1. Identify biomarkers and risk factors that associate with fibrosis progression or predict transformation into a rapid progressive (fibrosing) phenotype and acute exacerbations in IPF and FPF patients.2. Identify biomarkers and risk factors that…
ID
Source
Brief title
Condition
- Respiratory disorders congenital
- Autoimmune disorders
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Pulmonary function test.
- Inflammatory and Fibrosis Extent assessed by High-resolution Computed
Tomography (HRCT) analyzed by using artificial intelligence software.
- Biomarkers related to pulmonary fibrosis will be measured in plasma and
serum.
- Peripheral Blood Mononuclear Cell (PBMC) populations in blood.
- Exhaled breath analysis including volatile organic compounds (VOCs) analysis
by gas chromatography-mass spectrometry (GC-MS).
Secondary outcome
- Disease-relevant questionnaires.
- Genomics, epigenomics, and transcriptome analysis in blood.
- Biomarkers related to pulmonary fibrosis will be measured in bronchoalveolar
lavage fluid (BALF), if it has been collected at clinical grounds or has been
performed in the subgroups.
- Lung tissue will be analyzed with histochemical techniques if available from
clinical context e.g., diagnostic biopsies or lung explants.
- A subgroup of participants will be sampled using a ReCIVA breath analyzer
from Owlstone and using a PExA instrument from PExA.
- External exposome analyses of thephysical/chemical environment.
- Biomarkers related to pulmonary fibrosis will be measured in a 24-hour urine
collection.
- Metabolome analyses in urine and blood.
- Microbiome analyses in stool and nasal swabs.
Background summary
Interstitial Lung Disease (ILD) encompasses a heterogeneous group of lung
disorders. Patients suffering from an ILD are at risk for the development of
pulmonary fibrosis (PF). This subgroup as a whole is called fibrotic ILD (fILD)
patients. PF is characterized by excessive deposition of extracellular matrix
(ECM) by activated fibroblasts in the lungs, leading to irreversible pulmonary
function decline, respiratory failure, and eventually death in patients.
Idiopathic Pulmonary fibrosis (IPF) is the most frequent fibrotic ILD with the
worst prognosis compared to other ILDs. IPF and Familial Pulmonary Fibrosis
(FPF) exhibit comparable clinical trajectories and are treated similarly, but
treatment options are limited. Both IPF and FPF patients are at risk for the
development of acute exacerbations, which are episodes of sudden and severe
progression of the disease that appear to be irreversible (lost lung function
will not be restored). In arm 1 of this study, we aim to identify biomarkers
and risk factors that associate with fibrosis progression or can predict the
transformation into a rapidly progressive (fibrosing) phenotype and acute
exacerbations in IPF and FPF patients.
The development of progressive pulmonary fibrosis (PPF) is also frequently seen
in other forms of ILD, indicating common underlying mechanisms. Currently, the
definition of PPF is based on changes in clinical parameters over time (see
Table 1), meaning that at the time of diagnosis, loss of pulmonary function due
to irreversible fibrosis has already occurred. Consequently, the optimal timing
for initiating treatment is a subject of ongoing debate, emphasizing the
critical importance of early detection of PPF-ILD. Arm 2 of this study aims to
identify biomarkers and risk factors that can predict the development of a PPF
phenotype among various forms of fILDs, enabling early detection and
intervention.
Moreover, to get a better understanding of the development of clinically
significant (progressive) fILD, we will investigate interstitial lung
abnormalities (ILAs). ILAs are considered radiologic abnormalities that are
characteristic of early-stage ILDs and can be detected without clinical
suspicion of an ILD. It is unknown which ILAs progress to clinically relevant
ILDs with fibrosis and at what rate. Arm 3 of this study aims to identify
biomarkers and risk factors for the development of a clinically relevant fILD
in ILA patients. The results from this part of the study will contribute to the
development of monitoring strategies for ILA patients and provide further
insights into disease development.
Study objective
1. Identify biomarkers and risk factors that associate with fibrosis
progression or predict transformation into a rapid progressive (fibrosing)
phenotype and acute exacerbations in IPF and FPF patients.
2. Identify biomarkers and risk factors that predict the development of a PPF
phenotype among different forms of fILD.
3. Define biomarkers and risk factors for the development of clinically
significant fILD among ILA patients.
4. Identify biomarkers and define risk factors that might predict treatment
response within fILD (secondary objective).
Study design
Non-Interventional Prospective Observational Cohort Study
Study burden and risks
Participants will visit the clinic multiple times for the collection of
clinical data and samples. The visits of patients in arm 1 and 2 align with the
regular diagnostic path and follow-up process outlined in the ILD/IPF Care Path
Protocol of Amsterdam UMC (referred to as Zorgpad in Dutch), which can be found
in Appendix 15.1. No additional study visits are requested for these
participants. Pulmonary function tests and high-resolution Chest Tomography
(HRCT) scans obtained from routing clinical care will be used and will not be
obtained as part of the study protocol. Also immunological BALF and lung tissue
biopsies will only be collected during procedures that are necessary for
clinical care purposes. For the participants in arm 1 and 2 only minimally
invasive measurements will be obtained during routine clinical visits.
ILA participants of arm 3 will be recruited from different routes, e.g. the
Dutch thoracic radiology network, from the NVvR (in Dutch: Nederlandse
Vereniging voor Radiologie (NVvR);, Dutch Society of Radiologists), P4O2
PARASOL cohort and the national lung cancer screening protocols. ILA
individuals that are identified, will be asked to participate in the study
protocol and to align with the study visits as described. Even though these
individuals are at risk for the development of a symptomatic ILD, currently
there is no indication for clinical follow-up of these patients. The study
visits, including pulmonary function tests and yearly HRCT are an additional
burden compared to patients in arm 1 and 2, but may also show a clinical
benefit as progression to a clinically relevant ILD will be observed earlier.
Moreover, this study may provide valuable data that may provide clues for
important clinical follow-up of ILA individuals in the future. All measurements
and data collections are similar to the participants in arm 1 and 2 which also
allows for proper comparison between the different arms.
Additionally, extra measurements will be performed during one of the following
events: 1. signs of rapid progression outside the fixed time points; 2.
treatment switch; 3. lung transplantation; 4. acute exacerbation; or 5.
development of pulmonary hypertension. Again, this corresponds with extra
visits needed for standard clinical care during these events, allowing for easy
integration of the additional study measurements. Standard patient care will
not be interfered with or compromised at any time, and no (therapeutic)
interventions will be performed in the study protocol.
Next to these events we will ask two subgroups, 30 participants in arm 2 and 30
participants in arm 3, to undergo (an additional) bronchoscopy with
immunological BAL for biomarker measurements and immune cell analysis in BALF.
The 30 participants in arm 2 will be selected if a bronchoscopy with
immunological BAL was performed at baseline also. For the participants in arm 3
we will perform this procedure in the first year after recruitment. This
procedure is frequently performed in pulmonary practice and carries a small
risk of potential complications, including fever, bleeding, respiratory
depression, or pneumothorax, which occurs in less than 1% of the cases.
For all participants, the specific data collected at each time point are
described in detail in Section 3 of this protocol. In short, upon signing the
informed consent form, baseline measurements (T0) will be performed, including
the collection of clinical data, the completion of questionnaires, blood and
urine sample collection, pulmonary function tests, HRCT scans, exhaled breath
analysis, stool sample collection, and nasal brush sampling. Exposome samples,
which capture the air contents of the participants* living environments, will
be collected during two separate visits at the participants* homes,
corresponding to different seasons (spring and autumn). Whenever possible,
procedures that are already performed as part of routine clinical care, like
HRCT scans, pulmonary function tests and blood sampling, will be used to
minimize any additional burden on participants.
Pulmonary function tests and exhaled breath analysis have little to no burden,
although some participants may experience dizziness after the tests. Additional
blood samples needed for biomarker analysis usually do not pose an extra
burden, as these patients are typically monitored for clinical or
pharmacological parameters. In some cases, an additional vena puncture has to
be performed, but this procedure is generally well-tolerated by participants.
Vena punctures are also performed for clinical care and will be combined with
protocol vena punctures, with each puncture limited to 75ml per time point. To
assess quality of life, disease-relevant questionnaires will be obtained at
baseline and at 6, 12, 24, 36, 48, and 60 months. The burden of the nasal
brushes is also mild, although participants may find the procedure slightly
uncomfortable for a very short duration. Other sample collections, such as
urine, stool, and exposome sampling, require minimal effort and time from the
participant.
HRCT scans obtained in arm 3 will result in increased radiation exposure of the
participants as these or not part of standard clinical care. Radiation exposure
of an HRCT scan is however very low (5.5mSv for in- and expiration scan) which
is slightly more than two times the average annual radiation exposure per
individual in the Netherlands which is 2.6mSv (Central Organization For
Radioactive Waste [COVRA]). Clinical follow-up of ILA participants may show
clinical benefit in a subgroup of these patients leading to earlier detection
and intervention of a clinical relevant ILD.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
To be eligible to participate in this study, subjects must meet all of the
following criteria:
Arm 1
- IPF/FPF diagnosis (non-stratified) within 1 year prior to screening, based on
the guidelines set by ATS/ERS/JRS/ALAT (Raghu et al., 2022)(Zhang & Newton,
2021). A chest HRCT should have been performed within 12 months prior to
screening, meeting the minimum requirements for IPF diagnosis by
multidisciplinary consultation consensus in the ILD-expertise center based on
HRCT or HRCT and lung biopsy if available. If no HRCT is available prior to
screening, it can be performed at the screening;
- Meeting all of the following criteria during the screening period:
1. FVC >=45% predicted for normal.
2. FEV1/FVC >=0.7.
3. DLco corrected for Hb >=40% predicted of normal.
- Able to provide written informed consent as approved by the independent
ethics committee;
- Able to undergo a CT scan and perform pulmonary function testing;
- Age >18 years and <80 years;
- Understanding the Dutch or English language.
Arm 2
- Fibrotic ILD diagnosis based on the ATS/ERS/JRS/ALAT guidelines, classified
into one of the four defined subgroups (chronic/fibrotic HP, iNSIP, CTD-ILD, or
unclassifiable ILD; non-stratified)(Raghu et al., 2020; Ryerson et al., 2013;
Shao et al., 2021; Travis et al., 2013). A chest HRCT should have been
performed within 12 months prior to screening, meeting the minimum requirements
for fILD diagnosis by multidisciplinary consultation consensus in the
ILD-expertise center based on HRCT or HRCT, serologic markers (e.g.,
antibodies, biomarkers), and/or BALF/ung biopsy (if available). If no HRCT is
available prior to screening, it can be performed at the screening;
- Minimum of 10% involvement of the lung parenchyma on HRCT and signs of
fibrosis, defined as traction bronchiectasis/bronchiolectasis, lobar volume
loss, and/or honeycombing (investigator-determined);
- Meeting all of the following criteria during the screening period:
1. FVC >=45% predicted for normal.
2. FEV1/FVC >=0.7.
3. DLco corrected for Hb >=40% predicted of normal.
- Able to provide written informed consent as approved by the independent
ethics committee;
- Able to undergo a CT scan and perform pulmonary function testing;
- Age >18 years and <80 years;
- Understanding the Dutch or English language.
Criteria BAL candidates Arm 2/ f-ILD-group:
- BAL at diagnosis available;
- Progression after 1 year of follow-up;
- No contra-indications for performing BAL e.g. allergies;
- Performance of BAL is low-risk estimated by clinical physician.
Arm 3
- ILA is defined according to the current guidelines set by the Fleischner
Society (Hatabu et al., 2020). A chest HRCT should have been performed within
12 months prior to screening, meeting the minimum requirements for ILA
diagnosis by multidisciplinary consultation consensus in the ILD-expertise
center based on HRCT only or HRCT and lung biopsy if available.
- Meeting all of the following criteria during the screening period:
1. FVC >=45% predicted for normal.
2. FEV1/FVC >=0.7.
3. DLco corrected for Hb >=40% predicted of normal.
- Able to provide written informed consent as approved by the independent
ethics committee;
- Able to undergo a CT scan and perform pulmonary function testing;
- Age >18 years and <80 years;
- Understanding the Dutch or English language.
Criteria BAL candidates Arm 3/ILA-group:
- BAL at diagnosis possible;
- No contra-indications for performing BAL e.g., allergies;
- Performance of BAL is low-risk estimated by clinical physician.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
Arm 1
- Combined pulmonary fibrosis and emphysema (CPFE) is defined by the
coexistence of pulmonary fibrosis and emphysema, as described in the latest
paper by Cottin et al. (2022). To meet the criteria for CPFE on high-resolution
computed tomography (HRCT), patients must exhibit: emphysema of any subtype,
characterized by well-demarcated areas of low attenuation delimited by a very
thin wall (<1 mm) or no wall, involving at least 5% of the total lung volume
and lung fibrosis of any subtype (Cottin et al., 2022).
- Chronic obstructive lung disease (COPD) with an FEV1/FVC <70%;
- Uncontrolled severe asthma;
- Active malignancy, except for squamous cell carcinoma of the skin, low-risk
breast cancer, and low-risk prostate cancer;
- Pregnancy or lactating.
Arm 2
- Combined pulmonary fibrosis and emphysema (CPFE) is defined by the
coexistence of pulmonary fibrosis and emphysema, as described in the latest
paper by Cottin et al. (2022). To meet the criteria for CPFE on high-resolution
computed tomography (HRCT), patients must exhibit: emphysema of any subtype,
characterized by well-demarcated areas of low attenuation delimited by a very
thin wall (<1 mm) or no wall, involving at least 5% of the total lung volume
and lung fibrosis of any subtype (Cottin et al., 2022).
- Chronic obstructive lung disease (COPD) with an FEV1/FVC <70%;
- Uncontrolled severe asthma;
- Active malignancy, except for squamous cell carcinoma of the skin, low-risk
breast cancer, and low-risk prostate cancer;
- Pregnancy or lactating.
Arm 3
- Combined pulmonary fibrosis and emphysema (CPFE) is defined by the
coexistence of pulmonary fibrosis and emphysema, as described in the latest
paper by Cottin et al. (2022). To meet the criteria for CPFE on high-resolution
computed tomography (HRCT), patients must exhibit: emphysema of any subtype,
characterized by well-demarcated areas of low attenuation delimited by a very
thin wall (<1 mm) or no wall, involving at least 5% of the total lung volume
and lung fibrosis of any subtype (Cottin et al., 2022).
- Chronic obstructive lung disease (COPD) with an FEV1/FVC <70%;
- Uncontrolled severe asthma;
- Active malignancy, except for squamous cell carcinoma of the skin, low-risk
breast cancer, and low-risk prostate cancer;
- Medical history with pulmonary related auto-immune diseases;
- Family history with familial fibrosis (FPF);
- Pregnancy or lactating.
Additional exclusion criteria for the subgroups (n=60):
- In a subgroup of participants from arm 2 (n=30) and arm 3 (n=30), who undergo
an (additional) immunological bronchoalveolar lavage (iBAL) procedure,
participants with absolute contra-indications to undergo bronchoscopy with iBAL
will be excluded. Absolute-contra-indications are allergies to lidocaine,
midazolam, or xylometazoline, acute myocardial ischemia, and hemodynamic
instability in accordance with the protocol Bronchoscopy with immunological BAL
(in Dutch: Bronchoscopie met immunologische B.A.L) of the Amsterdam UMC (added
in Appendix 15.2).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL84006.018.23 |