Clinical trial NCT04867954: Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis
Official title: Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cirrhosis, Liver
Gastroesophageal Varices
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2021-04-30
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed 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 for tracer administration
* 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.
  * 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.

Eligibility criteria: 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
* 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.

Primary outcomes:
measure: Receiver operation characteristic (ROC) curve analysis to determine diagnostic accuracy
timeFrame: 2 hours
measure: Variation in postprandial flow after Meal Challenge
timeFrame: pre and post meal (approximately 2 hours)
measure: Repeatability of 4D flow MRI: measured by summary measures of test-retest agreement with 95% Confidence intervals(CIs).
timeFrame: 2 hours
Secondary outcomes:
measure: Aspartate aminotransferase-to-platelet ratio index (APRI)
timeFrame: Within 3 months
measure: Fibrosis 4 (FIB-4) index
timeFrame: Within 3 months
measure: Liver and spleen stiffness measurement by 2D spin-echo MR elastography
timeFrame: Within 3 months
measure: Liver proton density fat fraction (PDFF) as assessed by chemical shift encoded MRI (CSE-MRI)
timeFrame: Within 3 months
measure: Hepatic iron level quantitation by in vivo R2* MRI method
timeFrame: Within 3 months
measure: Child-Turcotte-Pugh (CTP) score for prognosis of cirrhosis
timeFrame: Within 3 months
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin, Madison
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Scott Reeder, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: