Trial Outcomes & Findings for Intra-Individual Reproducibility of the Non-Invasive Assessment of the Portal Circulation (NCT NCT01579162)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

48 participants

Primary outcome timeframe

Average of all three study visits performed within 30 days

Results posted on

2021-07-15

Participant Flow

Participant milestones

Participant milestones
Measure	Healthy Controls 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. Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	Chronic HCV Patients With F0-F2 Fibrosis Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	Chronic HCV Patients With F3-F4 Fibrosis Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	NASH Patients With F0-F2 Fibrosis Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	NASH Patients With F3-F4 Fibrosis Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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
Overall Study STARTED	16	8	8	8	8
Overall Study COMPLETED	16	8	8	8	8
Overall Study NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Healthy Controls n=16 Participants 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. Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	Chronic HCV Patients With F0-F2 Fibrosis n=8 Participants Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	Chronic HCV Patients With F3-F4 Fibrosis n=8 Participants Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	NASH Patients With F0-F2 Fibrosis n=8 Participants Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	NASH Patients With F3-F4 Fibrosis n=8 Participants Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	Total n=48 Participants Total of all reporting groups
Age, Continuous	32.9 years n=5 Participants	54.9 years n=7 Participants	55.4 years n=5 Participants	45.9 years n=4 Participants	53.2 years n=21 Participants	48.4 years n=10 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants	4 Participants n=21 Participants	20 Participants n=10 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	7 Participants n=7 Participants	6 Participants n=5 Participants	3 Participants n=4 Participants	4 Participants n=21 Participants	28 Participants n=10 Participants
Race/Ethnicity, Customized Non-Hispanic White	12 Participants n=5 Participants	7 Participants n=7 Participants	7 Participants n=5 Participants	6 Participants n=4 Participants	7 Participants n=21 Participants	39 Participants n=10 Participants
Race/Ethnicity, Customized Hispanic	2 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants	5 Participants n=10 Participants
Race/Ethnicity, Customized Black	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=10 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=10 Participants
Region of Enrollment United States	16 participants n=5 Participants	8 participants n=7 Participants	8 participants n=5 Participants	8 participants n=4 Participants	8 participants n=21 Participants	48 participants n=10 Participants

PRIMARY outcome

Timeframe: Average of all three study visits performed within 30 days

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.

Outcome measures

Outcome measures
Measure	Healthy Controls n=16 Participants 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. Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	Chronic HCV Patients With F0-F4 Fibrosis n=16 Participants Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	NASH Patients With F0-F4 Fibrosis n=16 Participants Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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
Cholate Shunt Test	28.0 SHUNT % Standard Deviation 5.5	37.6 SHUNT % Standard Deviation 11.6	33.4 SHUNT % Standard Deviation 7.3

SECONDARY outcome

Timeframe: All three study visits within 30 days

Population: The goal of the analysis was to obtain the intra-individual results, so the subjects were not stratified by groups for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Healthy Controls n=48 Participants 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. Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	Chronic HCV Patients With F0-F4 Fibrosis Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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	NASH Patients With F0-F4 Fibrosis Cholate-24-13C (IND 65121) \& Cholate-2,2,4,4-d4 (IND 65123): 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
Intra-individual Reproducibility of the Cholate SHUNT Test Across All Subjects	0.74 ICC Interval 0.63 to 0.84	—	—

SECONDARY outcome

Timeframe: Average of DSIs obtained from all three study visits within 30 days

Population: This analysis was conducted by histological fibrosis stage, so subjects with liver disease are grouped into two groups, either NASH \& Chronic HCV patients with F0-F2 fibrosis or with F3-F4 fibrosis.

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.