Noninvasive Subharmonic Aided Pressure Estimation of Portal Hypertension; Renewal

Study Overview
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Brief Summary
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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.

Detailed Description
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For each SHAPE study (Cohorts 1, 2, 3 and 4), a dose of three vials with 60 μL of Sonazoid microbubbles (6 mL) will be prepared. An infusion of Sonazoid (1.44 μL microbubbles/kg/hour) and saline (120 mL/hour) through an IV line in the antecubital vein (or, if need be, in another suitable vein) will be started. The duration of contrast agent infusion will range from 6 to 10 minutes. For the direct contrast agent comparison in Cohort 1, two vials of Definity will be mixed and diluted in 50 mL of normal saline, yielding a concentration of 49.4 μL/mL, and infused over approximately 10-12 minutes. A waiting period of at least 30 minutes will be observed in Cohort 1 between infusing contrast agents and the order of the contrast agents will be randomized. Once the infusion of contrast has started, ultrasound imaging will be performed with the C1-6-D curvi-linear array (GE Healthcare) to guide SHAPE ROI placement into the portal vein (while also visualizing a hepatic vein). The SHAPE optimization algorithm will be activated and the acoustic power will be adjusted to produce the maximum change in subharmonic amplitudes (i.e., maximizing the sensitivity of SHAPE). Subharmonic raw DICOM data from the microbubbles (i.e., SHAPE) will be acquired at the optimal acoustic power setting in 5 s segments during the infusion of the Sonazoid (or Definity) suspension. All measurements will be repeated three times to allow for averaging of the resulting SHAPE pressure estimates. The SHAPE pressure estimates will be calculated on the Logiq E10 and recorded. Finally, all digital clips will be transferred off-line for backup and to permit repeat calculations of the portal pressure estimates in case new processing parameters are developed as part of this study.

Official Title
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Noninvasive Subharmonic Aided Pressure Estimation of Portal Hypertension

Conditions
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Liver Diseases, Portal Hypertension

Intervention / Treatment
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* Drug: SHAPE measurement (Sonazoid ultrasoud contrast agent)
* Drug: SHAPE measurement (Definity ultrasoud contrast agent)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects accepted for this trial must fulfill all the following criteria: Be at least 18 years of age. Be medically stable. If a female of child-bearing potential, must have a negative pregnancy test. Be conscious and able to comply with study procedures. Have read and signed the IRB-approved Informed Consent form for participating in the study. Also there are specific inclusion criteria for each cohort: Cohort 1: • Be scheduled for transjugular liver biopsy where HVPG measurements will be obtained Cohort 2: • Have clinically significant portal hypertension undergoing routine HCC surveillance Cohort 3: • Have a diagnosis of portal hypertension and starting treatment with non-selective β-blockers Cohort 4: • Have clinically significant portal hypertension and be scheduled for endoscopy to screen for varices Exclusion Criteria: Females who are pregnant or nursing. Patients with pulmonary hypertension or unstable cardiopulmonary conditions Patients currently on chemotherapy or with other primary cancers requiring systemic or hepatic loco-regional treatment. Patients who are medically unstable, patients who are seriously or terminally ill, and patients whose clinical course is unpredictable. For example: Patients on life support or in a critical care unit. Patients with unstable occlusive disease (e.g., crescendo angina) Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia. Patients with uncontrolled congestive heart failure (NYHA Class IV) Patients with recent cerebral hemorrhage. Patients who have undergone surgery within 24 hours prior to the study sonographic examination. Patients with a history of anaphylactic allergy to eggs or egg products, manifested by one or more of the following symptoms: generalized urticaria, difficulty in breathing, swelling of the mouth and throat, hypotension, or shock. (Subjects with nonanaphylactic allergies to eggs or egg products may be enrolled in the study, but must be watched carefully for 1 hour following the administration of Sonazoid). Patients with congenital heart defects. Patients with severe emphysema, pulmonary vasculitis, or a history of pulmonary emboli. Patients with respiratory distress syndrome Patients with thrombosis within the hepatic, portal, or mesenteric veins. Patients with grade 2 and above of hepatic encephalopathy within the last 3 months Also there is one additional exclusion criteria for cohort 1: • Patients with a history of anaphylactic allergy to perflutren (PEG) or any other components of Definity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reproducibility - Cohort 1<br>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. | Drug: SHAPE measurement (Sonazoid ultrasoud contrast agent)<br>* 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.<br>* Other names: Sonazoid;Drug: SHAPE measurement (Definity ultrasoud contrast agent)<br>* 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.<br>* Other names: Definity;|
| Experimental: HCC monitoring - Cohort 2<br>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. | Drug: SHAPE measurement (Sonazoid ultrasoud contrast agent)<br>* 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.<br>* Other names: Sonazoid;|
| Experimental: New β-blockers - Cohort 3<br>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. | Drug: SHAPE measurement (Sonazoid ultrasoud contrast agent)<br>* 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.<br>* Other names: Sonazoid;|
| Experimental: Ccreening for varices - Cohort 4<br>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. | Drug: SHAPE measurement (Sonazoid ultrasoud contrast agent)<br>* 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.<br>* Other names: Sonazoid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reproducibility of SHAPE liver pressure measurements | Evaluate the use of in vivo SHAPE with 2 ultrasound contrast agents (Sonazoid and Definity) for determining the presence of portal hypertension in patients undergoing a transjugular liver biopsy using catheter based pressure measurements as the reference standard. | during procedure | 
| Number of subjects who develop ascites during follow-up | Determine if SHAPE estimates of portal vein pressures in patients with compensated cirrhosis can predict the development of ascites (i.e., the progression into decompensated cirrhosis or HVPG > 16 mmHg). | up to 18 months | 
| Number of subjects who experience clinical decompensation events (including the development of variceal bleeding) during follow-up | Determine if SHAPE measurements can monitor treatment response (i.e., the ability to accurately assess the response to non-selective beta blockers) in patients newly diagnosed with portal hypertension better than elastography. | up to 18 months | 
| Number of subjects who present with esophageal or gastric varices on endoscopy | In subjects allocated to endoscopic screening for varices based on their clinical risk assessment the outcome of the endoscopic procedure will be compared to their SHAPE values | baseline |