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

Study Overview
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Brief Summary
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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.

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

Conditions
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Hepatocellular Carcinoma, HBV

Intervention / Treatment
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* Drug: Hepatect CP 50 I.E./ml infusion solution


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HBIG treatment<br> | Drug: Hepatect CP 50 I.E./ml infusion solution<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBsAg change from baseline to week 6 | 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 | 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 | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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 |