Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01687946 |
| Other study ID # |
RESOLVE - WP2 |
| Secondary ID |
HEALTH-F4-2008-2 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
August 23, 2012 |
| Last updated |
March 15, 2016 |
| Start date |
June 2010 |
| Est. completion date |
August 2014 |
Study information
| Verified date |
March 2016 |
| Source |
Medical University of Vienna |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Austria: Ethikkommission |
| Study type |
Observational
|
Clinical Trial Summary
RESOLVE's 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.
acute/chronic 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.
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 and/or 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. RESOLVE's 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: inclusion/exclusion 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 mg/kg 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 (n=12) as defined by histopathology (assessment by two independent and
experienced pathologists not involved in the study) and/or 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 (n=12) 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
(n=12) diagnosed by histopathology, radiology and lab testing;
Group D:
(Acute HP) Patients with acute HP (n=9) 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 and/or
- Radiological signs suggestive of UIP
- No signs of widespread ground-glass opacities in CT scans
- No symptoms suggestive of chronic bronchitis/bronchiolitis, 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 and/or cytologic proof of lesions consistent with chronic HP in
transbronchial and/or 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 bronchitis/bronchiolitis, 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 and/or cytological proof of lesions consistent with acute HP in
transbronchial and biopsies and/or 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, and/or 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.
