Precision Diagnosis and Care for Families With Pulmonary Fibrosis in Ireland

Official title

Precision Diagnosis and Care for Families With Pulmonary Fibrosis in Ireland [PRECISE-PF]

Overview

This study aims to improve the understanding of how genes and the environment can influence and cause pulmonary fibrosis. By identifying the presence of genes and other factors that can put people at risk of developing pulmonary fibrosis, the influence these factors have on the progression of the disease can be studied. Interstitial lung disease (ILD) is the medical term given to a group of lung diseases affecting the same part of the lung, the interstitium, each with similar symptoms. In some of these diseases, inflammation leads to lung scarring, known as fibrosis. Idiopathic Pulmonary Fibrosis (IPF) is one of these diseases; it has a particular pattern on computed tomography (CT) scans. IPF is 'idiopathic' as it is not yet fully understood why it happens. It has a poor prognosis. The average survival time is three to five years after diagnosis. While new antifibrotic drugs offer hope of slowing disease progression, lung transplant is the only cure, and it comes with its significant risks. Although it is not fully understood what causes IPF, it is known that genetic factors significantly increase the risk of developing the disease. Up to a quarter (25%) of people with IPF with a family history appear to have a causative genetic variant. Familial-pulmonary-fibrosis (FPF), the term for people with at least one relative with IPF, may have worse disease when compared to those without a family history. However, this needs more research. Patients with specific genes, telomere-related gene variants, appear to have a greater risk of developing blood disorders from medications given to suppress the body's immune system after a lung transplant. Progressive pulmonary fibrosis is pulmonary fibrosis where there is irreversible worsening of the disease, worsening of lung function, respiratory symptoms and even early death. It is of growing importance regardless of the cause, whether it be idiopathic, familial or secondary to a connective tissue disease. ILD is increasingly recognised as a complication of connective tissue diseases. It is the leading cause of death in people with systemic sclerosis. The new antifibrotic drugs slow the progression of CTD-ILD. People with progressive pulmonary fibrosis who have a greater than 10% drop over one year in a measure of their lung function, called the forced vital capacity, benefit most from antifibrotic therapy. Early identification of people with progressive disease would allow the commencement of treatment quicker. At-home spirometry may be a way of identifying those who are worsening early. This study hypothesises that by improving knowledge of factors that affect disease behaviour and progression and assessing tools for the early identification of progressive disease, such as at-home spirometry and CT scan pattern determination by deep-learning analysis, we can provide 'precision' diagnosis and treatment. It is hoped that this improved understanding will help reduce the clinical risk for people with pulmonary fibrosis and their families. This study aims to recruit 300 patients: 100 with IPF, 100 with FPF, and 100 with CTD ILD. Each participant will be followed for one year. This observational study aims to help answer a number of questions: 1. What genetic variants cause people to develop ILD, and which increase a person's risk of developing ILD are present in the study population? 2. How does pulmonary fibrosis behave in people who have a family history of IPF compared to those who do not and in people with CTD-ILD? 3. Are different types of pulmonary fibrosis more progressive than others i.e. Is pulmonary fibrosis in those with a family history of pulmonary fibrosis more progressive than in those who do not have a family history? 4. Is the disease in those with a genetic variant known to cause ILD worse than in those who don't have a gene? 5. Can at-home spirometry help identify people at risk of progressive disease early? 6. Can deep-learning analysis (AI) be used to find CT scan patterns to predict when pulmonary fibrosis will worsen?

Interventions

• Diagnostic test Six minute walk test (6MWT)
  Assessment of exercise capacity by the carrying out of a 6MWT at 0, 6 and 12 months.
• Diagnostic test Computer-tomography of the thorax (CT Thorax)
  Radiological assessment via CT Thorax, preferably high-resolution CT thorax at baseline on entering the study and at one year. CT images will be collected on study end. CT images in all subjects will be evaluated by three readers blinded to any other interpretation and conforming to ATS-guidelines. Coded data from CT scans will be shared with our collaborator Professor Simon Walsh at Imperial College, London who will use computational methods to identify novel radiologic phenotypes linked to dis
• Other Quality of life questionnaires.
  Qality of life questionnaires including; modified Medical Research Council (mMRC) dyspnea scale, The King's Brief Interstitial Lung Disease Questionnaire (KBILD), The Leister Cough Questionnaire and the EQ-5D-3L questionnaire are measured at 0, 6 and 12 months
• Diagnostic test Genetic Testing
  10ml of serum will be collected for DNA extraction and analysed for causative and at risk genetic mutations
• Diagnostic test Spirometry
  We will carry out spirometry at baseline, 6 and 2 months including forced vital capacity and diffusing capacity of the lungs for carbon monoxide.
• Diagnostic test Serology
  Serology which may indicate an underlying diagnosis of ILD will be carried out on study entry. This will include a full blood count, renal profile, liver profile, C-reactive protein, creatine kinase, erythrocyte sedimentation rate, antinuclear antibodies, anticyclic citrullinated peptide antibodies, rheumatoid factor, an extended myositis antibody panel, sjögren's antibodies, scleroderma antibodies and a hypersensivity pneumonitis panel if clinically indicated.
• Other Other Quality of Life Questionnaires
  Patient Global Assessment and Clinician Global Assessment scores completed at 0, 6 and 12 months
• Other PatientMPower Home Monitoring App
  Continuous at home monitoring of patients using home-based digital spirometry and pulse-oximetry with real-time feedback readings to patient and clinician. Smartphone app for patients, spirometer and pulse oximeter are connected to the app via Bluetooth. Patients are asked to take 2 readings per week.

Primary outcome measures

• Determine if familial-pulmonary-fibrosis is more progressive than sporadic-IPF [Time frame: 12-months of entering the study]

Secondary outcome measures (8)

• All-cause mortality [Time frame: Time of censoring or 12 months]
• Identify genotypes present in our study population [Time frame: Within first 6 months of study recruitment]
• Change in quality of life scores from baseline to 1 year [Time frame: From date of study entry (baseline) until 12-month-assessment questionnaire completed, 12 months]
• Change in 6MWT from baseline to 1 year [Time frame: On entry to study (baseline) to end of observation period (12 months)]
• Change in pulmonary function tests from baseline to 1 year [Time frame: Baseline (0 months) to 12 month follow-up]
• Changes and patterns in at home-spirometry with the patientMpower App [Time frame: 12 Months]
• Change in HRCT scan [Time frame: 12 months]
• Identify radiological phenotypes linked to disease behavior in pulmonary fibrosis [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Able and willing to give written informed consent.
• An MDT diagnosis of fibrotic ILD which fall into one of the following three catagories;

• Have a multidisciplinary team (MDT) diagnosis of a fibrotic interstitial lung disease, reporting one or more relatives with a fibrotic form of ILD
• Have a MDT diagnosis of IPF in accordance with consensus criteria, ATS, ERS, JRS, ALAT guidelines without a family history of pulmonary fibrosis.
• Meet the American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis, scleroderma, Sjogren's syndrome, idiopathic inflammatory myopathy and systemic lupus erythematosus.

Exclusion criteria

• Currently participating in an interventional clinic trial.
• Change in clinical phenotype from initial radiological diagnosis to screening.
• Acute or chronic hypersensitivity pneumonitis with consensus criteria (appropriate exposure history, radiological features ± avian and fungal precipitins).
• Asbestosis (appropriate occupational history and radiological evidence of asbestos exposure)
• Life expectancy for any disease, including ILD <12 months (investigator assessment)
• Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Ireland · 1 center

• Beaumont Hospital — Dublin

Publications

• Peljto AL, Blumhagen RZ, Walts AD, Cardwell J, Powers J, Corte TJ, Dickinson JL, Glaspole I, Moodley YP, Vasakova MK, Bendstrup E, Davidsen JR, Borie R, Crestani B, Dieude P, Bonella F, Costabel U, Gudmundsson G, Donnelly SC, Egan J, Henry MT, Keane MP, Kennedy MP, McCarthy C, McElroy AN, Olaniyi JA, O'Reilly KMA, Richeldi L, Leone PM, Poletti V, Puppo F, Tomassetti S, Luzzi V, Kokturk N, Mogulkoc PMID 36602845
• Zhang D, Newton CA. Familial Pulmonary Fibrosis: Genetic Features and Clinical Implications. Chest. 2021 Nov;160(5):1764-1773. doi: 10.1016/j.chest.2021.06.037. Epub 2021 Jun 26. PMID 34186035
• Cutting CC, Bowman WS, Dao N, Pugashetti JV, Garcia CK, Oldham JM, Newton CA. Family History of Pulmonary Fibrosis Predicts Worse Survival in Patients With Interstitial Lung Disease. Chest. 2021 May;159(5):1913-1921. doi: 10.1016/j.chest.2021.01.026. Epub 2021 Jan 21. PMID 33484728
• Borie R, Kannengiesser C, Hirschi S, Le Pavec J, Mal H, Bergot E, Jouneau S, Naccache JM, Revy P, Boutboul D, Peffault de la Tour R, Wemeau-Stervinou L, Philit F, Cordier JF, Thabut G, Crestani B, Cottin V; Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P). Severe hematologic complications after lung transplantation in patients with telomerase complex mutations. PMID 25612863
• Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Muller-Ladner U, Distler O, Iannone F, Pellerito R, Pileckyte M, Miniati I, Ananieva L, Gurman AB, Damjanov N, Mueller A, Valentini G, Riemekasten G, Tikly M, Hummers L, Henriques MJ, Caramaschi P, Scheja A, Rozman B, Ton E, Kumanovics G, Coleiro B, Feierl E, Szucs G, Von Muhlen CA, Riccieri V, Novak S, Chizzolini PMID 20551155
• Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, Fogarty A, Hubbard RB. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax. 2011 Jun;66(6):462-7. doi: 10.1136/thx.2010.148031. Epub 2011 Apr 27. PMID 21525528
• Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, Raghu G, Sauter W, Girard M, Alves M, Clerisme-Beaty E, Stowasser S, Tetzlaff K, Kuwana M, Maher TM; SENSCIS Trial Investigators. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med. 2019 Jun 27;380(26):2518-2528. doi: 10.1056/NEJMoa1903076. Epub 2019 May 20. PMID 31112379
• Yang M, Wu Y, Liu X, Zhao C, Li T, Li T, Zhang X, Jiang H, Mao B, Liu W. Efficacy and safety of antifibrotic agents in the treatment of CTD-ILD and RA-ILD: A systematic review and meta-analysis. Respir Med. 2023 Sep;216:107329. doi: 10.1016/j.rmed.2023.107329. Epub 2023 Jun 12. PMID 37315742

Identifiers

NCT: NCT06702228 · PRECISE-PF

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗