Chronic Liver Disease
Conditions
Brief summary
The purpose of this study is to validate the Disease Severity Index (DSI) from the HepQuant SHUNT Liver Diagnostic Kit (Test) for likelihood of large esophageal varices.
Detailed description
The purpose of this study is to validate the Disease Severity Index (DSI) from the HepQuant SHUNT Liver Diagnostic Kit (Test) for likelihood of large esophageal varices. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial training dataset demonstrated that the DSI 18.3 had sensitivity 95%, specificity 54%, positive predictive value (PPV) 19%, negative predictive value (NPV) \>99%, negative likelihood ratio (NLR) 0.09, and positive likelihood ratio (PLR) 2.09 for large varices. To validate DSI 18.3 as a cutoff for large varices, we will enroll 420 subjects with chronic liver disease (CLD) of mixed etiologies from 15 to 25 US clinical centers (CLD Validation dataset). The target prevalence of large varices is ≥20%. Each subject will have been scheduled for an esophago-gastro-duodenoscopy (EGD) as part of their standard of care for either variceal or non-variceal indications. Enrolled subjects will undergo standard clinical assessment, laboratory tests, and the HepQuant SHUNT Test. The EGD will be performed within 6 weeks following the HepQuant SHUNT Test. The relationship of DSI to large varices will be analyzed by univariate and multivariate logistic regression analyses, area under the receiver operating characteristic curve (AUROC), and linear and nonlinear regression and correlation coefficients. Diagnostic performance of the DSI cutoff will be defined in the CLD Validation dataset and validated for likelihood of large esophageal varices. The validated DSI cutoff will identify subjects who are either unlikely or likely to have large esophageal varices.
Interventions
COMBINATION_PRODUCTHepQuant SHUNT Liver Diagnostic Test
One time testing using the HepQuant SHUNT Liver Diagnostic Test kit (the combination product) in subjects with CLD and undergoing a standard of care EGD. The SHUNT test will be completed prior to the EGD. Each subject will receive an IV push dose of 13C Cholate mixed with Albumin simultaneously with an oral dose of d4 Cholate
Sponsors
HepQuant, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
All subjects receive HepQuant SHUNT test and DSI measurement prior to a standard of care (SOC) EGD, to be done within 42 days of the SHUNT test. HepQuant SHUNT is a combination product where 24-13C-cholic acid (13C cholate) 20mg is administered intravenously once for each test and 2,2,4,4-D4-cholic acid (d4 cholate) 40mg is administered once orally for each test
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to have a peripheral venous catheter for administration of the 13C cholate * Ability to take the oral dose of d4-cholate * Ability to hold morning doses of medications for the 90-minute duration of the HepQuant SHUNT Test * Meets the protocol defined criteria for CLD in addition to having the diagnoses of CLD for \>6 months * Is scheduled, or in the process of being scheduled, for a standard of care EGD
Exclusion criteria
* Unable to give informed consent * Unable to obtain venous access for administration of intravenous cholate * Unable to absorb orally-administered cholate * Known hypersensitivity to human serum albumin * Known hypersensitivity to any of the components of the HepQuant SHUNT Liver Diagnostic Kit * Acute hepatitis or Acute Liver Failure * Acute drug-induced liver disease (DILI) * Noncirrhotic causes for portal hypertension and varices * Ongoing active alcoholic hepatitis * Child-Pugh class C defined by Child-Pugh score 10 or higher * Dialysis * Active infection or febrile illness within the last month * Documented history of esophageal or gastric variceal hemorrhage * Documented history of treatment of esophageal varices * Documented history of endoscopic findings of large esophageal varices * Hepatocellular carcinoma beyond Milan or University of California, San Francisco (UCSF) criteria * Thrombosis of main portal vein * Liver transplant recipient * Pregnancy * Women who are breast-feeding * Serious intercurrent medical or surgical illness, such as acute myocardial infarction, acute cerebral hemorrhage, sepsis, or other immediate life-threatening illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Severity Index (DSI) Less Than/Equal to 18.3 to Rule Out Large Varices | 1 day | The primary objective of this study is to measure the subjects' liver function using DSI ≤18.3 for those that are not likely to have large esophageal varices. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DSI and Probability of Large Esophageal Varices | 1 day | Logistic regression analysis of DSI as predictor of large varices |
Countries
United States
Participant flow
Recruitment details
A total of 367 subjects were screened for the study.
Pre-assignment details
A total of 306 subjects were enrolled in the study. For the analyses of all primary, secondary, and exploratory endpoints, only subjects who completed the HepQuant SHUNT Test and esophagogastroduodenoscopy (EGD) examination (N=280) were considered.
Participants by arm
| Arm | Count |
|---|---|
| Open Label All subjects receive HepQuant SHUNT Liver Diagnostic Test within 42 days of the scheduled EGD. Test includes 20mg of 13C Cholate mixed with Albumin via IV push, and 40mg of d4 Cholate mixed with juice orally, both doses given simultaneously one time.
HepQuant SHUNT Liver Diagnostic Test: One time testing using the HepQuant SHUNT Liver Diagnostic Test kit (the combination product) in subjects with CLD and undergoing a standard of care EGD. The SHUNT test was completed prior to the EGD. Each subject received an IV push dose of 13C Cholate mixed with Albumin simultaneously with an oral dose of d4 Cholate. | 280 |
| Total | 280 |
Baseline characteristics
| Characteristic | Open Label |
|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 10.44 |
| Body Mass Index (BMI) | 33.48 kg/m^2 STANDARD_DEVIATION 7.865 |
| Child-Pugh Score | 5.4 units on a scale STANDARD_DEVIATION 0.84 |
| MELD Score | 8.2 units on a scale STANDARD_DEVIATION 2.66 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 44 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 236 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 14 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Other | 7 Participants |
| Race/Ethnicity, Customized Race White | 257 Participants |
| Sex: Female, Male Female | 140 Participants |
| Sex: Female, Male Male | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 297 |
| other Total, other adverse events | 40 / 297 |
| serious Total, serious adverse events | 5 / 297 |
Outcome results
Primary
Disease Severity Index (DSI) Less Than/Equal to 18.3 to Rule Out Large Varices
The primary objective of this study is to measure the subjects' liver function using DSI ≤18.3 for those that are not likely to have large esophageal varices.
Time frame: 1 day
Population: Of the 280 subjects who completed the HepQuant SHUNT Test and EGD examination, 275 had both HepQuant SHUNT Test and EGD results.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open Label | Disease Severity Index (DSI) Less Than/Equal to 18.3 to Rule Out Large Varices | Large varices and DSI > 18.3 | 33 Participants |
| Open Label | Disease Severity Index (DSI) Less Than/Equal to 18.3 to Rule Out Large Varices | Large varices and DSI <= 18.3 | 3 Participants |
| Open Label | Disease Severity Index (DSI) Less Than/Equal to 18.3 to Rule Out Large Varices | No large varices and DSI > 18.3 | 171 Participants |
| Open Label | Disease Severity Index (DSI) Less Than/Equal to 18.3 to Rule Out Large Varices | No large varices and DSI <= 18.3 | 68 Participants |
Comparison: The performance goal for validation of DSI ≤18.3 was the upper limit of the confidence interval (CI) for negative likelihood ratio (NLR) to rule out an NLR of \>0.52. For the null and alternate hypotheses, the upper limit of the 95% CI was NLR \>0.52 and the upper limit of the 95% CI was NLR \<=0.52, respectively. The confidence level for the CI was adjusted to maintain a 1-sided type I error rate of 0.025.95% CI: [0.097, 0.882]
Comparison: The performance goal for validation of DSI \<= 18.3 was the observed sensitivity must have been \>0.85. The confidence level for the confidence interval (CI) was adjusted to maintain a 1-sided type I error rate of 0.025.95% CI: [0.775, 0.982]
Secondary
DSI and Probability of Large Esophageal Varices
Logistic regression analysis of DSI as predictor of large varices
Time frame: 1 day
Population: Of the 280 subjects who had the HepQuant SHUNT Test and EGD examination, 275 subjects had both HepQuant SHUNT Test and EGD.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open Label | DSI and Probability of Large Esophageal Varices | Large varices and DSI <= 18.3 | 3 Participants |
| Open Label | DSI and Probability of Large Esophageal Varices | No large varices and DSI > 18.3 | 171 Participants |
| Open Label | DSI and Probability of Large Esophageal Varices | Large varices and DSI > 18.3 | 33 Participants |
| Open Label | DSI and Probability of Large Esophageal Varices | No large varices and DSI <= 18.3 | 68 Participants |
p-value: <0.000195% CI: [1.047, 1.143]Regression, Logistic
p-value: <0.000195% CI: [1.058, 1.163]Regression, Logistic
p-value: <0.00195% CI: [1.041, 1.145]Regression, Logistic
p-value: <0.00195% CI: [1.038, 1.142]Regression, Logistic