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SHAPE of Portal Hypertension in Children

Primary Purpose

Hypertension, Portal

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
SHAPE measurement using the ultrasound contrast agent Sonazoid (perfluorobutane microbubbles)
SHAPE measurement using the ultrasound contrast agent Lumason (sulfur hexafluoride lipid-type A microspheres)
Sponsored by
Thomas Jefferson University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Hypertension, Portal

Eligibility Criteria

6 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with a diagnosis of chronic liver disease without portal hypertension.
  • Patients with a diagnosis of chronic liver disease with portal hypertension.

Exclusion Criteria:

  • Subjects who are pregnant.
  • Patients with known or suspected hypersensitivity to egg phosphatidyl serine or with a history of anaphylactic allergy to eggs or egg products.
  • Subjects with allergy to egg products or other components of the ultrasound contrast agents will be excluded.
  • History of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na), palmitic acid)
  • History of allergic reaction to Sonazoid
  • Patients with biliary atresia with asplenia or polysplenia.
  • Patients with prior liver transplant.
  • Patients with cystic fibrosis.
  • Patients with chronic lung disease.
  • Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein.
  • Adults not competent/impaired.
  • Patients with significant heart disease or severe congenital heart disease

Sites / Locations

  • The Children's Hospital of PhiladelphiaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

SHAPE with Sonazoid

SHAPE with Lumason

Longitudinal SHAPE

Arm Description

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).

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).

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.

Outcomes

Primary Outcome Measures

The rate (%) of adverse events that occur with Sonazoid compared to the current rate of adverse events that have been reported in the Lumason package insert for pediatric use (0.001%)
Calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins will differentiate between the portal hypertension and non-portal hypertension groups with an accuracy of 94%

Secondary Outcome Measures

Changes in calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins over time will predict the development of complications of portal hypertension (variceal bleeding, ascites, hepatopulmonary syndrome, etc)
Calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins and liver fibrosis stage (on a scale from 0-4 as determined by liver biopsy) will correlate with a p<0.05
Compare the calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins obtained with Lumason and Sonazoid, respectively, for their ability to differentiate between the portal hypertension and non-portal hypertension groups
Compare calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins to shear wave elastography values (in m/s) using regression analysis

Full Information

First Posted
January 4, 2021
Last Updated
July 10, 2023
Sponsor
Thomas Jefferson University
Collaborators
Children's Hospital of Philadelphia, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT04720456
Brief Title
SHAPE of Portal Hypertension in Children
Official Title
Noninvasive Subharmonic Aided Pressure Estimation of Portal Hypertension in Children
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 3, 2021 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
August 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Thomas Jefferson University
Collaborators
Children's Hospital of Philadelphia, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Early diagnosis of portal hypertension is difficult as symptoms rarely manifest until the later stages of liver disease. Both cirrhotic and non-cirrhotic portal hypertension can result in life-threatening complications, the most frequent of which is bleeding from esophageal varices. In children, variceal bleeds are associated with mortality rates of 1-3 %, while life-threatening complications have been reported in up to 20 % of children with cirrhosis. Despite the high incidence of portal hypertension in children with liver disease, a noninvasive modality to monitor disease progression and risk of complications is currently lacking. Hence, this trial will investigate the safety and efficacy of subharmonic aided pressure estimation (SHAPE) as a noninvasive ultrasound technique for diagnosing portal hypertension in children.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Portal

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
A prospective randomized cohort study with a longitudinal arm. There will be 2 cohorts.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
SHAPE with Sonazoid
Arm Type
Experimental
Arm Description
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).
Arm Title
SHAPE with Lumason
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Longitudinal SHAPE
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
SHAPE measurement using the ultrasound contrast agent Sonazoid (perfluorobutane microbubbles)
Intervention Description
The ultrasound contrast agent will be infused thorough an IV line and SHAPE ultrasound imaging and data acquisition will be performed with a Logiq E10 (GE Medical Systems, Waukesha, WI) ultrasound scanner.
Intervention Type
Drug
Intervention Name(s)
SHAPE measurement using the ultrasound contrast agent Lumason (sulfur hexafluoride lipid-type A microspheres)
Intervention Description
The ultrasound contrast agent will be infused thorough an IV line and SHAPE ultrasound imaging and data acquisition will be performed with a Logiq E10 (GE Medical Systems, Waukesha, WI) ultrasound scanner.
Primary Outcome Measure Information:
Title
The rate (%) of adverse events that occur with Sonazoid compared to the current rate of adverse events that have been reported in the Lumason package insert for pediatric use (0.001%)
Time Frame
2 hours
Title
Calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins will differentiate between the portal hypertension and non-portal hypertension groups with an accuracy of 94%
Time Frame
2 hours
Secondary Outcome Measure Information:
Title
Changes in calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins over time will predict the development of complications of portal hypertension (variceal bleeding, ascites, hepatopulmonary syndrome, etc)
Time Frame
on average 18 months
Title
Calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins and liver fibrosis stage (on a scale from 0-4 as determined by liver biopsy) will correlate with a p<0.05
Time Frame
2 hours
Title
Compare the calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins obtained with Lumason and Sonazoid, respectively, for their ability to differentiate between the portal hypertension and non-portal hypertension groups
Time Frame
2 hours
Title
Compare calibrated subharmonic microbubble signals (in dB) between the portal and hepatic veins to shear wave elastography values (in m/s) using regression analysis
Time Frame
2 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with a diagnosis of chronic liver disease without portal hypertension. Patients with a diagnosis of chronic liver disease with portal hypertension. Exclusion Criteria: Subjects who are pregnant. Patients with known or suspected hypersensitivity to egg phosphatidyl serine or with a history of anaphylactic allergy to eggs or egg products. Subjects with allergy to egg products or other components of the ultrasound contrast agents will be excluded. History of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na), palmitic acid) History of allergic reaction to Sonazoid Patients with biliary atresia with asplenia or polysplenia. Patients with prior liver transplant. Patients with cystic fibrosis. Patients with chronic lung disease. Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein. Adults not competent/impaired. Patients with significant heart disease or severe congenital heart disease
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Morgan L Gabbert, MA
Phone
267-426-0820
Email
gabbertm@email.chop.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Flemming Forsberg, PhD
Organizational Affiliation
Thomas Jefferson University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sudha A Anupindi, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Morgan L Gabbert, MA
Phone
267-426-0820
Email
gabbertm@email.chop.edu
First Name & Middle Initial & Last Name & Degree
Kathleen M Loomes, MD
First Name & Middle Initial & Last Name & Degree
Susan J Back, MD
First Name & Middle Initial & Last Name & Degree
Kassa Darge, MD, PhD
First Name & Middle Initial & Last Name & Degree
Ryne Didier, MD
First Name & Middle Initial & Last Name & Degree
Sudha A Anupindi, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data generated from the proposed study will be shared to make the results available to the scientific community. Presentations at national scientific meetings. Lectures. Post-graduate training. Approximately 12 months after the completion of the trial (when the main manuscript has been published) individual researchers can contact the PIs and request the final, complete data-set from this trial without any protected health information
IPD Sharing Time Frame
Approximately 12 months after the completion of the trial when the main manuscript has been published
IPD Sharing Access Criteria
On an individual basis - contact the PIs
Citations:
PubMed Identifier
23525208
Citation
Eisenbrey JR, Dave JK, Halldorsdottir VG, Merton DA, Miller C, Gonzalez JM, Machado P, Park S, Dianis S, Chalek CL, Kim CE, Baliff JP, Thomenius KE, Brown DB, Navarro V, Forsberg F. Chronic liver disease: noninvasive subharmonic aided pressure estimation of hepatic venous pressure gradient. Radiology. 2013 Aug;268(2):581-8. doi: 10.1148/radiol.13121769. Epub 2013 Mar 22.
Results Reference
result
PubMed Identifier
33201789
Citation
Gupta I, Eisenbrey JR, Machado P, Stanczak M, Wessner CE, Shaw CM, Gummadi S, Fenkel JM, Tan A, Miller C, Parent J, Schultz S, Soulen MC, Sehgal CM, Wallace K, Forsberg F. Diagnosing Portal Hypertension with Noninvasive Subharmonic Pressure Estimates from a US Contrast Agent. Radiology. 2021 Jan;298(1):104-111. doi: 10.1148/radiol.2020202677. Epub 2020 Nov 17.
Results Reference
result

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SHAPE of Portal Hypertension in Children

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