The Edinburgh Lung Fibrosis Molecular Endotyping (ELFMEN) Study (ELFMEN)

To prospectively study novel blood and lung biomarkers of disease activity in patients with IPF and other interstitial lung disease with the aims of prognostic modelling and disease clustering

Study Overview

• Status: Unknown
• Conditions: Idiopathic Pulmonary Fibrosis; Interstitial Lung Disease; Asbestosis

Detailed Description

BACKGROUND

Idiopathic pulmonary fibrosis (IPF) is a progressive form of lung scarring for which there is no proven treatment. Steroids and other potentially toxic drugs are often used but their efficacy is uncertain. The management of patients with IPF is particularly complex because firstly there are a number of closely related fibrosing lung conditions that 'look' like IPF but in which the prognosis is generally better and which more often respond to steroids and secondly even within the group of patients with IPF, there is a variability in the rate of progression so that it is hard to provide individual patients with a reasonable estimate of prognosis.

Currently the best the investigators can offer patients with IPF or probable IPF is serial measurement of lung function over time and observation of decline. The uncertainty regarding disease prognosis and progression in a given patient is hugely unsettling for both the individual and the clinician. A far more powerful tool would be a measurement or 'biomarker' of disease activity that one could monitor from the time of diagnosis and throughout the illness and which predicted for decline in lung function or poor prognosis. This biomarker (or biomarkers) might include molecules associated with inflammation and scarring in blood or in lung fluid, new more sensitive measures of lung function (e.g. the six-minute walking test) or novel non-invasive imaging methods. Once established, a robust biomarker would serve several important functions including:

1. A means of distinguishing definite IPF from other closely related conditions;
2. Categorisation of individuals with IPF into 'good' and 'poor' prognosis
3. Identifying targets for potential new therapies in IPF

4. A marker of disease response to drugs used in therapeutic trials in IPF.

   AIMS To prospectively study novel blood and lung biomarkers of disease activity in patients with IPF and other interstitial lung disease

   STUDY DESIGN Inclusion criteria Patients attending or referred to the Edinburgh Royal Infirmary and the Western General Hospital lung fibrosis clinics with a diagnosis of definite or probable idiopathic pulmonary fibrosis. For comparison patients with other idiopathic interstitial pneumonias, hypersensitivity pneumonitis, asbestosis or interstitial lung disease associated with connective tissue diseases will also be recruited since these conditions often have a similar clinical presentation to IPF but a more variable prognosis. All clinical details for these patients are already being collated in a REC-approved clinical database (REC 06/S0703/53). Patients aged 18 through 99 years, inclusive.

   Exclusion criteria and restrictions Candidates not a suitable for enrolment or unlikely to comply with the requirements of this study, in the opinion of the investigator, will be excluded.

   The biomarkers will include assays that test the activity of circulating blood inflammatory cells in laboratory conditions. A relatively large volume of blood (up to 80ml a time) is required to purify sufficient numbers of these inflammatory cells for use in laboratory studies. It is anticipated however that as data is gathered, subsequent experiments can be refined such that less blood is required.

   No more than 320ml of blood over a 12 month period will be taken from any study participant for research purposes. No more than 100ml of blood over a twelve month period will be taken from any study participant with a moderate or severe anaemia, defined as a haemoglobin >10% below lower limit of normal. Anaemia is not a recognised complication of idiopathic pulmonary fibrosis.

   Participants that are deemed unsuitable for bronchoscopy, based on established national and local guidelines, will be excluded from this aspect of the study.

   WHAT WILL HAPPEN TO THE RESEARCH PARTICIPANTS

   * indicates routine clinical investigations performed on all patients with IPF or other interstitial lung disease

   • indicates study investigations, some of which are may performed as part of routine clinical care

   Within 1 month of presentation or recruitment to the study participants will undergo:

   *Blood samples for routine biochemistry, haematology, auto-immune screen and other clinically relevant tests

   *Full lung function tests and incremental walking test

   *HRCT scan

   •Bronchoalveolar lavage (BAL) - note that this may be performed for clinical diagnostic indications in many patients with suspected IPF.

   •Blood sample for biomarkers (average 40ml, not >80ml)

   At 3 months following recruitment participants will undergo:

   *Blood sample for biomarkers (average 40ml, not >80ml)

   At 6 months following recruitment participants will undergo:

   • Blood sample for biomarkers (average 40ml, not >80ml)

   At 9 months following recruitment participants will undergo:

   •Blood sample for biomarkers (average 40ml, not >80ml)

   At 12 months following recruitment participants will undergo:

   •Bronchoalveolar lavage

   •Blood sample for biomarkers (average 40ml, not >80ml)

   Thereafter repeated every 6 months for up to 3 years, participants will undergo:

   •Blood sample for biomarkers (average 40ml, not >80ml)

   In patients that have a lung biopsy for clinical indications, resected lung tissue that is deemed not critical to the diagnostic process by pathologist i.e. excess fresh tissue, will be used for research purposes. To ensure this is safely achieved, excess lung tissue will stored and not used for research until the pathologist has confirmed that available material is sufficient for clinical purposes. In practice, this means a sample of fresh tissue form the 'staple' margins of the resected specimen. Formalin fixed archived tissue from subjects will be included for use in this study. This protocol was used in a previous ethically approved study (09/S1101/52, Molecular markers of hypoxia, cell injury and fibrosis in lung tissue. This study ended 31/3/15 having collected 40 consecutive fresh lung fibrosis specimens without incident.

   STUDY OUTCOMES (see endpoints) Identification of prognostics biomarkers in all entities of ILD including IPF that define disease progression and death Identification of novel disease entity clusters define by clinical, imaging and molecular features

• Study Type: Observational
• Enrollment (Actual): 800

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with all entities of interstitial lung disease

Description

Inclusion Criteria:

• patients with interstitial lung disease attending the Edinburgh Lung Fibrosis service

Exclusion Criteria:

• candidates not a suitable for enrolment or unlikely to comply with the requirements of this study, in the opinion of the investigator, will be excluded.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to death (all cause)	Biomarkers that are associated with increased all-cause mortality	15 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of decline in vital capacity	Biomarkers that are associated with increased rate of decline in vital capacity (VC)	15 years
Time to death (lung-related)	Biomarkers that are associated with increased lung-related mortality	15 years
Rate of decline in TLCO	Biomarkers that predict rate of change in gas transfer (TLCO)	15 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of novel disease clusters	Identification of discrete disease entities based on clinical, imaging and molecular data	15 years
Time to oxygen prescription	Biomarkers that are associated with reduced time to prescription of long term oxygen	15 years

Collaborators and Investigators

• Sponsor: University of Edinburgh

Publications and helpful links

General Publications

• Allen RJ, Stockwell A, Oldham JM, Guillen-Guio B, Schwartz DA, Maher TM, Flores C, Noth I, Yaspan BL, Jenkins RG, Wain LV; International IPF Genetics Consortium. Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis. Thorax. 2022 Aug;77(8):829-833. doi: 10.1136/thoraxjnl-2021-218577. Epub 2022 Jun 10.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2007
• Primary Completion (Anticipated): March 31, 2022
• Study Completion (Anticipated): January 1, 2023

Study Registration Dates

• First Submitted: March 29, 2019
• First Submitted That Met QC Criteria: July 10, 2019
• First Posted (Actual): July 11, 2019

Study Record Updates

• Last Update Posted (Actual): July 11, 2019
• Last Update Submitted That Met QC Criteria: July 10, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Occupational Diseases; Pneumoconiosis; Lung Injury; Fibrosis; Lung Diseases; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Asbestosis
• Other Study ID Numbers: 07/S1102/20; 2007/R/RES/02 (Other Identifier: University of Edinburgh and NHS Lothian)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: sharing of individual participant data will be determined on a case-by-case basis contingent of data security governance

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No