Noninvasive Ultrasound Technique for Portal Hypertension

Overseen by Sudha A Anupindi, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Thomas Jefferson University

Disqualifiers: Pregnancy, Egg allergy, Liver transplant, Cystic fibrosis, Chronic lung disease, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

Early diagnosis of portal hypertension is difficult as symptoms rarely manifest until the later stages of liver disease. Both cirrhotic and non-cirrhotic portal hypertension can result in life-threatening complications, the most frequent of which is bleeding from esophageal varices. In children, variceal bleeds are associated with mortality rates of 1-3 %, while life-threatening complications have been reported in up to 20 % of children with cirrhosis. Despite the high incidence of portal hypertension in children with liver disease, a noninvasive modality to monitor disease progression and risk of complications is currently lacking. Hence, this trial will investigate the safety and efficacy of subharmonic aided pressure estimation (SHAPE) as a noninvasive ultrasound technique for diagnosing portal hypertension in children.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment SHAPE measurement using the ultrasound contrast agent Sonazoid for portal hypertension?

Research shows that Sonazoid, a contrast agent used in ultrasound imaging, is effective in characterizing liver conditions and distinguishing between different types of liver diseases, which suggests it may be useful in assessing portal hypertension. ^{1 2 3 4 5}

Is the noninvasive ultrasound technique using Lumason or Sonazoid safe for humans?

Studies have shown that Sonazoid, which contains perfluorobutane microbubbles, is safe for use in imaging liver conditions. Lumason, containing sulfur hexafluoride microbubbles, is also widely used and considered safe for characterizing liver lesions. ^{1 2 3 4 6}

How is the treatment using ultrasound contrast agents Lumason and Sonazoid for portal hypertension different from other treatments?

This treatment is unique because it uses noninvasive ultrasound with contrast agents to assess portal hypertension, avoiding the need for invasive procedures to measure portal pressure. The use of microbubble-based contrast agents like Lumason and Sonazoid enhances the ability to visualize blood flow and assess liver conditions without surgery. ^{5 7 8 9 10}

Research Team

Flemming Forsberg, PhD

Principal Investigator

Thomas Jefferson University

Sudha A Anupindi, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for children with chronic liver disease, both with and without portal hypertension. It's not for kids with lung issues, portal vein problems, heart disease, or those who've had a liver transplant. Also excluded are pregnant subjects or those allergic to egg products or certain ultrasound contrast agents.

Inclusion Criteria

I have chronic liver disease but no portal hypertension.

I have chronic liver disease with increased blood pressure in the portal vein.

Exclusion Criteria

Subjects who are pregnant

I have cystic fibrosis.

I have had a liver transplant in the past.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial SHAPE Measurement

Participants undergo a single visit for SHAPE measurement using ultrasound contrast agents Sonazoid or Lumason

1 day

1 visit (in-person)

Longitudinal SHAPE Monitoring

Participants identified with portal hypertension are monitored using SHAPE every 6 months for up to 18 months

18 months

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the initial SHAPE measurement

4 weeks

Treatment Details

Interventions

• SHAPE measurement using the ultrasound contrast agent Lumason (sulfur hexafluoride lipid-type A microspheres) (Procedure)
• SHAPE measurement using the ultrasound contrast agent Sonazoid (perfluorobutane microbubbles) (Procedure)

Trial Overview The trial tests SHAPE measurements using two different ultrasound contrast agents (Sonazoid and Lumason) to diagnose portal hypertension noninvasively in children. This could help monitor the progression of liver disease and risk of complications early on.

Participant Groups

Group I: SHAPE with Sonazoid Experimental Treatment 1 Intervention

Up to 60 children (6-21 years of age) with a diagnosis of chronic liver disease, including some who will have portal hypertension who are followed at The Children's Hospital of Philadelphia (CHOP) will be enrolled in this arm. A SHAPE measurement using the ultrasound contrast agent Sonazoid® (perfluorobutane microbubbles) will be performed during a single visit. A dose of three vials with 16 μL each of microbubbles will be prepared. An infusion of the ultrasound contrast agent at the rate of 0.18 mL/kg/hour will be co-infused with an infusion of saline at the rate of 120 mL/hour resulting in an effective dosage of 1.44 μL microbubbles/kg/hour as per the FDA approved IND through an IV line in a peripheral vein. The total duration of contrast agent infusion is expected to range from 4 to 8 minutes, which includes a 2 min calibration period followed by 2-6 minutes of SHAPE acquisition (i.e., ultrasound imaging).

Group II: Longitudinal SHAPE Experimental Treatment 2 Interventions

SHAPE will be used to monitor subjects identified in the initial examination as having portal hypertension for up to 18 months. These subjects will undergo laboratory testing every 6 months as a part of their clinical standard of care. During these times the SHAPE examination will also be repeated using the same ultrasound contrast agent and infusion methodologies (including dosages) as during the initial study.

Group III: SHAPE with Lumason Active Control 1 Intervention

Up to 60 children (6-21 years of age) with a diagnosis of chronic liver disease, including some who will have portal hypertension who are followed at CHOP will be enrolled in this arm. A SHAPE measurement using the ultrasound contrast agent LUMASON® (sulfur hexafluoride lipid-type A microspheres) will be performed during a single visit. Two doses of 0.03 mL/kg (or 2.4 mL maximum) as per package labeling will be prepared and mixed with saline at a 1:10 dilution in a 50 ml bag of saline. The diluted preparation of Lumason will be through an IV line in a peripheral vein up to 4 mL/min using an infusion setup. The total duration of contrast agent infusion is expected to range from 4 to 8 minutes, which includes a 2 min calibration period followed by 2-6 minutes of SHAPE acquisition (i.e., ultrasound imaging).

Who Is Running the Clinical Trial?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

Dr. Eugene Kennedy

Thomas Jefferson University

Chief Medical Officer since 2020

MD

Dr. Joseph G. Cacchione

Thomas Jefferson University

Chief Executive Officer since 2022

MD, MBA

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Joseph W. St. Geme III

Children's Hospital of Philadelphia

Chief Medical Officer since 2021

MD, PhD, MPH

Madeline Bell

Children's Hospital of Philadelphia

Chief Executive Officer since 2015

BSc in Nursing from Villanova University, MSc in Organizational Dynamics from the University of Pennsylvania

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Dr. Griffin P. Rodgers

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Chief Executive Officer since 2007

MD, M.A.C.P.

Dr. Griffin P. Rodgers

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Chief Medical Officer since 2007

MD, M.A.C.P.

Findings from Research

Contrast-enhanced sonography using Sonazoid effectively differentiates between well-differentiated and moderately differentiated hepatocellular carcinoma in patients with chronic liver disease, with specific enhancement patterns correlating to tumor differentiation.

The study analyzed 59 nodules from 47 patients, showing that certain enhancement patterns on sonography were significantly associated with the histological classification of the tumors, indicating its potential as a reliable diagnostic tool.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis of hepatocellular carcinoma nodules in patients with chronic liver disease using contrast-enhanced sonography: usefulness of the combination of arterial- and kupffer-phase enhancement patterns. Suzuki, K., Okuda, Y., Ota, M., et al.[2016]

In a study involving 54 individuals, Sonazoid was found to be well tolerated as a contrast agent for ultrasound imaging of focal liver lesions, with only mild treatment-emergent adverse events reported in 24.1% of patients.

The most common adverse effects were mild abdominal pain and heart rate irregularity, with no serious adverse effects observed, indicating that Sonazoid is a safe option for enhancing liver imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Perfluorobutane (Sonazoid) in Characterizing Focal Liver Lesions. Chou, YH., Liang, JD., Wang, SY., et al.[2022]

In a study of 226 patients with hypervascular hepatocellular carcinoma, those with an irregular defect pattern during the Kupffer phase of Sonazoid contrast-enhanced sonography had a significantly higher 5-year critical recurrence rate of 49% compared to 17% for those with a smooth or no defect (P < .01).

The study found that the defect pattern, along with tumor size and specific biomarker levels, were independent factors influencing both critical recurrence and overall survival rates, with 5-year survival rates of 46% for the irregular-defect group versus 61% for the no-irregular-defect group (P < .01).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kupffer Imaging by Contrast-Enhanced Sonography With Perfluorobutane Microbubbles Is Associated With Outcomes After Radiofrequency Ablation of Hepatocellular Carcinoma. Nuta, J., Tamai, H., Mori, Y., et al.[2017]

Sonazoid, a new ultrasound contrast agent, consists of microspheres made from perfluorobutane stabilized by a phospholipid membrane, which allows for effective detection and characterization of liver lesions.

The product shows good stability after reconstitution and can withstand high pressure, making it a reliable option for medical imaging without significant changes in its properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physicochemical characteristics of Sonazoid, a new contrast agent for ultrasound imaging. Sontum, PC.[2022]

Contrast-enhanced 3D ultrasound using Sonazoid can effectively visualize the intrahepatic portal vein structure, showing potential as a non-invasive method to differentiate between idiopathic portal hypertension (IPH) and cirrhosis in patients.

In a study of 16 patients, the 3D ultrasound demonstrated good sensitivity and specificity for diagnosing cirrhosis and IPH, with diagnostic agreement comparable to that of the traditional percutaneous transhepatic portography (PTP) method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive portography: a microbubble-induced three-dimensional sonogram for discriminating idiopathic portal hypertension from cirrhosis. Maruyama, H., Okugawa, H., Kobayashi, S., et al.[2021]

Lumason (sulfur hexafluoride microbubbles) has recently been FDA approved for characterizing focal liver lesions (FLL) in both pediatric and adult patients, which is expected to increase its use in routine clinical practice.

The literature indicates that contrast-enhanced ultrasound (CEUS) using Lumason is accurate for FLL characterization, with existing studies comparing its effectiveness to contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CEMRI).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast enhanced ultrasound for focal liver lesions: how accurate is it? Barr, RG.[2019]

Ultrasound (US) is a simple, noninvasive imaging technique that has advanced significantly in evaluating portal hypertension in patients with cirrhosis, making it widely accessible for assessing chronic liver diseases.

Recent developments, including Doppler techniques and microbubble-based contrast agents, have improved the ability of ultrasound to detect blood flow abnormalities and assess portal hemodynamics effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasonography for Noninvasive Assessment of Portal Hypertension. Maruyama, H., Yokosuka, O.[2022]

In a study involving 60 rats with carbon tetrachloride-induced cirrhotic portal hypertension, ultrasound elastography techniques (STE and STQ) effectively measured liver and spleen stiffness, correlating positively with portal pressure (PP).

The techniques demonstrated high reliability as noninvasive tools for assessing the severity of portal hypertension, particularly effective for identifying PP levels of 10 mmHg or higher.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Sound Touch Elastography and Sound Touch Quantification for the Noninvasive Evaluation of Portal Hypertension in a Rat Model. Dong, B., Lyu, G., Wang, H., et al.[2023]

This study demonstrates a promising noninvasive method to assess portal vein pressure (PVP) using ultrasound contrast agents (UCA), showing strong linear correlations between subharmonic amplitude (SA) and bionic portal vein pressure (BPVP) in controlled experiments.

The method achieved high correlation coefficients (up to 0.968) when using specific UCA concentrations, indicating that this approach could enhance the accuracy of PVP evaluations in clinical settings for patients with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Experimental studies for noninvasive assessment of portal vein pressure based on contrast enhanced subharmonic sonographic imaging]. Xiang, H., Yang, R., Zou, Y., et al.[2023]

Contrast-enhanced sonography can be a feasible noninvasive method for assessing portal venous pressure, as shown in a study involving 20 healthy individuals and 18 patients with portal hypertension.

Key sonographic parameters (Qp/Qa, Ip/Ia, and βp/βa) were found to have significant inverse correlations with portal venous pressure, suggesting they could serve as reliable indicators for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast-enhanced sonography for quantitative assessment of portal hypertension in patients with liver cirrhosis. Qu, EZ., Zhang, YC., Li, ZY., et al.[2016]

References

1. England pubmed.ncbi.nlm.nih.gov

Diagnosis of hepatocellular carcinoma nodules in patients with chronic liver disease using contrast-enhanced sonography: usefulness of the combination of arterial- and kupffer-phase enhancement patterns. [2016]

2. India pubmed.ncbi.nlm.nih.gov

Safety of Perfluorobutane (Sonazoid) in Characterizing Focal Liver Lesions. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Kupffer Imaging by Contrast-Enhanced Sonography With Perfluorobutane Microbubbles Is Associated With Outcomes After Radiofrequency Ablation of Hepatocellular Carcinoma. [2017]

4. England pubmed.ncbi.nlm.nih.gov

Physicochemical characteristics of Sonazoid, a new contrast agent for ultrasound imaging. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Non-invasive portography: a microbubble-induced three-dimensional sonogram for discriminating idiopathic portal hypertension from cirrhosis. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Contrast enhanced ultrasound for focal liver lesions: how accurate is it? [2019]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Ultrasonography for Noninvasive Assessment of Portal Hypertension. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Use of Sound Touch Elastography and Sound Touch Quantification for the Noninvasive Evaluation of Portal Hypertension in a Rat Model. [2023]

9. China pubmed.ncbi.nlm.nih.gov

[Experimental studies for noninvasive assessment of portal vein pressure based on contrast enhanced subharmonic sonographic imaging]. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Contrast-enhanced sonography for quantitative assessment of portal hypertension in patients with liver cirrhosis. [2016]