PET/MRI of Primary Sclerosing Cholangitis

Official title

PET/MRI Evaluation in Patients With Primary Sclerosing Cholangitis Using Intercellular Matrix Radiopharmaceuticals

Overview

This study aims to use positron emission tomography (PET)/magnetic resonance imaging (MRI) to diagnose and quantify PSC-related biliary tract fibrosis and to improve upon the currently available non-invasive diagnostic capabilities by investigating the ability of combined PET/MRI to detect and quantify fibrosis using a novel collagen-binding radiotracer. Specifically, the investigators will be comparing \[68Ga\]CBP8- and \[18F\]-FAPI-74 PET/MRI to a liver transient elastography scan in the diagnosis of biliary tree fibrosis.

Detailed description

Imaging in the form of cholangiography plays an essential role in diagnosing and managing PSC. In the past decade, magnetic resonance cholangiopancreatography (MRCP) has become preferred over endoscopic retrograde cholangiopancreatography (ERCP) for the diagnosis of PSC because it is non-invasive, thereby safer, and cheaper than ERCP. MRCP's sensitivity and specificity for diagnosing PSC are high, 86% and 94%, respectively. However, to quantify liver fibrosis, MRCP is only accurate in more advanced stages of the disease. Intrahepatic biliary stricture severity was a poor discriminator between the different grades of liver fibrosis measured on magnetic resonance elastography and the different risk strata according to the Mayo Risk Score and The Amsterdam-Oxford prognostic index (AOPI). Other non-invasive diagnostic tests, such as transient elastography, lack full-organ evaluation and may be subject to variation between measurements, despite being the current gold standard for non-invasive fibrosis quantification.

This study aims to use \[68Ga\]CBP8- or \[18F\]FAPI PET/MRI to diagnose and quantify PSC-related biliary tract fibrosis. The novel radiopharmaceutical collagen-binding probe 8 labeled with Gallium-68 selectively binds to collagen type I, the predominant extracellular protein in fibrosis. \[68Ga\]CBP8 has already been investigated in patients affected by pulmonary fibrosis with success. Fibroblast activation protein (FAP) is a type II transmembrane serine protease that is overexpressed in CAFs and, to a lesser extent, in benign processes. It is associated with extracellular matrix remodeling, for example, chronic inflammation, degenerative bone and spine disease, arthritis, and cardiac remodelling after myocardial infarction. Quinolone-based FAP inhibitors (FAPIs) constitute a class of molecules with high affinity to FAP deployed to assess many types of solid tumors and some benign pathologies. 68Ga-FAPIs and, to a lesser extent, 18F-FAPI are being extensively studied in oncologic and non-oncologic positron emission tomography/computed tomography (PET/CT) and, to a lesser extent, PET/MRI, both in Europe and Asia.

In this open-label, single-arm, single-center prospective study, the investigators will recruit 10 patients with known primary sclerosing cholangitis (PSC) who have previously undergone other modalities for the evaluation of hepatic fibrosis, such as liver biopsy and/or transient elastography (FibroScan) and/or MR liver elastography and/or US liver elastography.No healthy volunteers will be included. Patients will be referred to \[68Ga\]CBP8 or \[18F\]-FAPI-74 PET/MRI by their primary treating physicians (e.g., hepatologist). After a phone-call pre-screening, electronic medical records verification, and a screening visit, subjects will be imaged with \[68Ga\]CBP8 or \[18F\]-FAPI-74 PET/MRI. A blood draw might also be performed to measure serum biomarkers of liver fibrosis.

Transient liver elastography has a diagnostic accuracy ranging from 65% in the initial stages to 90% for severe fibrosis in the setting of PSC. There is no data regarding the use of \[68Ga\]CBP8 PET/MRI to diagnose or quantify fibrosis in PSC. Therefore, the investigators lack sufficient evidence to estimate power with a reasonable degree of certainty. By enrolling 10 patients for this initial pilot study in the evaluation of hepatic/biliary fibrosis with \[68Ga\]CBP8 PET/MRI, the investigators will be able to acquire enough data to determine the optimal sample size for a larger study. A paired McNemar's test will be used for hypothesis testing regarding differences in sensitivity, specificity, accuracy, negative predictive value, and positive predictive value between \[68Ga\]CBP8 PET/MRI and FibroScan. Moreover, the investigators will analyze quantitative features of PET (SUV) and obtain their correlation to the actual fibrosis as reported by the gold standard test. These will be performed using Spearman's correlation coefficient and regression analysis.

Interventions

• Drug Radiotracer Injection
  An intravenous catheter will be placed in an arm or hand vein for injection of \[68Ga\]CBP8; * 6-10 mCi of \[68Ga\]CBP8 or 5-9 mCi of FAPI will be injected into the Biograph mMR system. The injected dose and the time of injection will be recorded; * The catheter will be flushed with 0.9% saline solution; * The subjects will then be positioned on the scanner table; support devices under the back or legs will be used to enable the patient to maintain his/her position throughout the scan comfortab
• Drug Contrast Media, Magnetic Resonance
  The same intravenous catheter used to inject the radiotracer will be used to inject the hepatospecific gadolinium contrast agent Eovist (Bayer, Whippany, NJ); * After being positioned on the PET/MRI table, the nuclear medicine technologist will connect the patient to the MRI-safe power injector; * The catheter will be flushed before and after injection with 0.9% saline solution; * About halfway through the imaging session, the study staff will inform the patient that they are going to be admini
• Diagnostic test Imaging
  MRI and PET scanner to be used: 3.0 T Laboratory (Bay 7) Siemens Biograph mMR. Magnetic resonance images of the abdomen will be acquired using the Martinos Center's combined 3 Tesla PET/MRI scanner. The image quality on these 3 Tesla devices will be very high, equivalent to or better than any other standard clinical MRI system. PET images of the target body site will be acquired When necessary, the data acquisition will be started shortly before radiotracer injection; Coincidence event data wi

Primary outcome measures

• Diagnostic accuracy in detection of fibrotic components in patients with PSC [Time frame: (1-2 Months)]
• Quantification of fibrotic components in PSC [Time frame: From date of PET/MRI examination to date of final histopathology result: (max. 1-2 Months)]

Secondary outcome measures (2)

• Correlation of PET parameters with clinical and imaging biomarkers/tests for fibrosis [Time frame: 1-2 Months]
• Correlation of PET parameters with MRI parameters [Time frame: 1-2 Months]

Eligibility criteria

Inclusion criteria

• Established clinical diagnosis of large duct PSC
• Participants receiving treatment for IBD are allowed if on a stable dose from screening and expected to remain stable for the duration of the study
• Serum AST and ALT concentration ≤ 8 times the upper limit of normal

Exclusion criteria

• Other causes of chronic liver disease, including secondary sclerosing cholangitis or viral, metabolic, or alcoholic liver disease, as assessed clinically
• Known or suspected overlapping clinical or histologic diagnosis of autoimmune hepatitis
• Subjects less than 18 years of age or greater than 85 years of age.
• Subjects with electrical implants, such as cardiac pacemakers or perfusion pumps.
• Subjects with ferromagnetic implants such as aneurysm clips, surgical clips, prostheses, artificial hearts, prosthetic heart valves that are not compatible with the gradient maps of our scanners, metal fragments, shrapnel, metallic tattoos anywhere on the body, tattoos near the eye, or steel implants ferromagnetic objects such as jewelry or metal clips in clothing.
• Subjects who anticipate being pregnant or breastfeeding (a negative STAT quantitative serum hCG pregnancy test is required on the day of the scan before the subject can participate).
• Subjects with claustrophobic reactions
• Subjects with more significant than average potential for cardiac arrest.
• Subjects with a history of major head trauma (i.e., multiple concussions, traumatic brain injury).
• Subjects with a history of bleeding disorders.
• Subjects whose research-related radiation exposure exceeds current Radiology Department guidelines (i.e., 50 mSv in the prior 12 months).
• Subjects unable to lie comfortably on a bed inside the PET/MRI bore as assessed by physical examination and medical history (e.g., back pain, arthritis).
• Subjects under the direct supervision of the principal investigator;
• Subjects with a body weight of > 300 lbs (operational weight limit of the PET/MRI table) or BMI >33 kg/m2 (the Athinoula A. Martinos Center standard procedure to avoid claustrophobia or mechanical impossibility of fitting the subject into the scanner bore, which is less than 60 cm wide).
• A history of acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m2
• Perioperative liver transplantation period.
• A history of systemic lupus, multiple myeloma, nephrogenic systemic fibrosis, or other comorbidities resulting in chronic kidney disease stage IV or higher

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

United States · 1 center

• Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harva — Charlestown

Publications

• Ludwig J. Surgical pathology of the syndrome of primary sclerosing cholangitis. Am J Surg Pathol. 1989;13 Suppl 1:43-9. PMID 2699167
• Lindor KD, Kowdley KV, Harrison ME; American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015 May;110(5):646-59; quiz 660. doi: 10.1038/ajg.2015.112. Epub 2015 Apr 14. PMID 25869391
• Dave M, Elmunzer BJ, Dwamena BA, Higgins PD. Primary sclerosing cholangitis: meta-analysis of diagnostic performance of MR cholangiopancreatography. Radiology. 2010 Aug;256(2):387-96. doi: 10.1148/radiol.10091953. PMID 20656832
• Tafur M, Cheung A, Menezes RJ, Feld J, Janssen H, Hirschfield GM, Jhaveri KS. Risk stratification in primary sclerosing cholangitis: comparison of biliary stricture severity on MRCP versus liver stiffness by MR elastography and vibration-controlled transient elastography. Eur Radiol. 2020 Jul;30(7):3735-3747. doi: 10.1007/s00330-020-06728-6. Epub 2020 Mar 4. PMID 32130494
• Vuppalanchi R, Sanyal AJ. Myths and mysteries about staging hepatic fibrosis by fibroscan. Clin Gastroenterol Hepatol. 2015 Apr;13(4):780-2. doi: 10.1016/j.cgh.2014.10.030. Epub 2014 Nov 5. No abstract available. PMID 25451885
• Montesi SB, Izquierdo-Garcia D, Desogere P, Abston E, Liang LL, Digumarthy S, Seethamraju R, Lanuti M, Caravan P, Catana C. Type I Collagen-targeted Positron Emission Tomography Imaging in Idiopathic Pulmonary Fibrosis: First-in-Human Studies. Am J Respir Crit Care Med. 2019 Jul 15;200(2):258-261. doi: 10.1164/rccm.201903-0503LE. No abstract available. PMID 31161770
• Catalano OA, Gee MS, Nicolai E, Selvaggi F, Pellino G, Cuocolo A, Luongo A, Catalano M, Rosen BR, Gervais D, Vangel MG, Soricelli A, Salvatore M. Evaluation of Quantitative PET/MR Enterography Biomarkers for Discrimination of Inflammatory Strictures from Fibrotic Strictures in Crohn Disease. Radiology. 2016 Mar;278(3):792-800. doi: 10.1148/radiol.2015150566. Epub 2015 Oct 5. PMID 26436860
• Catalano OA, Wu V, Mahmood U, Signore A, Vangel M, Soricelli A, Salvatore M, Gervais D, Rosen BR. Diagnostic performance of PET/MR in the evaluation of active inflammation in Crohn disease. Am J Nucl Med Mol Imaging. 2018 Feb 5;8(1):62-69. eCollection 2018. PMID 29531862

Identifiers

NCT: NCT06252610 · 2022P002225

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗