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

NCT04867954 | Recruiting FDA Device

• 5 other identifiers: 2021-02201R01DK125783A539300SMPH/RADIOLOGY/RADIOLOGYProtocol Version 1/7/26
• Study Type: observational
• Target: 146
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Fontan Procedure; Cirrhosis, Liver; Gastroesophageal Varices

Outcome Measures

Primary Outcomes (4)

• 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

• 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)

• 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

• 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

  Baseline

Secondary Outcomes (9)

• Aspartate aminotransferase-to-platelet ratio index (APRI)

  Within 3 months

• Fibrosis 4 (FIB-4) index

  Within 3 months

• Liver and spleen stiffness measurement by 2D spin-echo MR elastography

  Within 3 months

• Liver proton density fat fraction (PDFF) as assessed by chemical shift encoded MRI (CSE-MRI)

  Within 3 months

• Hepatic iron level quantitation by in vivo R2* MRI method

  Within 3 months

Study Arms (6)

Healthy volunteers

7 healthy participants will be recruited.

Other: Pre-clinical validation contrast enhanced MRI

Patients with small, low-risk GEV

Patients with small, low-risk Gastroesophageal varices (GEV) will be recruited.

Other: Pre-clinical validation contrast enhanced MRI

Patients with large, high-risk GEV

Patients with large, high-risk Gastroesophageal varices (GEV) will be recruited.

Other: Pre-clinical validation contrast enhanced MRI

Patients scheduled for screening or surveillance esophagogastroduodenoscopy (EGD)

100 patients diagnosed with cirrhosis and scheduled for screening or surveillance esophagogastroduodenoscopy (EGD) procedure will be recruited. Participants will complete a single research visit, lasting approximately 2 hours, that will include the following procedures: * Participants will fast for 12 hours prior to arriving. * An IV will be placed and a blood sample collected (\~11 mL, if necessary). * All participants will undergo research MRI lasting approximately 1.5 hours

Other: Ensure Plus®; Other: Clinical validation MRI

Obese patients

20 obese patients will be recruited

Other: Pre-clinical validation contrast enhanced MRI + fasting

Participants with Fontan repair and diagnosed Fontal associated liver disease (FALD)

5 participants with Fontan repair and diagnosed FALD will be recruited.

Other: Ensure Plus®; Other: Clinical validation MRI

Interventions

Ensure Plus® OTHER

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.

Participants with Fontan repair and diagnosed Fontal associated liver disease (FALD); Patients scheduled for screening or surveillance esophagogastroduodenoscopy (EGD)

Clinical validation MRI OTHER

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 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.

Also known as: MRI

Participants with Fontan repair and diagnosed Fontal associated liver disease (FALD); Patients scheduled for screening or surveillance esophagogastroduodenoscopy (EGD)

Pre-clinical validation contrast enhanced MRI + fasting OTHER

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.

Also known as: MRI

Obese patients

Pre-clinical validation contrast enhanced MRI OTHER

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.

Also known as: MRI

Healthy volunteers; Patients with large, high-risk GEV; Patients with small, low-risk GEV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study 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.

You may qualify if:

• 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

You may not qualify if:

• 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.
• Adults (\>18 years) with known cirrhosis
• Contraindications to MRI
• Recent treatment (\< 1 year) for varices
• 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
• Participants requiring conscious sedation for imaging are not eligible; participants requiring mild, oral anxiolytics for the clinical MRI scan will be allowed to participate as long as the following criteria are met:
• The participant has their own prescription for the medication
• The informed consent process is conducted prior to the self-administration of the medication.
• The participant comes to the research visit with a driver.

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Wisconsin, Madison

Madison, Wisconsin, 53704, United States

RECRUITING

MeSH Terms

Conditions

Liver Cirrhosis

Interventions

Ensure Plus

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Scott Reeder, MD, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Radiology Studies

CONTACT

608-282-8349; radstudy@uwhealth.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2021
• First Posted: April 30, 2021
• Study Start: October 28, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: April 9, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)