Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age18+
SponsorUniversity of Wisconsin, Madison
About this trial
The goal of this research is to validate novel non-invasive Magnetic resonance imaging (MRI) biomarkers to detect Gastroesophageal varices (GEV) in patients with cirrhosis, including fractional flow change in the portal vein and elevated azygos flow.
End-stage liver disease (cirrhosis) is characterized by advanced fibrosis, liver failure, and portal hypertension. There are many causes of cirrhosis, including viral hepatitis, alcohol abuse, and perhaps most importantly, non-alcoholic fatty liver disease (NAFLD) and its aggressive subset, non-alcoholic steatohepatitis (NASH). 3 million new cases of end-stage liver disease (cirrhosis) are expected over the next decade. In cirrhosis, portosystemic collaterals that shunt blood away from the liver develop due to increased portal pressure. Gastroesophageal varices (GEV) are the most clinically relevant because they can cause fatal internal bleeding. GEV bleeding carries \~20% mortality at 6 weeks, and \~34% overall mortality. Identification of at-risk varices, prior to bleeding, is of paramount importance to initiate primary prophylaxis. To identify and treat at-risk patients, current guidelines recommend regular esophagogastroduodenoscopy (EGD) and variceal band ligation. Detection of high-risk GEV is key to initiating primary prophylaxis, which can reduce mortality by 50-70%.
However, endoscopy is invasive and often unnecessary when no treatment is required. Therefore, the American Association for the Study of Liver Diseases has identified the development of "non-invasive markers that predict the presence of high-risk varices" as a major unmet need.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
Healthy volunteers: Adults (>18 years) with no known liver pathology
Obese volunteers: Adults (>18 years), no known liver pathology, body mass index (BMI) ≥ 35
Patients: Adults (>18 years) with known cirrhosis and known Gastroesophageal varices
Disqualifiers
contraindications to MRI
hypersensitivity reactions to both contrast agents
patients with recent treatment for varices with embolization, TIPS, or other endovascular treatment
patients with active GEV bleeding; known occlusive thrombus in portal vein, splenic vein, or superior mesenteric vein.
Trial population
For pre-clinical validation (Aim 1), a total of 21 participants will be recruited: 7 healthy volunteers, 14 patients with GEV. For clinical validation (Aim 2-4), 100 patients will be recruited from the UWHC endoscopy clinics. For Aim 5, 5 participants will be recruited from from the UWHC endoscopy clinics.
Trial design
Design model
Cohort
Time perspective
Prospective
Treatments tested in this trial
Ensure Plus®
Other interventionIn-between two MRI exams, patients will ingest a standardized meal of two cans (16oz) of Ensure Plus® (Abbott Laboratories), providing a 700cal meal (13g protein, 11g fat, 50g carbohydrates), proven to elicit a strong hyperemic splanchnic response.
Pre-clinical validation contrast enhanced MRI
Other interventionParticipants will be asked to complete a single research visit that will include a contrast enhanced MRI scan lasting up to 1 hour. Participants will be asked to fast for at least 5 hours prior to the exam. Participants will be screened a final time for contraindications to contrast enhanced MR imaging; an IV will be placed; and participants will be positioned in the MR scanner, asked to lie as still as possible and to follow some breath hold instructions.
Clinical validation MRI
Other interventionParticipants will be screened for any previous reactions to Ferumoxytol or GBCAs and dosing will be consistent with standard of care. Participants will then undergo a research MRI lasting approximately 1.5 hours. * All participants will be positioned in the MRI scanner for the initial scanning session (30 min) during which a 1/2 or 3/4 of the full dose of gadolinium based contrast agent (GBCA) or the total dose of Ferumoxytol will be administered. * The first 50 participants will be removed from the scanner bore, repositioned, and scanned for an additional 15 minutes (repeatability testing). * All participants will then be removed from the scanner and asked to consume 16 ounces of Ensure Plus®. After 20 minutes, they will be repositioned in the scanner for an additional scanning session (15 minutes) during which, the remaining 1/4 or 1/2 dose of GBCA will be administered, if required.
Pre-clinical validation contrast enhanced MRI + fasting
Other interventionParticipants will be asked to complete a single research visit that will include a contrast enhanced MRI scan lasting up to 1.5 hours. Participants will be asked to fast for at least 5 hours prior to the exam. Participants will be screened a final time for contraindications to contrast enhanced MR imaging; an IV will be placed; and participants will be positioned in the MR scanner, asked to lie as still as possible and to follow some breath hold instructions.
Treatment groups
146 Participants
are divided into 6 treatment groups6
Treatment groupsSee each treatment group below.
Group A: Healthy volunteers1 intervention
Group B: Patients with small, low-risk GEV1 intervention
Group C: Patients with large, high-risk GEV1 intervention
Group D: Patients scheduled for screening or surveillance esophagogastroduodenoscopy (EGD)2 interventions
Group E: Obese patients1 intervention
Group F: Participants with Fontan repair and diagnosed Fontal associated liver disease (FALD)2 interventions
Trial outcomes
Primary outcomes
1
Receiver operation characteristic (ROC) curve analysis to determine diagnostic accuracy
Receiver operation characteristic (ROC) curve analysis will be performed to determine the diagnostic accuracy of 4D flow MRI to differentiate high-risk GEV from absent or low-risk GEV. The area under the curve (AUC) will be estimated for each flow measurement with 95% confidence intervals. The primary analysis is based on fractional flow change in the portal vein.
Time frame
2 hours2
Variation in postprandial flow after Meal Challenge
Variations in flow after a meal will be analyzed under(log-)linear mixed effects (LME) models.
Time frame
pre and post meal (approximately 2 hours)3
Repeatability of 4D flow MRI: measured by summary measures of test-retest agreement with 95% Confidence intervals(CIs).
Repeatability of all flow measurements and fractional flow changes will be measured using intra-class correlation coefficient (ICC), and the wishing-subject coefficient of variation (wCV) will be estimated as summary measures of test-retest agreement with 95% CIs.
Time frame
2 hours4
Diagnostic accuracy of 4D Flow MRI to detect high-risk gastroesophageal varices (GEV) compared to esophagogastroduodenoscopy (EGD) as the reference standard
Sensitivity and specificity of fractional flow change in the portal vein (FFCPV) and azygos flow thresholds
Time frame
BaselineSecondary outcomes
1
Aspartate aminotransferase-to-platelet ratio index (APRI)
APRI is a way for doctors to measure how healthy a patient's liver is when they have a liver disease. APRI = \[(AST/upper limit of normal)/platelet count\]x100
Time frame
Within 3 months2
Fibrosis 4 (FIB-4) index
The Fibrosis-4 score helps to estimate the amount of scarring in the liver. FIB-4 = age (years) × AST \[IU/L\] / \[platelet count × sqr(ALT \[IU/L\])\]
Time frame
Within 3 months3
Liver and spleen stiffness measurement by 2D spin-echo MR elastography
2D spin-echo MR elastography will be acquired to assess liver and spleen stiffness, using a single or dual-paddle system to ensure adequate wave-propagation in the liver and spleen
Time frame
Within 3 months4
Liver proton density fat fraction (PDFF) as assessed by chemical shift encoded MRI (CSE-MRI)
Liver proton density fat fraction (PDFF) is a biomarker of hepatic steatosis. It will be measured by Chemical shift encoded MRI (CSE-MRI; IDEAL IQ, GE Healthcare),pioneered at UW-Madison. It will help characterizing the possible confounders affecting 4D flow MRI
Time frame
Within 3 monthsSponsors and contacts
Click on the lead sponsor to view all of their trials.
University of Wisconsin, Madison
Lead sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
Source ClinicalTrials.gov