Case-Control Study of the Glycotest™ HCC Panel vs AFP for the Detection of Early-stage Hepatocellular Carcinoma

Clinical guidelines (AASLD) recommend the use of abdominal ultrasound (US) for surveillance testing for the early detection of Hepatocellular Carcinoma (HCC). The serum protein biomarker alpha-fetoprotein (AFP) is commonly used to augment US but its use alone is not recommended by clinical guidelines. Despite evidence that HCC surveillance improves early detection and reduces mortality from HCC, current HCC surveillance tests lack sensitivity, leaving a significant proportion of patients to present with late-stage disease. The Glycotest HCC Panel has shown better sensitivity than AFP, which is ineffective for the detection of early-stage HCC. This clinical study seeks to validate the Glycotest HCC Panel using a large multicenter cohort of cases and controls that includes patients diagnosed with early-stage HCC against a background of cirrhosis and cirrhotic patients without HCC (at risk) undergoing an established surveillance protocol.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Hepatocellular; Cirrhosis, Liver

Detailed Description

Study Rationale:

This study is designed to compare the ability of the Glycotest HCC Panel with that of AFP to differentiate between patients with early-stage Hepatocellular Carcinoma (HCC) against a background of cirrhosis from cirrhotic patients without HCC (at risk).

Primary Objective:

The primary objective of this study is to determine whether the Glycotest HCC Panel outperforms AFP in terms of area under the receiver operating characteristic curve (AUROC) for the differentiation of patients with early-stage HCC from those without HCC in the at-risk population.

Secondary Objective:

The secondary objective of this study is to determine whether the Glycotest HCC Panel outperforms AFP in terms of clinical sensitivity (as estimated using the 90% specificity estimate as the decision threshold) for the detection of patients with early-stage HCC.

Study Design:

This is a phase 2, multicenter, laboratory-blinded, case-control study of the Glycotest HCC Panel vs AFP for the discrimination of patients with early-stage HCC from those at risk. Case and control samples will be obtained from multiple institutions using prospective collection. The study will consist of a screening/baseline visit for all patients; controls initially assessed by abdominal US will also undergo a 6-month follow-up visit to confirm absence of HCC at enrollment. Assays will be performed by Glycotest with analysts blinded to clinical data.

Population:

The study population will comprise male and female adult patients with early-stage HCC against a background of cirrhosis (cases) as well as at-risk cirrhotic patients (controls). Enrollment of the aggregate of HCC cases with single lesions ≥ 3 cm and with multiple lesions will be capped at 50% of total cases. Enrollment of Chronic Hepatitis C cases and controls with sustained virologic response (SVR) to therapy will be matched. Cases and controls will be matched based on age, sex and etiology.

Number of Subjects:

Maximum of 388 cases and 378 controls;

• 150 cases and 140 controls (training set)
• Maximum of 238 cases and 238 controls (validation set)

Study Duration:

30 months ( approximately 24 months accrual + 6 month follow up)

Study Phases Patients potentially eligible for the study population will undergo informed consent prior to screening/baseline visits.

Screening Once consented, a subject's demographics, medical record, laboratory data, and imaging will be reviewed. Patients are considered eligible for enrollment once they meet all study enrollment criteria.

Enrollment Screening data will be re-reviewed if necessary and recorded. Serum from blood samples (5 mL) will be obtained for measurement of Glycotest HCC Panel score (which includes AFP).

Follow up Medical record review/imaging at 6 months from enrollment for control patients originally assessed using abdominal US.

• Study Type: Observational
• Enrollment (Estimated): 766

Contacts and Locations

• Study Contact: Name: Charles S Swindell, PhD; Phone Number: 484-431-3483; Email: charles@glycotest.com

Study Locations

• Israel
  • Jerusalem, Israel, 91120
    • Hebrew University- Hadassah Medical Center
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90048
      • Cedars- Sinai Medical Center
    • San Francisco, California, United States, 94115
      • Kaiser Permanente Northern California
    • San Francisco, California, United States, 94115
      • University of California- San Francisco
    • Stanford, California, United States, 94304
      • Stanford University School of Medicine
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
    • Miami, Florida, United States, 33125
      • Miami VA Healthcare System
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Baltimore
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016
      • NYU Langone Health
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania (HUP)
  • Texas
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75201
      • Baylor Scott & White Research Institute
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will comprise male and female adult patients with early-stage HCC against a background of cirrhosis (cases) as well as at-risk cirrhotic patients (controls). Enrollment of the aggregate of HCC cases with single lesions ≥ 3 cm and with multiple lesions will be capped at 50% of total cases. Enrollment of Chronic Hepatitis C cases and controls with sustained virologic response (SVR) to therapy will be matched. Cases and controls will be matched based on age, sex and etiology.

Description

Inclusion Criteria:

Cases

1. Males and females ages 18 years or older.
2. Treatment-naïve HCC as defined by LI-RADS (Liver Imaging Reporting and Data System) LR-5 or OPTN (Organ Procurement and Transplantation Network) 5 CT or MRI criteria (all lesions must exhibit arterial phase hyper-enhancement), or histologic evidence.
3. Early-stage HCC defined by single lesion ≤ 5 cm or ≤ 3 lesions ≤ 3 cm determined at enrollment or within 100 days prior without vascular invasion.
4. Cirrhosis based on serum biomarkers (FibroSure®/FibroTest > 0.74, APRI (AST to Platelet Ratio Index) > 2, or FIB-4 (Fibrosis-4) > 3.25), histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease.
5. Child-Pugh score A-B8.
6. Subject must be able to understand and provide informed consent.

Controls

1. Males and females ages 18 or older.
2. Cirrhosis based on serum biomarkers (FibroSure®/FibroTest > 0.74, APRI > 2, or FIB-4 > 3.25), histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease.

3. Evidence of the absence of a solid hepatic mass, suspicious for HCC, at enrollment or within 100 days prior based on one of the following:

   1. Negative multiphase CT scan or MRI with contrast at screening/baseline visit, OR
   2. Negative abdominal US at both screening/baseline visit AND 6-month follow-up visit, OR
   3. Negative abdominal US at screening/baseline visit AND negative multiphase CT scan or MRI with contrast at 6-month or earlier follow-up visit.
4. Child-Pugh score A-B8.
5. Subject must be able to understand and provide informed consent.

Exclusion Criteria:

Cases

1. Uncontrolled ascites.
2. Uncontrolled encephalopathy.
3. History of liver transplant.
4. Diagnosis of active malignancy or history of active malignancy within 5 years prior to enrollment, including mixed HCC-CCA (cholangiocarcinoma). If previously diagnosed with malignancy, subject must be in remission for at least 5 years prior to enrollment. Prior history of HCC, including resection of HCC at any time, is excluded.
5. Prior treatment of tumor.
6. Any significant non-liver-related medical condition in which expected survival is less than 1 year.

Controls

1. Imaging evidence of solid hepatic mass, suspicious for HCC, including lesions meeting LI-RADS LR-3 or LR-4, OPTN-3 or OPTN-4, or LI-RADS LR-M criteria.
2. Uncontrolled ascites.
3. History of liver transplantation.
4. Uncontrolled encephalopathy.
5. Diagnosis of active malignancy or history of active malignancy within 5 years prior to enrollment (if previously diagnosed with malignancy, subject must be in remission for at least 5 years prior to enrollment). History of HCC including resection of HCC at any time, is excluded.
6. Any significant non-liver-related medical condition in which expected survival is less than 1 year.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cases; Male and female adult patients with early-stage hepatocellular carcinoma against a background of liver cirrhosis.
Controls; Male and female adult patients with liver cirrhosis at risk for hepatocellular carcinoma.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUROC	Area under the receiver operating characteristics curve	At enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity	Clinical sensitivity for the detection of early-stage hepatocellular carcinoma as estimated using the 90% specificity estimate as the decision threshold	At enrollment

Collaborators and Investigators

• Sponsor: Glycotest, Inc.
• Investigators: Principal Investigator: Amit Singal, MD, UT Southwestern Medical Center; Principal Investigator: Josep Llovet, MD, Icahn School of Medicine at Mount Sinai; Principal Investigator: Jorge Marrero, MD, University of Pennsylvania Medical Center

Publications and helpful links

General Publications

• Wang M, Sanda M, Comunale MA, Herrera H, Swindell C, Kono Y, Singal AG, Marrero J, Block T, Goldman R, Mehta A. Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC. Cancer Epidemiol Biomarkers Prev. 2017 May;26(5):795-803. doi: 10.1158/1055-9965.EPI-16-0974. Epub 2017 Feb 21.

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2019
• Primary Completion (Actual): August 25, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: March 15, 2019
• First Submitted That Met QC Criteria: March 15, 2019
• First Posted (Actual): March 18, 2019

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Fibrosis; Carcinoma; Carcinoma, Hepatocellular; Liver Cirrhosis
• Other Study ID Numbers: G-1001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No