Noninvasive SHAPE for Portal Hypertension

Recruiting at 2 trial locations

Overseen By Kevin Anton, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Thomas Jefferson University

Must be taking: Non-selective β-blockers

Must not be taking: Chemotherapy

Disqualifiers: Pulmonary hypertension, Unstable cardiopulmonary, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 6

Duration: 18-24 months

660 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to measure blood pressure in the liver using ultrasound, called SHAPE (Subharmonic Aided Pressure Estimation), to manage portal hypertension and related liver issues. It includes four groups: one to assess the consistency of SHAPE measurements; another for individuals with significant portal hypertension to evaluate if SHAPE can predict liver problems; a third for those beginning treatment with specific blood pressure medications to monitor progress; and a fourth to determine if SHAPE can guide screening for varices (swollen veins). Suitable participants include those with portal hypertension who are already monitored for liver cancer, starting new treatment, or scheduled for certain medical procedures. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are starting treatment with non-selective β-blockers, you will continue with that medication as part of the study.

What prior data suggests that SHAPE is safe for portal hypertension?

Research has shown that SHAPE (Subharmonic Aided Pressure Estimation) using Definity and Sonazoid, special ultrasound contrast agents, has been studied for safety and effectiveness in measuring body pressures. These agents are generally safe for humans.

Specifically, past studies have used Definity and Sonazoid to detect high blood pressure in the liver's portal vein, demonstrating their safety. While mild discomfort may occur during the procedure, serious side effects are rare.

Since this trial is in a later stage, earlier research has already provided some confidence in the safety of these agents. For any concerns, discussing them with the study team or your doctor is advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores SHAPE, a cutting-edge technique using ultrasound contrast agents, for assessing portal hypertension. Unlike traditional methods that often rely on invasive procedures like endoscopy, SHAPE offers a noninvasive alternative, which can be much more comfortable for patients. This technique employs advanced ultrasound contrast agents like Sonazoid and Definity to provide real-time imaging, potentially offering more frequent and easier monitoring of liver conditions. By comparing different ultrasound agents for accuracy and effectiveness, the trial aims to refine and validate this method, potentially revolutionizing the management of portal hypertension.

What evidence suggests that SHAPE is effective for portal hypertension?

Research has shown that SHAPE, a new method, looks promising for measuring high blood pressure in the liver, known as portal hypertension. In this trial, different cohorts will undergo SHAPE measurements using special contrast agents, Definity and Sonazoid, to assess their effectiveness in accurately measuring liver pressure levels. Specifically, Sonazoid tracked pressure changes very precisely in animal studies, with only a small margin of error. Both agents have effectively identified portal hypertension in patients, offering a noninvasive alternative to traditional methods. This approach could aid in monitoring and managing liver-related conditions. ^{2 3 6 7 8}

Who Is on the Research Team?

Flemming Forsberg, PhD

Principal Investigator

Thomas Jefferson University

Are You a Good Fit for This Trial?

Adults with stable health and diagnosed liver disease, specifically portal hypertension. They must be able to follow study procedures and provide consent. Women of childbearing age need a negative pregnancy test. Excluded are those with pulmonary issues, other cancers, severe illnesses, certain allergies (to PEG or eggs), recent surgery, unstable heart conditions, or hepatic encephalopathy.

Inclusion Criteria

I have portal hypertension and am starting treatment with non-selective β-blockers.

Have read and signed the IRB-approved Informed Consent form for participating in the study

I am scheduled for a liver biopsy to measure my liver pressure.

Exclusion Criteria

You have had a severe allergic reaction to eggs or food containing eggs in the past.

You have a serious or terminal illness, or your condition is very unpredictable.

I do not have severe, uncontrolled heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo SHAPE procedures using ultrasound contrast agents to estimate portal pressures and monitor liver conditions

18-24 months

Follow-up ultrasound scans every 6 ± 2 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including the development of ascites and other liver-related events

up to 18 months

What Are the Treatments Tested in This Trial?

Interventions

• SHAPE measurement (Definity ultrasound contrast agent)
• SHAPE measurement (Sonazoid ultrasound contrast agent)

Trial Overview The trial tests SHAPE measurements using Sonazoid and Definity ultrasound contrast agents for estimating portal pressures in patients with liver disease across four cohorts based on their specific condition related to portal hypertension.

How Is the Trial Designed?

Group I: Reproducibility - Cohort 1 Experimental Treatment 2 Interventions

Patients scheduled for hepatic venous pressure gradient (HVPG) measurements will subsequently undergo two consecutive SHAPE procedures using different ultrasound contrast agents (Definity and Sonazoid in randomized order) to estimate portal pressures with a Logiq E10 scanner (GE Healthcare). Three vials with 48 µl of Sonazoid (GE Healthcare, Oslo, Norway) microbubbles (6 ml) will be prepared and drawn into a 10 ml syringe, placed in a syringe pump. Sonazoid will be co-infused at a rate of 0.024 µl/kg body weight/minute (suspension infusion rate of 0.18 ml/kg/hour) together with a 0.9% NaCl solution infused at a rate of at least 2 ml/min. Two vials with 3 mL of Definity will be mixed and diluted in 50 mL of normal saline, yielding a concentration of 49.4 μL/mL, and infused at a rate of at least 4 ml/min.

Group II: New β-blockers - Cohort 3 Experimental Treatment 1 Intervention

Patients newly diagnosed with portal hypertension and starting treatment with non-selective β-blockers will be monitored with SHAPE Three vials with 48 µl of Sonazoid (GE Healthcare, Oslo, Norway) microbubbles (6 ml) will be prepared and drawn into a 10 ml syringe, placed in a syringe pump. Sonazoid will be co-infused at a rate of 0.024 µl/kg body weight/minute (suspension infusion rate of 0.18 ml/kg/hour) together with a 0.9% NaCl solution infused at a rate of at least 2 ml/min.

Group III: HCC monitoring - Cohort 2 Experimental Treatment 1 Intervention

Patients identified as having CSPH will be monitored every 6 ± 2 months to check for HCC by SHAPE with Sonazoid for the duration of this project ( for 18-24 months on average). Three vials with 48 µl of Sonazoid (GE Healthcare, Oslo, Norway) microbubbles (6 ml) will be prepared and drawn into a 10 ml syringe, placed in a syringe pump. Sonazoid will be co-infused at a rate of 0.024 µl/kg body weight/minute (suspension infusion rate of 0.18 ml/kg/hour) together with a 0.9% NaCl solution infused at a rate of at least 2 ml/min.

Group IV: Ccreening for varices - Cohort 4 Experimental Treatment 1 Intervention

Patients with compensated advanced chronic liver disease scheduled for an endoscopy examination for screening of varices according to the Baveno VI or the expanded-Baveno VI criteria as well as the AST to Platelet Ratio Index and FIB-4 will undergo a SHAPE examination. Three vials with 48 µl of Sonazoid (GE Healthcare, Oslo, Norway) microbubbles (6 ml) will be prepared and drawn into a 10 ml syringe, placed in a syringe pump. Sonazoid will be co-infused at a rate of 0.024 µl/kg body weight/minute (suspension infusion rate of 0.18 ml/kg/hour) together with a 0.9% NaCl solution infused at a rate of at least 2 ml/min.

Who Is Running the Clinical Trial?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

University of Bern

Collaborator

Trials

377

Recruited

1,393,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

The study successfully developed a customized interface for real-time intracardiac pressure estimation using ultrasound contrast agents, which could provide a noninvasive alternative to traditional cardiac catheterization.

Optimal parameters for using microbubbles Definity and Sonazoid were identified, with specific transmit frequencies and pulse shaping options yielding the highest correlations with actual pressure measurements, indicating effective functionality for clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing an Interface and Investigating Optimal Parameters for Real-Time Intracardiac Subharmonic-Aided Pressure Estimation. Esposito, C., Dickie, K., Forsberg, F., et al.[2023]

Subharmonic aided pressure estimation (SHAPE) effectively monitors disease progression in patients with portal hypertension, showing a significant reduction in SHAPE signal among treatment responders compared to nonresponders.

In a study of 21 patients, those who responded to treatment exhibited a notable decrease in SHAPE signal, correlating with improved clinical outcomes such as better MELD scores and liver function tests, suggesting SHAPE's potential utility in clinical management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Noninvasive Ultrasound Based Technique to Identify Treatment Responders in Patients with Portal Hypertension. Gupta, I., Fenkel, JM., Eisenbrey, JR., et al.[2022]

This study established a strong linear correlation between portal vein pressure (PVP) and the subharmonic signal amplitude from SonoVue microbubbles in a canine model, indicating that ultrasound contrast agents can be used for non-invasive pressure measurement.

The method demonstrated a sensitivity of -2.003 dB/mmHg at an acoustic pressure of 453 kPa, which is significantly more sensitive than previous in vitro methods, suggesting its potential for clinical applications in diagnosing portal hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation Between Portal Vein Pressure and Subharmonic Scattering Signals From SonoVue Microbubbles in Canines. Lu, H., Xu, G., Wang, Y., et al.[2023]

The study evaluated different processing techniques for subharmonic-aided pressure estimation (SHAPE) using ultrasound contrast agents, specifically focusing on the extraction of subharmonic amplitudes from raw radiofrequency data.

The optimal processing method, which involved extracting subharmonic data within a 0.2 MHz bandwidth and applying a median filter, achieved a strong correlation with ambient pressure measurements (r2 = 0.90), indicating its potential for real-time applications in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Processing of subharmonic signals from ultrasound contrast agents to determine ambient pressures. Dave, JK., Halldorsdottir, VG., Eisenbrey, JR., et al.[2017]

The study developed a method called subharmonic aided pressure estimation (SHAPE) using microbubble ultrasound contrast agents to noninvasively estimate hydrostatic blood pressures, achieving excellent correlation with traditional pressure catheter measurements (r² = 0.87).

Among five tested ultrasound contrast agents, Sonazoid was found to be the most sensitive for pressure estimation, with optimal performance at a frequency of 2.5 MHz and acoustic pressure of 0.35 MPa, indicating its potential for real-time noninvasive blood pressure monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions. Halldorsdottir, VG., Dave, JK., Leodore, LM., et al.[2023]

Subharmonic-aided pressure estimation (SHAPE) is a promising noninvasive technique for diagnosing clinically significant portal hypertension, showing a strong correlation with the invasive hepatic venous pressure gradient (HVPG) measurements in a study of 125 participants.

SHAPE demonstrated high sensitivity (90%) and specificity (80%) for detecting portal hypertension, indicating it could be a safer alternative to the standard invasive methods currently used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosing Portal Hypertension with Noninvasive Subharmonic Pressure Estimates from a US Contrast Agent. Gupta, I., Eisenbrey, JR., Machado, P., et al.[2022]

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 of 20 dialysis patients, the noninvasive ultrasound technique called subharmonic-aided pressure estimation (SHAPE) showed a moderate correlation with hepatic venous pressure gradient (HVPG) and was better at predicting liver fibrosis stages compared to HVPG.

SHAPE demonstrated an 80% diagnostic accuracy for differentiating between mild and moderate to severe fibrosis, while HVPG did not show significant differences in fibrosis staging, suggesting SHAPE may be a more reliable method for assessing portal hypertension in dialysis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound Pressure Estimation for Diagnosing Portal Hypertension in Patients Undergoing Dialysis for Chronic Kidney Disease. Machado, P., Gupta, I., Fenkel, JM., et al.[2023]

Monodisperse microbubbles, created with precise size control, showed stable size distributions and significantly improved the sensitivity of subharmonic aided pressure estimation (SHAPE) for measuring hydrostatic pressures, achieving a sensitivity of -0.17 dB/mmHg, nearly double that of current polydisperse microbubbles used in clinical trials.

The study demonstrated that these microbubbles have a strong correlation between their size and resonance frequency, which enhances their effectiveness in generating subharmonic signals for pressure estimation, making them a promising tool for noninvasive clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Sensitivity of Ultrasound-Based Subharmonic Aided Pressure Estimation Using Monodisperse Microbubbles. van Hoeve, W., de Vargas Serrano, M., Te Winkel, L., et al.[2022]

Citations

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An experimental study on subharmonic-aided pressure ... This study evaluates the performance of subharmonic-aided pressure estimation (SHAPE) with ultrasound contrast agents using data obtained ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05470205

Noninvasive Subharmonic Aided Pressure Estimation of ... Evaluate the use of in vivo SHAPE with 2 ultrasound contrast agents (Sonazoid and Definity) for determining the presence of portal hypertension in patients ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33346203/

Contrast-Enhanced Subharmonic Aided Pressure Estimation ... Here an ultrasound system capable of performing real-time, subharmonic aided pressure estimation (SHAPE) is presented.

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/poh2.45

Subharmonic aided pressure estimation in portal ... Contrast-enhanced subharmonic aided pressure estimation (SHAPE) using ultrasound imaging with a focus on identifying portal hypertension.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0041624X2500277X

A comparative evaluation of two subharmonic-aided ... Pressure measurement in clinical practice is a valuable tool for diagnostic evaluation, especially in diseases such as portal hypertension.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8327282/

Contrast-Enhanced Subharmonic Aided Pressure ... A protocol for noninvasively, estimating ambient pressures utilizing subharmonic ultrasound imaging of infused contrast microbubbles.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S030156292400293X

Investigation Into the Subharmonic Response of Three ... The subharmonic responses of contrast agents can be exploited to perform subharmonic-aided pressure estimation. Methods. The subharmonic response of each ...

8. jacc.org jacc.org/doi/10.1016/j.jcmg.2022.09.013

Noninvasive Evaluation of Cardiac Chamber Pressures ... Subharmonic-aided pressure estimation (SHAPE) is a technique that combines the use of ultrasound and ultrasound contrast agents (UCA), and it ...