Impact of Hepatitis B Immunoglobulins in Patients With Chronic Hepatitis B on Hepatocellular Carcinoma - a Proof of Concept Study (HBIG)

January 17, 2024 updated by: Medical University of Graz

Impact of Hepatitis B Immunoglobulins in Patients With Chronic Hepatitis B on Hepatocellular Carcinoma

In the current literature, infection with the hepatitis B virus (HBV) is described as one of the main risk factors for the development of hepatocellular carcinoma (HCC).

According to the current study situation, the Hepatitis B surface antigen (HBsAg) is considered as an important marker, since low levels and sero-clearance of HBsAg are both correlated with a lower risk of HCC development / recurrence.Currently there is no treatment option available that efficiently targets HBsAg. Besides neutralizing infectious HBV virions, Hepatitis B immunoglobulins (HBIG) can directly bind and neutralize extracellular HBsAg/SVPs, and even intracellular HBsAg targeting is reported. In addition, HBIGs can initiate effector-cell attack (via antibody-dependent cellular cytotoxicity, ADCC) towards infected hepatocytes.

The potential benefit of HBIGs in the HCC context is further underlined by recent evidence for the ability of HBIGs to reduce the viability, proliferation, and self-renewal of tumor-initiating cells (TICs) - isolated from HBV-HCC patients - accompanied by downregulation of stemness markers, e.g., OCT-4.According to the current study situation, the use of HBIGs significantly reduces the risk of HBV reinfection after transplantation and improves the results of liver transplantation in patients with chronic HBV infection. The potential benefit of treating HBV-HCC patients on the LTx (liver transplantation) waiting list with hepatitis B immunoglobulin is the possible stop or inhibition of tumor progression while waiting for an LTx. So far there is no clinical evidence of this.

Mechanistically, hepatitis B immunoglobulin could occur through neutralization of circulating HBsAg, which is an important driver of an immunosuppressive environment in HBV patients, and possibly through direct effects against HBV HCC tumor cells (through antibody-dependent cellular cytotoxicity, ADCC). Therefore, the idea behind preoperative HBIG administration before liver transplantation is to reduce the rate of patients in whom a transplantation would no longer have been possible due to tumor progression. Thus, due to tumor progression in HBV-positive HCC-patients there is a monthly drop-out from the waiting list of about 4%.

The basic idea behind the treatment of HBV-HCC patients before tumor resection with hepatitis B immunoglobulin is to potentially stop or positively influence tumor progression through the effects mentioned above, in the time between diagnosis and resection.

Zhou et al. (2015) have shown a connection between HBsAg levels and HCC relapses after resection, although the exact role of HBsAg is still unclear. In no case will the treatment postpone the time of tumor resection, as only patients are considered who, for clinical reasons, can expect a certain time until resection. The present proof of concept study aims to quantify HBsAg reduction due to preoperative administration of HBIGs in HBV-positive HCC-patients and serve as a template for future multicentre clinical trials.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

5

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients ≥ 19 years and ≤ 80 of age
  • HBsAg-positive HCC-patients scheduled for resection in ≥6 weeks or HBsAg-positive HCC- patients listed for LT
  • Ability of subjects to understand character and individual consequences of the clinical trial
  • Written informed consent must be available before enrolment in the trial

Exclusion Criteria:

  • Clinically significant illness (other than HBV) or any other major medical disorder that, in the opinion of the investigator, may interfere with subject treatment
  • No eligibility for resection / LT
  • Concurrent any other malignancy
  • Co-infection with hepatitis C virus (defined as HCV RNA positive, HCV RNA-negative/anti-HCV-positive patients can be included) and/or human immunodeficiency virus (HIV)
  • Clinical hepatic decompensation
  • Allergy to HBIG
  • Pregnant, lactating patients

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: HBIG treatment
Drug: Hepatect CP 50 I.E./ml infusion solution

Application of i.v. (intravenously) HBIGs for ≥6-weeks:

Day (D) 0-7: 10.000 IU D14 until end-of-treatment: 10.000 IU once per week HBIGs will be given until LT/liver resection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
HBsAg change from baseline to week 6
Time Frame: ≥6-weeks

Quantification of the magnitude of the effect of ≥6-week; unit: IU/ml treatment with Hepatitis B immunoglobulins in patients with chronic hepatitis B and HCC, determined by the HBsAg reduction after week 6

Evaluation of the safety and tolerability of Hepatitis B immunoglobulins administered for ≥6-weeks in patients with chronic hepatitis B and HCC
≥6-weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of HBsAg at different time points during treatment
Time Frame: baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
unit: IU/ml
baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Change of HCC response to treatment
Time Frame: Tumor material will be measured at baseline and at end of treatment (on average ≥6-weeks)
Tumor size (cm) will be investigated via MR Primovist (RECIST) or alternatively via CT (RECIST).
Tumor material will be measured at baseline and at end of treatment (on average ≥6-weeks)
Change of Biochemical response (B cells)
Time Frame: baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Immune responses during HBIG treatment (analysis of B cells); unit 10^9/l
baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Change of Biochemical response (NK cells)
Time Frame: baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Immune responses during HBIG treatment (analysis of NK cells); unit 10^9/l
baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Change of Biochemical response (T cells)
Time Frame: baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Immune responses during HBIG treatment (analysis of T cells); unit 10^9/l
baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Change of Cellular response (CD3)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD3); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD4)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD4); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD8)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD8); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD25)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD25); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD34)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD34); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD133)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD133); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD19)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD19); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD56)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD56); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (CD49f)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD49f); unit:10^9/L
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (FoxP3)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (FoxP3) unit: µg/ml
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (Ki67)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (Ki67) unit: %
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (HLA-DR)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (HLA-DR) unit: %
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Change of Cellular response (IFN gamma)
Time Frame: Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry
Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (IFN gamma) unit: IU/ml
Tumor material will be collected at baseline and end-of-treatment (on average ≥6-weeks) via liver biopsies and will be analysed by immune histochemistry

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical University of Graz

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

November 1, 2024

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

June 1, 2026

Study Registration Dates

First Submitted

March 14, 2022

First Submitted That Met QC Criteria

March 14, 2022

First Posted (Actual)

March 24, 2022

Study Record Updates

Last Update Posted (Actual)

January 18, 2024

Last Update Submitted That Met QC Criteria

January 17, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HBIG

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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