Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis

Cirrhosis, Liver Clinical Trial

Official title:

Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04867954
• Other study ID #: 2021-0220
• Secondary ID: 1R01DK125783A539
• Status: Recruiting
• Start date: October 28, 2021
• Est. completion date: April 2025

Study information

• Verified date: March 2024
• Source: University of Wisconsin, Madison
• Contact: Gemma Gliori, MS
• Phone: 608-262-7269
• Email: radstudy[@]uwhealth.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

The overall goal of this research is to implement advanced non-invasive 4D flow MRI biomarkers to predict the presence of treatable but potentially lethal GEV in patients with cirrhosis. This would facilitate the triage of patients with high-risk GEV to therapeutic EGD, while reducing unnecessary EGD procedures in patients without them. The primary biological mechanism for development of GEV is elevated portal pressure and reversal of flow in the left gastric vein (LGV). Applying 4D flow MRI, investigators aim to detect and quantify reversed flow in the LGV to detect GEV at risk for bleeding. Aim 1: Perform pre-clinical validations of an optimized, accelerated radial 4D flow MRI strategy, and of fat mitigation strategies for radial 4D flow MRI. Aim 2: Determine the diagnostic performance of radial 4D flow MRI, in cirrhotic adults including 1. diagnostic accuracy to identify high-risk GEV using EGD as reference standard, and 2. test-retest repeatability Aim 3: Evaluate the effects and added value of a meal challenge to assess for high-risk GEV. Aim 4: Compare the accuracy of 4D flow MRI to current non-invasive markers of liver disease. Research Procedures Pre-Clinical Validation (Phase 1): A total of 21 participants (7 healthy volunteers, 14 patients with GEV) to evaluate the optimized 4D flow methods, and 20 obese subjects to evaluate fat-mitigation strategies, will be enrolled. Participants 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 screening 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 (Phase 2-3): A total of 100 patients diagnosed with cirrhosis will be enrolled. Participants will be asked to complete a single research visit, lasting approximately 2 hours, that will include the following procedures: - Participants will be asked to fast for 12 hours prior to arriving. - An IV will be placed and a blood sample collected (~11mL, if necessary). - Participants will undergo a research MRI lasting approximately 1.5 hours (up to 1 hour of total scan time) - All participants will be positioned in the MRI scanner for the initial scanning session (30 min) during which the first dose of GBCA (3/4 of total dose) 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 min) during which, a second dose of GBCA (1/4 of total dose) will be administered if required.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 141
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria for Aim 1:

• 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

Exclusion Criteria for Aim 1:

• 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.
• patients with large HCC with known PC involvement.

Inclusion criteria for Aim 2-4:

• Adults (>18 years) with known cirrhosis scheduled for EGD to assess for GEV.

Exclusion Criteria for Aim 2-4:

• Contraindications to MRI
• Recent treatment (< 1 year) for varices
• recent (< 1 year) GEV bleeding
• Known occlusive thrombus in portal vein; splenic vein, or superior mesenteric vein
• Large hepatocellular carcinoma (HCC) with known PV involvement
• hypersensitivity reactions to both contrast agents

Related Conditions & MeSH terms

• Cirrhosis, Liver
• Fibrosis
• Gastroesophageal Varices
• Liver Cirrhosis

Intervention

Other:
• Ensure Plus®
In-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
Participants 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
Participants 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 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 dose of GBCA will be administered, if required.
• Pre-clinical validation contrast enhanced MRI + fasting
Participants 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.

Locations

Country	Name	City	State
United States	University of Wisconsin, Madison	Madison	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
University of Wisconsin, Madison	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	2 hours
Primary	Variation in postprandial flow after Meal Challenge	Variations in flow after a meal will be analyzed under(log-)linear mixed effects (LME) models.	pre and post meal (approximately 2 hours)
Primary	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.	2 hours
Secondary	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	Within 3 months
Secondary	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])]	Within 3 months
Secondary	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 dual-paddle system to ensure adequate wave-propagation in the liver and spleen	Within 3 months
Secondary	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	Within 3 months
Secondary	Hepatic iron level quantitation by in vivo R2* MRI method	R2* is an imaging method used in MRI. R2* = (1/T2*) where R2* is a relaxation rate measured in units of Hz ([1/sec]). R2* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron. The presence of the iron results in the shortening of proton relaxation times (T2*), thus increasing R2*. R2* will be measured by Chemical shift encoded MRI (CSE-MRI; IDEAL IQ, GE Healthcare), pioneered at University of Wisconsin (UW)-Madison. It will help characterizing the possible confounders affecting 4D flow MRI	Within 3 months
Secondary	Child-Turcotte-Pugh (CTP) score for prognosis of cirrhosis	The Child-Turcotte-Pugh (CTP) score is used to assess the severity of cirrhosis. Parameters included are Encephalopathy, Ascites, Bilirubin levels, Albumin levels, Prothrombin Time and International Normalized Ratio (PT/INR) . Parameters are scored on point 1-3. CTP score is obtained by adding the score for each parameter. CTP scores can be categorized into A= 5-6 points, B=7-9 points and C=10-15 points. Higher points correspond to more severe cirrhosis state.	Within 3 months