms of repair of the lung will be prospectively analyzed by means of a concomitant clinical and biological analysis guided by evaluated functional and radiological measures of clinical development The assessments will be made at the beginning of the study period visit 1 after three months of prospective observation visit 2 and after 12 months end of study allowing for a clinically relevant correlation of all biological data obtained
Three general conditions of repair will be chosen for systematic biological analysis as a result of their clinical diagnosis histopathology radiology and their association with age
Usual interstitial pneumonia UIP occurring almost exclusively at an age of 55-80 years
Hypersensitivity Pneumonitis HP both acute and chronic occurring at an age of 20-55 years and
Normal repair in young 18-40 years and old older than 55 years individuals
Methods
After securing the diagnosis see below inclusionexclusion criteria and following informed consent during the screening visit patients lacking any previous immunosuppressive treatment therapy-naïve patients will receive an immunosuppressive therapy with prednisolone daily dose of 1 mgkg BW for at least three months in order to exclude pathologies dominated by mechanisms of inflammation During the screening visit the results of the histopathological analysis will be secured and the clinical and functional history of the disease recorded This will include previous medication the results of previous pulmonary function tests PFT as well as the results of radiological analysis computed tomography including HR-CT and lab testing excluding collagen vascular disease and securing HP serology
Three months after the screening visit at visit 1 the functional and radiological stage of the pulmonary fibrosis will be assessed again and the patients will be finally enrolled into the study In accordance with the findings obtained at the screening visit and due to the functional and radiological results obtained at visit 1 the patients will be stratified into the following investigational groups
Group A
Limited UIP Patients with proven UIP and functionally and radiologically less advanced pulmonary fibrosis n12 as defined by histopathology assessment by two independent and experienced pathologists not involved in the study andor radiology computed tomography CT scans incl high-resolution CT independently assessed by an experienced radiologist not involved in the study and pulmonary function tests PFT PFT will consist of spirometry measurement with bodyplethysmograph single-breath measurement of carbon monoxide diffusion capacity and full cardiopulmonary exercise testing including assessment of pulmonary ventilation and gas exchange at rest and on exertion
Group B
Advanced UIP Patients with proven UIP n12 in a significantly more advanced stage of the disease as determined by PFT FVC at least 10 percent and DLCO at least 15 percent lower than in group A and CT scan
Group C
Chronic fibrosing Hypersensitivity Pneumonitis HP Patients with chronic fibrosing HP n12 diagnosed by histopathology radiology and lab testing
Group D
Acute HP Patients with acute HP n9 diagnosed by histopathology radiology and lab testing Group D acute HP
Group E
Regular Pulmonary Repair 9 young 18-40 years of age without any clinically evident pathology and 9 old volunteers 55-80 years of age without pulmonary fibrosis will serve as controls
All patients with UIP and HP will be followed during for a study period of 12 months The study period starts with visit 1 In addition to visit 1 two additional visits will be performed after 3 months visit 2 functional assessment and after 12 months visit 3 end of study
At all three visits the following investigations will be performed
Clinical examination
ECG
PFT
Cardiopulmonary exercise test
Blood drawing
CT scan
Bronchoscopy with removal of 5 transbronchial biopsies for biological assessment from areas suggesting maximum disease activity in the CT scan will only be performed at visits 1 and 3
Relevant inclusion criteria applying to Group A limited UIP
Informed consent
Histologic proof of lesions consistent with UIP in surgical lung biopsies andor
Radiological signs suggestive of UIP
No signs of widespread ground-glass opacities in CT scans
No symptoms suggestive of chronic bronchitisbronchiolitis such as coughing and signs of bronchial obstruction or hyperinflation
Difference of forced expiratory vital capacity FVC values 10 predicted to normal
Difference of carbon monoxide diffusion capacity DLCO at rest of 15 predicted to normal
Previous or current treatment with immunosuppressive drugs
Relevant inclusion criteria applying to Group B advanced UIP other than Group A
Signs of widespread ground glass opacities in CT scans
Symptoms suggestive of chronic bronchitis such as coughing and signs of bronchial obstruction or hyperinflation may be present
Forced expiratory vital capacity FVC values in difference 10 predicted to normal
Reduction of carbon monoxide diffusion capacity DLCO at rest of 15 predicted
Relevant inclusion criteria applying to Group C
Informed consent
Histologic andor cytologic proof of lesions consistent with chronic HP in transbronchial andor surgical lung biopsies transbronchial biopsies or bronchoalveolar lavage BAL samples
Radiological signs suggestive of chronic HP
Signs of widespread ground glass opacities in CT scans
Symptoms suggestive of active bronchitisbronchiolitis such as coughing and signs of bronchial obstruction or hyperinflation may be present
Serological proof of hypersensitivity if possible
Forced expiratory vital capacity FVC values in difference 10 predicted to normal
Reduction of carbon monoxide diffusion capacity DLCO at rest of 15 predicted
Previous or current treatment with immunosuppressive drugs
Relevant inclusion criteria applying to Group D other than Group C
Informed consent
Histologic andor cytological proof of lesions consistent with acute HP in transbronchial and biopsies andor bronchoalveolar lavage BAL samples
Radiological signs suggestive of acute HP
General exclusion criteria
Functionally significant cardiovascular morbidity
Respiratory insufficiency PaO2 55 mmHg PaCO2 50 mmHg
Significant pulmonary hypertension
Significant pulmonary emphysema
Non-functional contralateral lung
Cancer
Significant coronary heart disease
Coagulation dysfunction
Pregnancy or planning pregnancy during the trial or within three month period thereafter
Known drug or alcohol abuse within 3 years of screening
Presumed non-compliance
Known legal incapacity or limited legal capacity at screening
Biopsies
The lung specimens for biological analysis will be derived from both diagnostic surgical lung biopsies and transbronchial lung biopsies taken during the bronchoscopies performed at visit 1 and 3 In total five transbronchial biopsies will be taken at each visit for biological analysis All transbronchial lung specimens will be removed under radiologic control from peripheral lung areas previously specified in accordance with the latest CT scan The biopsies taken at visit 3 will be performed in the same lung segment as those taken at visit 1
Except for the results of the latest CT scan the investigator performing the bronchoscopy will be blinded for all clinical results obtained during the visits
Molecular Biology Assessment
Biological analysis will be independently performed All investigators involved in biological analysis will be blinded for diagnosis and clinical course of the patients and volunteers The participants will be solely identifiable by their study identification number ID The study samples will be numbered according to patient ID and sample description provided by the LIMS Biologic assessment will include measurement of whole genome transcriptomics protein analysis by mass spectrometry and EIA analysis of DNA methylation status and microRNA analysis The measurements will be based on lung specimens derived from diagnostic surgical lung biopsies if possible andor from transbronchial biopsies TbX taken during a bronchoscopy at visit 1 and 3 of the study month 0 and month 12 In addition BAL fluid will be stored and used for detection of proteins and lipids Materials for DNA methylation analysis will be obtained from both lung tissue and whole blood samples
After reaching adulthood the organs of the human body preserve their shape and function over a long period making directed repair one of the most important mechanisms throughout lifetime Regular wound healing after an injury consists of a well-ordered sequence of overlapping phases inflammation formation of supportive new tissue re-epithelization and final regeneration of epithelial and endothelial lining cells and essentially repeats the complex process of organ development In young adults damage to an organ is frequently answered by fully regenerative wound healing repeating mechanisms of embryonic organ growth called primary wound healing Repeated damage in younger individuals may cause secondary wound healing in form of scar formation serving as a rescue program to maintain surface integrity once epithelial andor endothelial reorganization has failed
Organ failure in the ageing organism however is different and essentially represents the loss of its capacity to achieve an orderly reactivation of organ development This different quality of wound healing consists of a combination of chronic inflammation and fibroproliferative non-regenerative repair Its pathology refers to a large group of diseases involving every organ of the human body
In the lung its most prominent form is characterized by a well-defined histopathology named usual interstitial pneumonia UIP Unfortunately this histopathology while identifying a particularly aggressive phenotype of the fibroproliferative repair response itself does not allow for an unambiguous clinical diagnosis as the UIP pattern may be found in different fibrotic diseases of the lung such as hypersensitivity pneumonitis HP especially in its chronic form
In addition various mechanisms of inflammation which are partly related to the wound healing response itself may profoundly intensify the aberrant wound healing response As a result the mechanisms leading to this condition and maintaining its characteristic clinical appearance are unknown
The current investigation belongs to the work package 2 of the RESOLVE study system FP7-HEALTH-F4-2008 Contract no 202047 which contains the clinical study protocol evaluating different forms of fibrotic repair in the human lung RESOLVEs main objective is to identify and characterize clinically validated molecular targets capable of shifting primary organ repair towards fibroproliferative wound healing In this pilot study different forms of repair of the lung will be prospectively analyzed by means of a concomitant clinical and biological analysis guided by evaluated functional and radiological measures of clinical development The assessments will be made at the beginning of the study period visit 1 after three months of prospective observation visit 2 and after 12 months end of study allowing for a clinically relevant correlation of all biological data obtained
Three general conditions of repair will be chosen for systematic biological analysis as a result of their clinical diagnosis histopathology radiology and their association with age
Usual interstitial pneumonia UIP occurring almost exclusively at an age of 55-80 years
Hypersensitivity Pneumonitis HP both acute and chronic occurring at an age of 20-55 years and
Normal repair in young 18-40 years and old older than 55 years individuals
Methods
After securing the diagnosis see below inclusionexclusion criteria and following informed consent during the screening visit patients lacking any previous immunosuppressive treatment therapy-naïve patients will receive an immunosuppressive therapy with prednisolone daily dose of 1 mgkg BW for at least three months in order to exclude pathologies dominated by mechanisms of inflammation During the screening visit the results of the histopathological analysis will be secured and the clinical and functional history of the disease recorded This will include previous medication the results of previous pulmonary function tests PFT as well as the results of radiological analysis computed tomography including HR-CT and lab testing excluding collagen vascular disease and securing HP serology
Three months after the screening visit at visit 1 the functional and radiological stage of the pulmonary fibrosis will be assessed again and the patients will be finally enrolled into the study In accordance with the findings obtained at the screening visit and due to the functional and radiological results obtained at visit 1 the patients will be stratified into the following investigational groups
Group A
Limited UIP Patients with proven UIP and functionally and radiologically less advanced pulmonary fibrosis n12 as defined by histopathology assessment by two independent and experienced pathologists not involved in the study andor radiology computed tomography CT scans incl high-resolution CT independently assessed by an experienced radiologist not involved in the study and pulmonary function tests PFT PFT will consist of spirometry measurement with bodyplethysmograph single-breath measurement of carbon monoxide diffusion capacity and full cardiopulmonary exercise testing including assessment of pulmonary ventilation and gas exchange at rest and on exertion
Group B
Advanced UIP Patients with proven UIP n12 in a significantly more advanced stage of the disease as determined by PFT FVC at least 10 percent and DLCO at least 15 percent lower than in group A and CT scan
Group C
Chronic fibrosing Hypersensitivity Pneumonitis HP Patients with chronic fibrosing HP n12 diagnosed by histopathology radiology and lab testing
Group D
Acute HP Patients with acute HP n9 diagnosed by histopathology radiology and lab testing Group D acute HP
Group E
Regular Pulmonary Repair 9 young 18-40 years of age without any clinically evident pathology and 9 old volunteers 55-80 years of age without pulmonary fibrosis will serve as controls
All patients with UIP and HP will be followed during for a study period of 12 months The study period starts with visit 1 In addition to visit 1 two additional visits will be performed after 3 months visit 2 functional assessment and after 12 months visit 3 end of study
At all three visits the following investigations will be performed
Clinical examination
ECG
PFT
Cardiopulmonary exercise test
Blood drawing
CT scan
Bronchoscopy with removal of 5 transbronchial biopsies for biological assessment from areas suggesting maximum disease activity in the CT scan will only be performed at visits 1 and 3
Relevant inclusion criteria applying to Group A limited UIP
Informed consent
Histologic proof of lesions consistent with UIP in surgical lung biopsies andor
Radiological signs suggestive of UIP
No signs of widespread ground-glass opacities in CT scans
No symptoms suggestive of chronic bronchitisbronchiolitis such as coughing and signs of bronchial obstruction or hyperinflation
Difference of forced expiratory vital capacity FVC values 10 predicted to normal
Difference of carbon monoxide diffusion capacity DLCO at rest of 15 predicted to normal
Previous or current treatment with immunosuppressive drugs
Relevant inclusion criteria applying to Group B advanced UIP other than Group A
Signs of widespread ground glass opacities in CT scans
Symptoms suggestive of chronic bronchitis such as coughing and signs of bronchial obstruction or hyperinflation may be present
Forced expiratory vital capacity FVC values in difference 10 predicted to normal
Reduction of carbon monoxide diffusion capacity DLCO at rest of 15 predicted
Relevant inclusion criteria applying to Group C
Informed consent
Histologic andor cytologic proof of lesions consistent with chronic HP in transbronchial andor surgical lung biopsies transbronchial biopsies or bronchoalveolar lavage BAL samples
Radiological signs suggestive of chronic HP
Signs of widespread ground glass opacities in CT scans
Symptoms suggestive of active bronchitisbronchiolitis such as coughing and signs of bronchial obstruction or hyperinflation may be present
Serological proof of hypersensitivity if possible
Forced expiratory vital capacity FVC values in difference 10 predicted to normal
Reduction of carbon monoxide diffusion capacity DLCO at rest of 15 predicted
Previous or current treatment with immunosuppressive drugs
Relevant inclusion criteria applying to Group D other than Group C
Informed consent
Histologic andor cytological proof of lesions consistent with acute HP in transbronchial and biopsies andor bronchoalveolar lavage BAL samples
Radiological signs suggestive of acute HP
General exclusion criteria
Functionally significant cardiovascular morbidity
Respiratory insufficiency PaO2 55 mmHg PaCO2 50 mmHg
Significant pulmonary hypertension
Significant pulmonary emphysema
Non-functional contralateral lung
Cancer
Significant coronary heart disease
Coagulation dysfunction
Pregnancy or planning pregnancy during the trial or within three month period thereafter
Known drug or alcohol abuse within 3 years of screening
Presumed non-compliance
Known legal incapacity or limited legal capacity at screening
Biopsies
The lung specimens for biological analysis will be derived from both diagnostic surgical lung biopsies and transbronchial lung biopsies taken during the bronchoscopies performed at visit 1 and 3 In total five transbronchial biopsies will be taken at each visit for biological analysis All transbronchial lung specimens will be removed under radiologic control from peripheral lung areas previously specified in accordance with the latest CT scan The biopsies taken at visit 3 will be performed in the same lung segment as those taken at visit 1
Except for the results of the latest CT scan the investigator performing the bronchoscopy will be blinded for all clinical results obtained during the visits
Molecular Biology Assessment
Biological analysis will be independently performed All investigators involved in biological analysis will be blinded for diagnosis and clinical course of the patients and volunteers The participants will be solely identifiable by their study identification number ID The study samples will be numbered according to patient ID and sample description provided by the LIMS Biologic assessment will include measurement of whole genome transcriptomics protein analysis by mass spectrometry and EIA analysis of DNA methylation status and microRNA analysis The measurements will be based on lung specimens derived from diagnostic surgical lung biopsies if possible andor from transbronchial biopsies TbX taken during a bronchoscopy at visit 1 and 3 of the study month 0 and month 12 In addition BAL fluid will be stored and used for detection of proteins and lipids Materials for DNA methylation analysis will be obtained from both lung tissue and whole blood samples
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| HEALTH-F4-2008-202047 | OTHER_GRANT | EC FP7 Health - Research Grant number HEALTH-F4-2008-202047 | None |