A Prospective, Interventional, Longitudinal Asia Pacific Study Evaluating Clinical Utility of Des-gamma-carboxyprothrombin (PIVKA-II) or GAAD Score Plus Ultrasound for Detection of Hepatocellular Carcinoma (HCC) in a High-risk Patient Population
A Prospective, Interventional, Longitudinal Asia Pacific Study Evaluating Clinical Utility of Des-gamma-carboxyprothrombin (PIVKA-II) or GAAD Score Plus Ultrasound for Detection of Hepatocellular Carcinoma (HCC) in a High-risk Patient Population
HCC surveillance is currently limited by underutilization and the suboptimal performance of AFP. This prospective, single-arm study investigates whether the GAAD score (Gender, Age, AFP, and PIVKA-II) enhances HCC detection when added to standard-of-care surveillance.
High-risk patients will undergo US plus GAAD score testing every six months for two years. The primary analysis compares the relative true positive rate (rTPR) and relative false positive rate (rFPR) of surveillance modalities (US, AFP, GAAD) against combined strategies (US+AFP; US+GAAD), utilizing a 2.57 GAAD cut-off. Secondary endpoints include longitudinal biomarker kinetics, early-stage HCC detection rates, and the impact on downstream imaging (CT/MRI) volume. Ultimately, this study seeks to define the role of GAAD as a surveillance adjunct and inform future clinical guidelines for biomarker-enhanced HCC screening.
This is a prospective, non-randomized, open-label, interventional diagnostic utility study Study procedure Upon enrollment, patients will be followed for 2 years. Surveillance visits will take place at every 6 months intervals according to national guidelines and usual clinical practice. Biomarkers will be assessed using routine blood draw taken at each surveillance visit. Hence, no additional blood draw will be required as per study protocol. Blood collection will be conducted according to local's standard procedures.
The following parameters will be assessed at baseline and each follow-up visit.
Due to its better performance, MRI is the preferred modality but CT can be performed alternatively.
Recall procedure
For MRI/CT, the following protocols must be applied in order to provide optimal diagnostic performance in accordance with local current clinical practice and Guidelines recommendation (AASLD1, EASL2 and APASL3).
The recall procedure with multiphasic contrast-enhanced CT or MRI will be triggered for each patient fulfilling one of the following criteria:
For patients with new lesion or lesion <1 cm lesion on abdominal ultrasound will undergo repeat short-interval evaluation (ultrasound, AFP, PIVKA measurements and GAAD score calculation) in approximately 3-4 months .
As part of the study, PIVKA II and GAAD score will be performed and patients with GAAD score ≥ 2.57 will be followed up with multiphasic contrast-enhanced CT or MRI as recall procedure.
Clinical decisions will be based on local radiologic assessment. Based on multiphasic contrast-enhanced CT or MRI - the diagnosis of HCC will be made in line with current clinical practice:
For patients with positive findings in any surveillance modality (refers to US, AFP or GAAD; if PIVKA-II alone is above MDP cut-off, this will not be considered a positive case), the following additional parameters will be documented upon diagnostic workup:
Right to withdraw Subjects have the right to withdraw from the study at any time for any reason. If lost to follow-up, the assigned study staff will try to contact the subject by telephone followed by registered mail to establish and document as completely as possible the reason for the withdrawal.
Subjects will be allowed to miss one scheduled visit. Subjects with >1 missed visits will be excluded from further follow-up.
Subjects will be informed of circumstances under which their participation may be terminated by the responsible investigator without the subject's consent. The investigator may withdraw subjects from the study in the event of intercurrent illness, adverse events, lack of compliance with the study and/or study procedures (e.g., study visits), or any reason where it is felt that it is in the best interest of the subject to be terminated from the study. Any administrative or other reasons for withdrawal will be documented and explained to the subject. If the reason for removal of a subject from the study is an Adverse Event, the principal specific event will be recorded in the medical record.
5. Statistics Primary and secondary endpoint(s) Primary endpoint
Exploratory Clinical performance of Elecsys® AFP, Elecsys® PIVKA-II, GAAD -score for the aid in diagnosis of early and all stages stage Hepatocellular Carcinoma (HCC).
Exploratory endpoint
Statistical methods Primary endpoints:
● Exploratory Clinical performance of Elecsys® AFP, Elecsys® PIVKA-II, GAAD -score for the aid in diagnosis of early and all stages stage Hepatocellular Carcinoma (HCC). - descriptive (PPV, NPV, Sens, Spec AUC/ROC)
Exploratory endpoints,
Sample size, level of significance, and power Sample size estimation:
As HCC has a low annual prevalence (consider 1.5% & 2% for now), the precision of the sensitivity estimate (i.e., width of the 95% confidence interval) is the main prerequisite for the sample size, as sensitivity is calculated from HCC cases. Assuming a decent target of 20% sensitivity 95% confidence interval width, a true sensitivity of 86.5% (MCE study), and a prevalence of 1.5% & 2% over two years follow-up, a sample size of 2100 samples would be required to achieve a 95% confidence interval width of 19% (1.5% annual prevalence) and 16% (2% annual prevalence) respectively, which is considered sufficient.
Inclusion Criteria:
Signed informed consent form (ICF).
Age above 18 years.
Patients with chronic liver disease who have an indication for HCC surveillance, including:
Exclusion Criteria: