Noninvasive Ultrasound Technique for Portal Hypertension

Overseen By Morgan L Gabbert, MA

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Thomas Jefferson University

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new ultrasound method called SHAPE for diagnosing portal hypertension (high blood pressure in the liver's portal vein) in children with chronic liver disease. Portal hypertension can lead to severe complications like bleeding from veins in the esophagus. The study will compare two ultrasound contrast agents, Sonazoid (perfluorobutane microbubbles) and Lumason (sulfur hexafluoride lipid-type A microspheres), to determine which works best with SHAPE. Children with chronic liver disease, with or without portal hypertension, may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in diagnosing liver conditions.

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 prior data suggests that this noninvasive ultrasound technique is safe for diagnosing portal hypertension in children?

A previous study found the ultrasound contrast agent Sonazoid, which contains tiny bubbles of perfluorobutane gas, to be safe and well-tolerated by patients. It caused no major side effects during liver imaging, suggesting general safety for medical imaging.

Research also shows that Lumason, another ultrasound contrast agent used in this trial, is safe. It contains tiny bubbles of sulfur hexafluoride gas and has FDA approval for use in both children and adults to help diagnose liver problems. Animal studies showed no harmful effects, and it has a strong safety record in humans.

Overall, past research has shown both Sonazoid and Lumason to be safe, making them promising options for this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a noninvasive ultrasound technique for measuring portal hypertension, using contrast agents like Lumason and Sonazoid. Unlike traditional methods that can be invasive or uncomfortable, this technique allows for a quick and safe measurement using microbubbles in the bloodstream to enhance ultrasound imaging. This method could make monitoring portal hypertension easier and more accessible, especially for children with chronic liver disease. The potential to offer a less invasive and more comfortable option for patients is a significant step forward in managing this condition.

What evidence suggests that this ultrasound technique is effective for diagnosing portal hypertension in children?

Research has shown that SHAPE, a noninvasive ultrasound technique, can effectively measure blood pressure changes in the portal vein. This method uses tiny bubbles to visualize blood flow and pressure inside the body. In this trial, participants will be divided into different arms to explore the effectiveness of two ultrasound contrast agents. One arm will use Sonazoid, which studies suggest can estimate portal vein pressure, crucial for diagnosing portal hypertension. Another arm will use Lumason, which has a proven track record in liver imaging, supporting its use in this context. Both treatments are being explored to provide a safe and effective way to monitor liver health and prevent complications in children with liver issues. ^{1 2 6 7 8}

Who Is on the Research Team?

Flemming Forsberg, PhD

Principal Investigator

Thomas Jefferson University

Sudha A Anupindi, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

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

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.

How Is the Trial Designed?

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+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04720456

NCT04720456 | SHAPE of Portal Hypertension in Children A SHAPE measurement using the ultrasound contrast agent LUMASON® (sulfur hexafluoride lipid-type A microspheres) will be performed during a single visit. Two ...

2. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/203684s009lbl.pdf

Lumason - accessdata.fda.gov No adverse developmental outcomes were observed in animal reproduction studies with administration of sulfur hexafluoride lipid-type A microspheres in pregnant ...

3. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT04720456/

Trial | NCT04720456 A SHAPE measurement using the ultrasound contrast agent LUMASON® (sulfur hexafluoride lipid-type A microspheres) will be performed during a single visit. Two ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5886815/

CONTRAST-ENHANCED ULTRASOUND OF THE LIVER Currently, there are two purely intravascular ultrasound contrast agents with proven track record in liver imaging available for clinical use in the USA.

5. fda.gov fda.gov/media/133813/download

CLINICAL REVIEW Lumason (sulfur hexafluoride lipid-type A microspheres). 1. CLINICAL REVIEW. Application Type. Pediatric Supplemental New Drug Application.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2019/203684s005lbl.pdf

lumason - accessdata.fda.gov Shake vigorously for 20 seconds, mixing all the contents in the vial (see Figure 6). A homogeneous white milky liquid indicates formation of sulfur hexafluoride ...

7. lumason.com lumason.com/liver/

Liver LUMASON is the 1st & only approved ultrasound contrast agent for use in pediatric & adult patients to characterize focal liver lesions. Learn more.

8. asecho.org asecho.org/wp-content/uploads/2019/07/2018-LUMASON-Formulary-Kit-APPROVED.pdf

LUMASON FORMULARY KIT LUMASON (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use or intravesical use full Prescribing Information.