Noninvasive SHAPE for Portal Hypertension
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
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
Pivotal Trial (Near Approval)
Prior Safety Data
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.
12345Is 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.
12345How 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.
16789Eligibility 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.
I am 18 years old or older.
Have read and signed the IRB-approved Informed Consent form for participating in the study
+6 more
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.
+13 more
Trial 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
Participant Groups
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.
4Treatment groups
Experimental Treatment
Group I: Reproducibility - Cohort 1Experimental Treatment2 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 3Experimental Treatment1 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 2Experimental Treatment1 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 4Experimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
Thomas Jefferson University, Dept of RadiologyPhiladelphia, PA
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Who Is Running the Clinical Trial?
Thomas Jefferson UniversityLead Sponsor
University of BernCollaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Collaborator
University of PennsylvaniaCollaborator
References
A Noninvasive Ultrasound Based Technique to Identify Treatment Responders in Patients with Portal Hypertension. [2022]Subharmonic aided pressure estimation (SHAPE) is based on the inverse relationship between the subharmonic amplitude of ultrasound contrast microbubbles and ambient pressure. The aim of this study was to verify if SHAPE can accurately monitor disease progression in patients identified with portal hypertension.
Improved Sensitivity of Ultrasound-Based Subharmonic Aided Pressure Estimation Using Monodisperse Microbubbles. [2022]Subharmonic aided pressure estimation (SHAPE) has been shown effective for noninvasively measuring hydrostatic fluid pressures in a variety of clinical applications. The objective of this study was to explore potential improvements in SHAPE sensitivity using monodisperse microbubbles.
Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions. [2023]Our group has proposed the concept of subharmonic aided pressure estimation (SHAPE) utilizing microbubble-based ultrasound contrast agent signals for the noninvasive estimation of hydrostatic blood pressures. An experimental system for in vitro SHAPE was constructed based on two single-element transducers assembled confocally at a 60 degree angle to each other. Changes in the first, second and subharmonic amplitudes of five different ultrasound contrast agents were measured in vitro at static hydrostatic pressures from 0-186 mmHg, acoustic pressures from 0.35-0.60 MPa peak-to-peak and frequencies of 2.5-6.6 MHz. The most sensitive agent and optimal parameters for SHAPE were determined using linear regression analysis and implemented on a Logiq 9 scanner (GE Healthcare, Milwaukee, WI). This implementation of SHAPE was then tested under dynamic-flow conditions and compared to pressure-catheter measurements. Over the pressure range studied, the first and second harmonic amplitudes reduced approximately 2 dB for all contrast agents. Over the same pressure range, the subharmonic amplitudes decreased by 9-14 dB and excellent linear regressions were achieved with the hydrostatic pressure variations (r = 0.98, p
Processing of subharmonic signals from ultrasound contrast agents to determine ambient pressures. [2017]Subharmonic-aided pressure estimation (SHAPE) is a technique that utilizes the subharmonic emissions, occurring at half the insonation frequency, from ultrasound contrast agents to estimate ambient pressures. The purpose of this work was to compare the performance of different processing techniques for the raw radiofrequency (rf) data acquired for SHAPE. A closed loop flow system was implemented circulating reconstituted Sonazoid (GE Healthcare, Oslo, Norway; 0.2 ml for 750 ml diluent) and the beam-formed unprocessed rf data were obtained from a 4 mm diameter lumen of a Doppler flow phantom (ATS Laboratories, Inc., Bridgeport, CT) using a SonixRP scanner (Ultrasonix, Richmond, BC, Canada). The transmit frequency and incident acoustic pressures were set to 2.5 MHz and 0.22 MPa, respectively, in order to elicit Sonazoid subharmonic emissions that are ambient-pressure sensitive. The time-varying ambient pressures within the flow phantom were recorded by a Millar pressure catheter. Four techniques for extracting the subharmonic amplitude from the rf data were tested along with two noise filtering techniques to process this data. Five filter orders were tested for the noise removing filters. The performance was evaluated based on the least root-mean-square errors reported after linear least-square regression analyses of the subharmonic data and the pressure catheter data and compared using a repeated ANOVA. When the subharmonic amplitudes were extracted as the mean value within a 0.2 MHz bandwidth about 1.25 MHz and when the resulting temporally-varying subharmonic signal was median filtered with an order of 500, the filtered subharmonic signal significantly predicted the ambient pressures (r2 = 0.90; p
Developing an Interface and Investigating Optimal Parameters for Real-Time Intracardiac Subharmonic-Aided Pressure Estimation. [2023]Thisstudy focuses on evaluating the real-time functionality of a customized interface and investigating the optimal parameters for intracardiac subharmonic-aided pressure estimation (SHAPE) utilizing Definity (Lantheus Medical Imaging Inc., North Billerica, MA, USA) and Sonazoid (GE Healthcare, Oslo, Norway) microbubbles. Pressure measurements within the chambers of the heart yield critical information for managing cardiovascular diseases. An alternative to current, invasive, clinical cardiac catheterization procedures is utilizing ultrasound contrast agents and SHAPE to noninvasively estimate intracardiac pressures. Therefore, this work developed a customized interface (on a SonixTablet, BK Ultrasound, Peabody, MA, USA) for real-time intracardiac SHAPE. In vitro, a Doppler flow phantom was utilized to mimic the dynamic pressure changes within the heart. Definity (15.0- [Formula: see text] microspheres corresponding to 0.1-0.15 mL) and Sonazoid (GE Healthcare; 0.4- [Formula: see text] microspheres corresponding to 0.05-0.15 mL) microbubbles were used. Data were acquired for varying transmit frequencies (2.5-4.0 MHz), and pulse shaping options (square wave and chirp down) to determine optimal transmit parameters. Simultaneously obtained radio frequency data and ambient pressure data were compared. For Definity, the chirp down pulse at 3.0 MHz yielded the highest correlation ( r = - 0.77 ± 0.2 ) between SHAPE and pressure catheter data. For Sonazoid, the square wave pulse at 2.5 MHz yielded the highest correlation ( r = - 0.72 ± 0.2 ). In conclusion, the real-time functionality of the customized interface has been verified, and the optimal parameters for utilizing Definity and Sonazoid for intracardiac SHAPE have been determined.
Diagnosing Portal Hypertension with Noninvasive Subharmonic Pressure Estimates from a US Contrast Agent. [2022]Background The current standard for assessing the severity of portal hypertension is the invasive acquisition of hepatic venous pressure gradient (HVPG). A noninvasive US-based technique called subharmonic-aided pressure estimation (SHAPE) could reduce risk and enable routine acquisition of these pressure estimates. Purpose To compare quantitative SHAPE to HVPG measurements to diagnose portal hypertension in participants undergoing a transjugular liver biopsy. Materials and Methods This was a prospective cross-sectional trial conducted at two hospitals between April 2015 and March 2019 (ClinicalTrials.gov identifier, NCT02489045). This trial enrolled participants who were scheduled for transjugular liver biopsy. After standard-of-care transjugular liver biopsy and HVPG pressure measurements, participants received an infusion of a US contrast agent and saline. During infusion, SHAPE data were collected from a portal vein and a hepatic vein, and the difference was compared with HVPG measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity of SHAPE. Results A total of 125 participants (mean age ± standard deviation, 59 years ± 12; 80 men) with complete data were included. Participants at increased risk for variceal hemorrhage (HVPG ≥12 mm Hg) had a higher mean SHAPE gradient compared with participants with lower HVPGs (0.79 dB ± 2.53 vs -4.95 dB ± 3.44; P < .001), which is equivalent to a sensitivity of 90% (13 of 14; 95% CI: 88, 94) and a specificity of 80% (79 of 99; 95% CI: 76, 84). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the HVPG measurements (r = 0.68). Conclusion Subharmonic-aided pressure estimation is an accurate noninvasive technique for detecting clinically significant portal hypertension. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kiessling in this issue.
Ultrasonography for Noninvasive Assessment of Portal Hypertension. [2022]Portal hypertension is a major pathophysiology in patients with cirrhosis. Portal pressure is the gold standard to evaluate the severity of portal hypertension, and radiological intervention is the only procedure for pressure measurement. Ultrasound (US) is a simple and noninvasive imaging modality available worldwide. B-mode imaging allows broad applications for patients to detect and characterize chronic liver diseases and focal hepatic lesions. The Doppler technique offers real-time observation of blood flow with qualitative and quantitative assessments, and the application of microbubble-based contrast agents has improved the detectability of peripheral blood flow. In addition, elastography for the liver and spleen covers a wider field beyond the original purpose of fibrosis assessment. These developments enhance the practical use of US in the evaluation of portal hemodynamic abnormalities. This article reviews the recent progress of US in the assessment of portal hypertension.
Ultrasound Pressure Estimation for Diagnosing Portal Hypertension in Patients Undergoing Dialysis for Chronic Kidney Disease. [2023]Hepatic venous pressure gradient (HVPG) is considered the standard in quantifying portal hypertension, but can be unreliable in dialysis patients. A noninvasive ultrasound technique, subharmonic-aided pressure estimation (SHAPE), may be a valuable surrogate of these pressure estimates. This study compared SHAPE and HVPG with pathology findings for fibrosis in dialysis patients.
Correlation Between Portal Vein Pressure and Subharmonic Scattering Signals From SonoVue Microbubbles in Canines. [2023]The current gold standard for the clinical diagnosis of portal hypertension (PH) is an invasive and indirect estimation of portal vein pressure (PVP). Therefore, the need for a non-invasive PVP measurement method is urgent. Subharmonic scattering of ultrasound contrast agent (UCA) microbubbles is under investigation in clinical research as a pressure indicator. However, the driving acoustic pressure must be optimized to improve the ambient pressure sensitivity of the subharmonic amplitude for different UCAs. In this study, for the first time, we obtained the relationship between the PVP and the amplitude of the subharmonic signal scattered from SonoVue microbubbles by using two canines to build the PH model. The results revealed a desirable linear correlation between the subharmonic amplitude and PVP (