The Role of Quantitative CT and Radiomic Biomarkers for Precision Medicine in Pulmonary Fibrosis

March 14, 2024 updated by: Imre Noth, MD, University of Virginia
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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Estimated)

160

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients diagnosed with Pulmonary Fibrosis as described above in inclusion criteria.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
University of Chicago
This cohort will have prior consent to the Natural History of Interstitial Lung Disease, which is an ongoing, longitudinal cohort of patients with clinically diagnosed ILD, including IPF. Patients are recruited from University of Chicago Interstitial Lung Disease Program during their clinic visit. Blood, plasma, and serum samples are collected upon enrollment and stored in a biorepository at University of Chicago. Subsets of patients have repeat blood draw at return clinic visits for specific research studies. The investigators propose collection of 1-year HRCTs, FVC, and DLCO.
Diagnostic test: HRCT
High resolution computed tomography (HRCT) scan is a medical imaging technique used to obtain detailed internal images of the body. HRCT images will be obtained at 0 and 12 months.
Diagnostic test: Blood Draw
During blood draw, someone uses a needle to take blood from a vein, usually in your arm.
University of Virginia
This cohort will have prior consent to the Natural History of Interstitial Lung Disease, which is an ongoing, longitudinal cohort of patients with clinically diagnosed ILD, including IPF. Patients are recruited from the UVA Interstitial Lung Disease Program during their clinic visit. Blood, plasma, and serum samples are collected upon enrollment and stored in a biorepository at UVA (Pinn Hall RM#2232B, IRB#20937). Subsets of patients have repeat blood draw at return clinic visits for specific research studies. The investigators propose collection of 1-year HRCTs, FVC, and DLCO.
Diagnostic test: HRCT
High resolution computed tomography (HRCT) scan is a medical imaging technique used to obtain detailed internal images of the body. HRCT images will be obtained at 0 and 12 months.
Diagnostic test: Blood Draw
During blood draw, someone uses a needle to take blood from a vein, usually in your arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Derivation of DTA in IPF only cases from the PFF-PR and its associations with disease severity and outcomes.
Time Frame: 12 months

Driven texture analysis (DTA) is a machine learning method capable of automatic detection and quantification of lung fibrosis on HRCT. It is trained to discriminate fibrosis using radiologist-identified image regions demonstrating normal lung parenchyma and usual interstitial pneumonia patterns.

Changes in Forced Vital Capacity (FVC) measured in liters, reflect increased elastic recoil caused by fibrosis. We will use linear-mixed effects models with random intercept to examine associations of repeated DTA-fibrosis scores with repeated percent predicted FVC measurements over time (12 months minimum). This approach will provide a more precise estimate, power, and account for baseline FVC at an individual level which has implications of how rapid a decline we anticipate. This is the most common approach to examine longitudinal changes of FVC in IPF studies. FVC decline greater than 10% has been shown to be prognostic of worse survival and is a common endpoint in IPF clinical trials.
12 months
Determine whether known IPF-risk genetic variants are associated with DTA score.
Time Frame: 12 months
This is a cross-sectional analysis to determine whether genetic variants that confer higher risk of disease and progression are associated with higher DTA scores from CT.
12 months
Identify novel genetic variants that associate with DTA score progression.
Time Frame: 12 months
Determine novel genetic variants that indicate higher risk of disease progression and are associated with higher DTA scores.
12 months
Determine if DTA or any constituent radiomic features correlate with select plasma proteins.
Time Frame: 12 months
MMP-7, CA-125, YKL, OPN, CCL18 are plasma proteins that have been shown to be associated with risk and prognosis in IPF.
12 months
Determine if DTA or any of constituent radiomic features correlate with transcriptomic
Time Frame: 12 months
We have previously published a transcriptomic classifier that is predictive of FVC decline in IPF.
12 months
Determine the best combination of markers (DTA, proteins and transcriptome) for machine learning algorithms for AUC evaluation of ROCs on all 3 cohorts.
Time Frame: 12 months
12-month FVC decline is a validated marker of disease progression in IPF as it's predictive of worse mortality. Receiver operating characteristic curve (ROC) is an analytical method, represented as a graph, that is used to evaluate the performance of a binary diagnostic classification method. The diagnostic test results need to be classified into one of the clearly defined dichotomous categories, such as the presence or absence of a disease. Area under the ROC curve (AUC) measures the entire two-dimensional area underneath the entire ROC curve.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determine associations of changes in DTA scores with 12-month changes in FVC and DLCO.
Time Frame: 12 months
FVC (L) and diffusing capacity of the lungs for carbon monoxide (DLCO) have been shown to be validated markers of disease progression in IPF. DLCO is a measurement to assess the lungs' ability to transfer gas from inspired air to the bloodstream. The normal range for DLCO: 80-120% of its predicted value for men. 76-120% of its predicted value for women.
12 months
Determine associations of changes in DTA scores with drug treatment (i.e., antifibrotics)
Time Frame: 12 months
Changes in DTA scores have been shown correlate strongly with changes in lung function. By establishing that changes in DTA scores occur in response to patients with IPF who start antifibrotic therapy, will provide supportive evidence of DTA as a potential tool to track treatment responses.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Virginia

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Noth Imre, MD, Division of Pulmonary and Critical Care
  • Principal Investigator: John Kim, Division of Pulmonary and Critical Care

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2024

Primary Completion (Estimated)

May 1, 2028

Study Completion (Estimated)

May 1, 2029

Study Registration Dates

First Submitted

March 7, 2024

First Submitted That Met QC Criteria

March 14, 2024

First Posted (Actual)

March 21, 2024

Study Record Updates

Last Update Posted (Actual)

March 21, 2024

Last Update Submitted That Met QC Criteria

March 14, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSR301252
  • R01HL171918 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Plan to share de-identified dicom images with Ambrahealth for CT analysis

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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