Conditionally Increased Output (CIO) Enhanced Ultrasound System

Study Overview
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Brief Summary
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This study aims to assess possible bioeffects that may be caused by the use of shear wave elastography (SWE) with conditionally increased acoustic output pressure (CIO). Bioeffects will be monitored by of a series of liver function tests (LFTs) with results graded according to the NCI scale for drug hepatoxicity. LFTs will be collected prior to SWE imaging using CIO, as well up to 7 days post-imaging. Secondarily, this study aims to understand the degree to which SWE imaging results have improved with the use of COI.

Detailed Description
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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States, with an estimated prevalence of approximately 30%. NAFLD is a disease with a spectrum that can be categorized as 1) simple steatosis/non-alcoholic fatty liver, defined as excess liver fat without inflammation, and 2) non-alcoholic steatohepatitis (NASH) in which excess liver fat is associated with inflammation, fibrosis, and healing, ultimately culminating in cirrhosis. Nonalcoholic steatohepatitis (NASH) can progress to conditions associated with high morbidity and mortality such as portal hypertension, cirrhosis, liver failure and hepatocellular carcinoma. NASH is currently the second most common indication for liver transplantation in the United States, and is expected to become the leading cause in the near future. Liver biopsy is currently accepted as the gold-standard method to detect liver fibrosis, though it is an invasive procedure with high morbidity and mortality rates. Alternatively, imaging is useful for NAFLD diagnosis, disease management, and monitoring treatment response. Several imaging methods are used for these purposes, including ultrasound, MRI, and CT based techniques. Ultrasound (US) is preferred by many physicians because it is a low-cost technique that is widely available. Shear wave elastography (SWE) is an ultrasound-based technique that is commonly used for liver fibrosis staging. When performing ultrasound imaging, it is known that several patient-related factors may influence the quality of the image. In NAFLD patients, several factors including high skin-to-liver capsule distance (SCD) may change the attenuation and aberration of the acoustic waves, change the quality of the image, and make diagnosis harder for radiologists. SCD is the distance between skin and Glisson's capsule, when assessed with standard B-mode ultrasound imaging. In patients with high SCD, and particularly in patients with abdominal obesity, the shear wave elasticity elastogram box may not fill properly, which may cause unreliable SWE measurements. Technical failure and unreliable SWE measurements have been previously reported. The current FDA guidelines recommend the use of a maximum derated spatial peak temporal average intensity (ISPTA) of ≤ 720 mW/cm2, and either the maximum MI should be ≤ 1.9 or the maximum derated spatial peak pulse average intensity (ISPPA) should be ≤ 190 W/cm2. In addition, clinical justification is required if the TI exceeds 6. Several diagnostic modes that are clinically used and FDA approved use acoustic output values that approach these maximum guidelines. These diagnostic modes include acoustic radiation force impulse (ARFI) based techniques, harmonic imaging techniques, and Doppler based techniques. In the past decade, the AIUM has published reports on the benefits and limitations of both the TI and MI, including recommendations that transient increases may be warranted if there were associated clinical benefit. Using the acoustic and thermal limits in current FDA guidelines, it is not always possible to get reliable SWE measurements. Therefore, conditionally increasing the acoustic pressure of a SWE system may help clinicians to obtain reliable and accurate SWE results from patients with abdominal obesity, potentially minimizing the need for liver biopsy. This study aims to assess possible bioeffects that may be caused by the use of SWE with conditionally increased acoustic output pressure (CIO). Bioeffects will be monitored by of a series of liver function tests (LFTs) with results graded according to the NCI scale for drug hepatoxicity. LFTs will be collected prior to SWE imaging using CIO, as well up to 7 days post-imaging. Secondarily, this study aims to understand the degree to which SWE imaging results have improved with the use of COI.

Official Title
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Improving the Performance of Ultrasound Shear Wave Elastography (SWE) in Obese Fatty Liver Disease Patients by Developing a Conditionally Increased Output (CIO) Enhanced Ultrasound System

Conditions
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Nonalcoholic Fatty Liver, Nonalcoholic Steatohepatitis, Fatty Liver

Intervention / Treatment
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* Device: GE ultrasound system with increased acoustic output settings


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 BMI 18.5-39.9 Able to undergo abdominal ultrasound Able to undergo repeated blood sampling Stable medication and supplement list and dosing for 30 days preceding enrollment Willing to participate Exclusion Criteria: Excess alcohol consumption: > 7 units/week (F) or > 14 units/week (M) Current diagnosis of drug induced liver injury Prior liver transplantation recipient Receiving drug/placebo in treatment trial now or within 30 days Received systemic chemotherapy within past 30 days. Confirmed or suspected pregnancy Pacemaker, nerve stimulator, or other implanted electronic device Plans to alter medication or supplement list or dosage during the study period Active or recent (within 30 days) acute illness Recent ultrasound contrast administration Recent alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase (ALP) greater than the laboratory upper limit of normal. Other factors that the PI considers likely to compromise study endpoints or subject safety

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 24 healthy adult volunteers<br> | Device: GE ultrasound system with increased acoustic output settings<br>* We will perform liver stiffness measurements with standard settings and an increased acoustic output enhanced ultrasound system. Pre and post ultrasound LFTs will be collected to monitor unexpected liver tissue damage.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean difference in aspartate transaminase (AST) value in U/L unit between pre-imaging and day7 post-imaging | AST value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 7 day after the ultrasound imaging (within 2 weeks timeframe) | 
| Mean difference in alanine transaminase (ALT) value in U/L unit between pre-imaging and day7 post-imaging | ALT value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 7 day after the ultrasound imaging (within 2 weeks timeframe) | 
| Mean difference in alkaline phosphatase (ALP) value in U/L unit between pre-imaging and day7 post-imaging | ALP value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 7 day after the ultrasound imaging (within 2 weeks timeframe) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean difference in IQR/Median ratio between standard and CIO SWE | IQR/median is a commonly accepted variability analysis tool for SWE. We are hoping to understand the variability difference between these two ultrasound modes in this safety study. | Single visit (1day) | 
| Mean difference in aspartate transaminase (AST) value in U/L unit between pre-imaging and day1 post-imaging | AST value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 1 day after the ultrasound imaging (within 2 weeks timeframe) | 
| Mean difference in aspartate transaminase (AST) value in U/L unit between pre-imaging and day2 post-imaging | AST value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 2 day after the ultrasound imaging (within 2 weeks timeframe) | 
| Mean difference in alanine transaminase (ALT) value in U/L unit between pre-imaging and day1 post-imaging | ALT value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 1 day after the ultrasound imaging (within 2 weeks timeframe) | 
| Mean difference in alanine transaminase (ALT) value in U/L unit between pre-imaging and day2 post-imaging | ALT value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 2 day after the ultrasound imaging (within 2 weeks timeframe) | 
| Mean difference in alkaline phosphatase (ALP) value in U/L unit between pre-imaging and day1 post-imaging | ALP value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 1 day after the ultrasound imaging (within 2 weeks timeframe) | 
| Mean difference in alkaline phosphatase (ALP) value in U/L unit between pre-imaging and day2 post-imaging | ALP value difference between pre and post imaging will be collected to monitor potential liver injury effect of the CIO enhanced liver stiffness measurement method in this safety study. | Pre-ultrasound imaging and 2 day after the ultrasound imaging (within 2 weeks timeframe) |