Intra-Individual Reproducibility of the Non-Invasive Assessment of the Portal Circulation

Study Overview
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Brief Summary
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HepQuant tests are new liver tests that are being developed to accurately measure liver function with sensitivity and specificity while being safe and non-invasive. The primary goal of this study is to define the intra-individual reproducibility of the HepQuant tests, that is, to see if a person is given the tests several times that the test results are essentially the same each time. Subjects for this study will include healthy controls and patients with chronic liver diseases. The chronic liver diseases will include hepatitis C virus (HCV) infection and a serious form of fatty liver disease, known as non-alcoholic steatohepatitis (NASH). The HCV and NASH patients will include men and women, and those with early stage and late stage liver disease as defined by the amount of fibrosis observed in their liver biopsies. Once a subject has been enrolled in the study they will be given the HepQuant tests on three separate days within the span of one month. The hypothesis of this study is that HepQuant tests will reproducibly report liver function in healthy controls and patients with all stages of chronic HCV and NASH liver disease and that liver function will decrease as the amount of liver fibrosis increases in the chronic liver disease patients.

Official Title
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Intra-Individual Reproducibility of the Non-Invasive Assessment of the Portal Circulation

Conditions
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Hepatitis C, Chronic, Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Device: Cholate-24-13C (IND 65121) & Cholate-2,2,4,4-d4 (IND 65123)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of chronic HCV or NASH Liver biopsy within 2 years of enrollment Compensated liver disease Exclusion Criteria: Decompensated liver disease Currently being treated with beta blockers, ACE inhibitors, or other agents affecting FMD Malignancy diagnosed within 5 years of study enrollment without demonstrated clearance History of congestive heart failure Renal insufficiency with chronic kidney disease stage 4 or 5 (GFR < 30 mL/min/1.73m2) Crohn's disease or any active intestinal inflammatory condition Having an ileal resection Diabetic Gastroparesis Pregnancy or intent to become pregnant. Urine pregnancy tests will be performed at each visit. Inability to consent for one's self

Ages Eligible for Study
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Minimum Age: 22 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: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Controls<br>Healthy controls will be recruited to have approximately equal numbers of men and women. Controls will be of healthy weight as defined by a BMI 18-25 and without liver disease or risk factors for liver disease. | Device: Cholate-24-13C (IND 65121) & Cholate-2,2,4,4-d4 (IND 65123)<br>* The FDA has indicated that liver function diagnostic testing with stable isotope labeled cholates would be considered a drug/device combination product. The drugs administered at each test visit will be: 20 mg Cholate-24-13C, IV (in the vein), dissolved in NaHCO3 and mixed with albumin. 40 mg Cholate-2,2,4,4-d4, oral, dissolved in NaHCO3 and mixed with juice. The 3 test visits will be on separate days within a span of 30 days<br>* Other names: Cholic acid-2,2,4,4-d4;|
| Experimental: chronic HCV patients with F0-F2 fibrosis<br> | Device: Cholate-24-13C (IND 65121) & Cholate-2,2,4,4-d4 (IND 65123)<br>* The FDA has indicated that liver function diagnostic testing with stable isotope labeled cholates would be considered a drug/device combination product. The drugs administered at each test visit will be: 20 mg Cholate-24-13C, IV (in the vein), dissolved in NaHCO3 and mixed with albumin. 40 mg Cholate-2,2,4,4-d4, oral, dissolved in NaHCO3 and mixed with juice. The 3 test visits will be on separate days within a span of 30 days<br>* Other names: Cholic acid-2,2,4,4-d4;|
| Experimental: chronic HCV patients with F3-F4 fibrosis<br> | Device: Cholate-24-13C (IND 65121) & Cholate-2,2,4,4-d4 (IND 65123)<br>* The FDA has indicated that liver function diagnostic testing with stable isotope labeled cholates would be considered a drug/device combination product. The drugs administered at each test visit will be: 20 mg Cholate-24-13C, IV (in the vein), dissolved in NaHCO3 and mixed with albumin. 40 mg Cholate-2,2,4,4-d4, oral, dissolved in NaHCO3 and mixed with juice. The 3 test visits will be on separate days within a span of 30 days<br>* Other names: Cholic acid-2,2,4,4-d4;|
| Experimental: NASH patients with F0-F2 fibrosis<br> | Device: Cholate-24-13C (IND 65121) & Cholate-2,2,4,4-d4 (IND 65123)<br>* The FDA has indicated that liver function diagnostic testing with stable isotope labeled cholates would be considered a drug/device combination product. The drugs administered at each test visit will be: 20 mg Cholate-24-13C, IV (in the vein), dissolved in NaHCO3 and mixed with albumin. 40 mg Cholate-2,2,4,4-d4, oral, dissolved in NaHCO3 and mixed with juice. The 3 test visits will be on separate days within a span of 30 days<br>* Other names: Cholic acid-2,2,4,4-d4;|
| Experimental: NASH patients with F3-F4 fibrosis<br> | Device: Cholate-24-13C (IND 65121) & Cholate-2,2,4,4-d4 (IND 65123)<br>* The FDA has indicated that liver function diagnostic testing with stable isotope labeled cholates would be considered a drug/device combination product. The drugs administered at each test visit will be: 20 mg Cholate-24-13C, IV (in the vein), dissolved in NaHCO3 and mixed with albumin. 40 mg Cholate-2,2,4,4-d4, oral, dissolved in NaHCO3 and mixed with juice. The 3 test visits will be on separate days within a span of 30 days<br>* Other names: Cholic acid-2,2,4,4-d4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cholate Shunt Test | The Cholate Shunt Test result is defined as the ratio of the IV Cholate Clearance to the Oral Cholate Clearance and is expressed as a percentage. The higher the SHUNT percentage, the more the blood flow is shunting around the liver, the more severe the liver disease. The average of the SHUNT test results (ratio of IV Cholate Clearance to Oral Cholate Clearance) from all three time points (3 visits within 30 days) for each participant was used in the calculation of the group SHUNT Test results. | Average of all three study visits performed within 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-individual Reproducibility of the Cholate SHUNT Test Across All Subjects | The intra-individual reproducibility of the Cholate Shunt Test (SHUNT %), will be defined by its average Coefficient of Variation (CV) and its Intra-Class Correlation (ICC). Each subject will be tested at baseline and then twice more on separate days within the span of one month. The CV of each subject's three replicate tests will be used to calculate the average CV for each type of test. All test results for each type of test will be used to calculate its ICC. | All three study visits within 30 days | 
| Intra-class Reproducibility of the Disease Severity Index (DSI) by Histological Fibrosis Stage | The intra-class correlation coefficients (ICCs) for reproducibility of the Disease Severity Index (DSI, an index value measuring severity of liver disease that can be calculated using the SHUNT Test results) were obtained by stage of liver fibrosis by liver biopsy. The DSI is a score on a scale from 0 (healthy) to 50 (severe liver disease), so the higher the DSI, the more severe the liver disease. Fibrosis scores increase with disease severity as well, so subjects with F0-F2 fibrosis have less severe liver disease than subjects with F3-F4 fibrosis. | Average of DSIs obtained from all three study visits within 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis, Fatty Liver