Clinical trial NCT06323876: The Role of Quantitative CT and Radiomic Biomarkers for Precision Medicine in Pulmonary Fibrosis
Official title: The Role of Quantitative CT and Radiomic Biomarkers for Precision Medicine in Pulmonary Fibrosis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: CT
biomarkers
gene expression
radiomic markers
Lead sponsor: University of Virginia
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2024-03-21
Enrollment: 160
Sex: ALL
Minimum age (years): 40
Maximum age (years): 101
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients diagnosed with Pulmonary Fibrosis as described above in inclusion criteria.

Brief summary: This observational study involves obtaining 2 chest CT scans; a historical baseline CT within ±1 year of enrollment into PRECISIONS, and a follow-up CT (either historical or prospective) 12 months ± 180 days after the baseline CT. Many IPF patients will have a CT scan every 12 months for disease monitoring and cancer screening. Participants will have the option to share historical CTs only or they can choose to have a research CT done for the follow-up scan, if a scan for clinical purposes is not available.

Detailed description: Idiopathic pulmonary fibrosis (IPF) remains deadly despite two FDA-approved therapies. Forced vital capacity (FVC), a one-dimensional assessment of lung function that requires three effort-dependent and error-prone maneuvers, is the standard for evaluating disease severity and monitoring progression. FVC indirectly measures disease activity and is thus insensitive to subtle change. These limitations hamper therapeutic trials. The Gender, Age, and Physiology (GAP) score improves on FVC alone and is the most used scoring model for prognostication, but gender and age aren't influenced by treatment. Modifiable intermediate molecular markers and other metrics for assessing disease severity and progression remain unmet needs for aiding drug development and clinical decision-making. Computed tomography (CT) captures morphologic patterns and the extent of fibrosis noninvasively. Advances in quantitative CT enable objective detection and quantitation of anatomy, and highly dimensional image features, often termed radiomic, can identify sub-visual characteristics. The investigators seek to evaluate radiomic features alone and in conjunction with other disease dimensions for prognostication and response to treatment in IPF.

The investigators overall objectives are to identify and validate radiologic features, such as total extent of lung fibrosis, for disease activity and intermediate response to therapy, and understand where to position these powerful markers. The investigators hypothesize that DTA scores will contribute to prediction of disease progression and that molecular markers will enhance that performance.

Aim 1: The investigators will validate quantitative CT and radiomic markers for disease progression by independent replication in separate cohorts. The investigators hypothesize that quantitative CT markers will predict disease progression in UVA/Chicago cohorts. Baseline and subsequent CT scans have been voluntarily collected in many PFF-PR cases. The investigators propose collection of 1-year HRCTs in UVA/Chicago participants to evaluate: a) the prognostic value of baseline quantitative CT and radiomic markers (i.e. DTA) in predicting time to progression defined as either 10% relative decline in FVC, lung transplant, or death from any cause, b) associations between changes in CT biomarkers on sequential CT and changes in 1-year FVC and DLCO, and c) change in CT associated with drug treatment. This aim will establish the relative and synergistic value of CT to established physiologic markers.

Aim 2: The investigators will determine if candidate genetic variants for IPF susceptibility and survival are associated with the DTA score and improve predictive performance for survival. The investigators hypothesize that variants in MUC5B, TOLLIP, and Telomere lengths (TL) will enhance DTA fibrosis score associations with progression-free survival in IPF. The investigators will perform a cross-sectional analysis of PFF-PR cases comparing quantitative CT and radiomic markers at baseline with and without "at risk" genotypes for association with severity and progression (decline in FVC over time). This will ascertain what markers improve performance of the DTA fibrosis extent scores using Cox regression analysis and accuracy metrics from Aim 1. Findings will be replicated in UVA/Chicago cohort and in the prospective PRECISIONS cohort. This aim will establish the additive value of genetic markers.

Aim 3: The investigators will assess whether DTA and radiomic markers are additive/synergistic with plasma protein and blood transcriptome markers for disease progression. The investigators hypothesize that selected protein and transcriptomic markers will prove additive to DTA fibrosis extent for prediction of progression-free survival whereas other markers correlated with DTA will not. The investigators have chosen published markers from a 4-protein panel signature, along with CCL18, as examples, given their current level of replication and promise. The investigators will also include a 25-gene FVC predictor for disease progression. Similar analyses, as outlined in Aims 1 and 2, will determine their additive information value.

Eligibility criteria: Inclusion Criteria:

1. ≥ 40 years of age
2. Diagnosed with IPF according to 2018 ATS/ERS/JRS/ALAT confirmed by the enrolling investigator
3. Signed informed consent

Exclusion Criteria:

1. Pregnancy or planning to become pregnant
2. Women of childbearing potential not willing to remain abstinent (refrain from heterosexual intercourse) or use two adequate methods of contraception, including at least one method with a failure rate of \<1% per year during study participation\*
3. Significant medical, surgical or psychiatric illness that in the opinion of the investigator would affect subject safety or potential to complete the research study

   * A woman is considered to be of childbearing potential if she is post-monarchical, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

Primary outcomes:
measure: Derivation of DTA in IPF only cases from the PFF-PR and its associations with disease severity and outcomes.
timeFrame: 12 months
measure: Determine whether known IPF-risk genetic variants are associated with DTA score.
timeFrame: 12 months
measure: Identify novel genetic variants that associate with DTA score progression.
timeFrame: 12 months
measure: Determine if DTA or any constituent radiomic features correlate with select plasma proteins.
timeFrame: 12 months
measure: Determine if DTA or any of constituent radiomic features correlate with transcriptomic
timeFrame: 12 months
measure: Determine the best combination of markers (DTA, proteins and transcriptome) for machine learning algorithms for AUC evaluation of ROCs on all 3 cohorts.
timeFrame: 12 months
Secondary outcomes:
measure: Determine associations of changes in DTA scores with 12-month changes in FVC and DLCO.
timeFrame: 12 months
measure: Determine associations of changes in DTA scores with drug treatment (i.e., antifibrotics)
timeFrame: 12 months
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: Division of Pulmonary and Critical Care
name: Noth Imre, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Pulmonary and Critical Care
name: John Kim
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018 May 10;378(19):1811-1823. doi: 10.1056/NEJMra1705751. No abstract available.
citation: Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, Poletti V, Buccioli M, Elicker BM, Jones KD, King TE Jr, Collard HR. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012 May 15;156(10):684-91. doi: 10.7326/0003-4819-156-10-201205150-00004.
citation: Podolanczuk AJ, Kim JS, Cooper CB, Lasky JA, Murray S, Oldham JM, Raghu G, Flaherty KR, Spino C, Noth I, Martinez FJ; PRECISIONS Study Team. Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial. BMC Pulm Med. 2022 Dec 13;22(1):475. doi: 10.1186/s12890-022-02281-8.
citation: Humphries SM, Swigris JJ, Brown KK, Strand M, Gong Q, Sundy JS, Raghu G, Schwarz MI, Flaherty KR, Sood R, O'Riordan TG, Lynch DA. Quantitative high-resolution computed tomography fibrosis score: performance characteristics in idiopathic pulmonary fibrosis. Eur Respir J. 2018 Sep 17;52(3):1801384. doi: 10.1183/13993003.01384-2018. Print 2018 Sep.
citation: Humphries SM, Yagihashi K, Huckleberry J, Rho BH, Schroeder JD, Strand M, Schwarz MI, Flaherty KR, Kazerooni EA, van Beek EJR, Lynch DA. Idiopathic Pulmonary Fibrosis: Data-driven Textural Analysis of Extent of Fibrosis at Baseline and 15-Month Follow-up. Radiology. 2017 Oct;285(1):270-278. doi: 10.1148/radiol.2017161177. Epub 2017 May 10.
citation: King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18.
citation: Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2071-82. doi: 10.1056/NEJMoa1402584. Epub 2014 May 18.
citation: Reichmann WM, Yu YF, Macaulay D, Wu EQ, Nathan SD. Change in forced vital capacity and associated subsequent outcomes in patients with newly diagnosed idiopathic pulmonary fibrosis. BMC Pulm Med. 2015 Dec 29;15:167. doi: 10.1186/s12890-015-0161-5.
citation: Schmidt SL, Tayob N, Han MK, Zappala C, Kervitsky D, Murray S, Wells AU, Brown KK, Martinez FJ, Flaherty KR. Predicting pulmonary fibrosis disease course from past trends in pulmonary function. Chest. 2014 Mar 1;145(3):579-585. doi: 10.1378/chest.13-0844.
citation: Paterniti MO, Bi Y, Rekic D, Wang Y, Karimi-Shah BA, Chowdhury BA. Acute Exacerbation and Decline in Forced Vital Capacity Are Associated with Increased Mortality in Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc. 2017 Sep;14(9):1395-1402. doi: 10.1513/AnnalsATS.201606-458OC.