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

Trial Summary

What is the purpose of this trial?

This is an open-label, non-randomized trial that will be conducted at three clinical sites, Thomas Jefferson University (TJU), the Hospital of the University of Pennsylvania (HUP) and University of Bern (UB). Enrollment will be allocated into one of 4 different cohorts depending on the inclusion criteria for each cohort. Cohort 1: Patients scheduled for hepatic vein pressure gradient (HVPG) measurements will subsequently undergo two consecutive SHAPE (subharmonic aided pressure estimation) procedures using different ultrasound contrast agents (Definity \[Lantheus Medical Imaging, N Bilerica, MA, USA\] and Sonazoid \[GE Healthcare, Oslo, Norway\] in randomized order) to estimate portal pressures with a Logiq E10 scanner (GE Healthcare, Waukesha, WI, USA) and determine the reproducibility of the SHAPE algorithm. Cohort 2: Patients identified as having clinically significant portal hypertension (CSPH) will be monitored by SHAPE with Sonazoid for the duration of this project (18-24 months on average). These subjects will have follow-up ultrasound scans every 6 ± 2 months to check for hepatocellular carcinoma (HCC) (using the Barcelona-Liver Cancer staging system) as well as ascites and at those times a repeat SHAPE examination will be performed. Liver stiffness values will be measured with elastography as well. This cohort will examine if serial SHAPE can accurately predict development of ascites and other liver related events in patients with compensated cirrhosis undergoing routine HCC surveillance in a multi-center setting. Cohort 3: Subjects newly diagnosed with portal hypertension and starting treatment with non-selective β-blockers will be monitored with SHAPE and results compared to elastography measurements of liver stiffness with standard assessments (e.g., serum liver function tests and measurement of spleen size as well as platelet count). This cohort will establish if SHAPE can be used to monitor treatment response in patients identified with portal hypertension. Cohort 4: Patients with compensated advanced chronic liver disease scheduled for an endoscopy examination for screening of varices relative to the Baveno VI and the expanded-Baveno VI criteria as well as the AST to Platelet Ratio Index will undergo a SHAPE examination. This cohort will compare the predictive ability of SHAPE for allocating patients with compensated advanced chronic liver disease to screening of varices compared to the current standard of care.

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 data supports the effectiveness of the treatment SHAPE measurement (Definity ultrasound contrast agent) for portal hypertension?

Research shows that SHAPE, which uses ultrasound contrast agents like Definity, can effectively measure blood pressure changes noninvasively. This technique has been validated in various clinical settings, suggesting it could be useful for monitoring portal hypertension. ^{1 2 3 4 5}

Is the SHAPE technique using ultrasound contrast agents safe for humans?

The studies primarily focus on the technical aspects and effectiveness of SHAPE for pressure estimation, but they do not provide specific safety data for humans. However, ultrasound contrast agents like Definity and Sonazoid, used in SHAPE, are generally considered safe when used according to guidelines. ^{1 2 3 4 5}

How does the SHAPE treatment differ from other treatments for portal hypertension?

The SHAPE treatment is unique because it uses a noninvasive ultrasound technique to estimate pressure in the portal vein, unlike the standard invasive method. This approach reduces risk and allows for routine monitoring of portal hypertension without the need for invasive procedures. ^{1 6 7 8 9}

Research Team

Flemming Forsberg, PhD

Principal Investigator

Thomas Jefferson University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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) 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]

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]

References

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

A Noninvasive Ultrasound Based Technique to Identify Treatment Responders in Patients with Portal Hypertension. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Improved Sensitivity of Ultrasound-Based Subharmonic Aided Pressure Estimation Using Monodisperse Microbubbles. [2022]

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

Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions. [2023]

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

Processing of subharmonic signals from ultrasound contrast agents to determine ambient pressures. [2017]

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

Developing an Interface and Investigating Optimal Parameters for Real-Time Intracardiac Subharmonic-Aided Pressure Estimation. [2023]

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

Diagnosing Portal Hypertension with Noninvasive Subharmonic Pressure Estimates from a US Contrast Agent. [2022]

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

Ultrasonography for Noninvasive Assessment of Portal Hypertension. [2022]

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

Ultrasound Pressure Estimation for Diagnosing Portal Hypertension in Patients Undergoing Dialysis for Chronic Kidney Disease. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Correlation Between Portal Vein Pressure and Subharmonic Scattering Signals From SonoVue Microbubbles in Canines. [2023]