- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03038802
A Randomised Controlled Phase 1 Study of Vaccine Therapy for Control or Cure of Chronic Hepatitis B Virus Infection (HBV003)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Prophylactic immunisation with HBsAg-based vaccines leads to development of HBsAg antibodies that provide protection against HBV infection. Modern HBV vaccines are based on recombinant HBsAg produced by expression in yeast expression systems. For infants whose mothers are HBsAg positive, the first HBV vaccine dose is given at birth and three further doses are administrated during the following 12 months at 2, 4 and 6 or 12 months. Studies have shown that these HBV vaccines are 90 to 95% effective in preventing children from developing chronic infection if they have not yet been infected. Since 1982 over one billion doses of HBV vaccine have been used worldwide. However a number of groups have poor responses to the existing HBV vaccines and these include older adults (age > 40) and patients with immunodeficiency, diabetes or renal impairment. A pilot clinical study demonstrated that standard anti-HBV vaccination could reduce HBV replication in 50% of chronic carriers. A multicentre trial, showed both the efficacy and the limitations of this approach. This study included 118 treatment-naive patients, with detectable serum HBV DNA using a standard liquid hybridization study and biopsy-proven chronic hepatitis pre-vaccination. Over a 12-month period, they were given either five intradermal injections of 20 µg of a pre S2:S HBV vaccine (GenHevac B.Pasteur-Merieux) or a standard HBV vaccine (Recombivax, MSD) or no treatment. Three months after the first three vaccine injections, the percentage of serum HBV DNA negativity was higher in the vaccine groups (15.5%) than in the control group (2.7%). After 1 year follow-up and five vaccine injections, there was no difference in the rate of serum HBV DNA negativity, but those receiving HBV vaccines had significantly decreased HBV viral load between 6 and 12 months when compared to the control group. The rate of HBe:anti-HBe seroconversion did not differ between the vaccinated and unvaccinated groups, but early HBeAg negativity and anti-HBe detection after 6 months of follow-up was seen only in vaccinated patients (8 and 15% in groups B (Recombivax.) and C (GenHevac B.), respectively, compared with 0% in the controls). Analysis of the vaccine-induced immune responses in 40 patients with HBV chronic hepatitis during this vaccine trial showed that vaccination elicited T cell proliferative responses in 7 of 27 patients who received the vaccine versus none of the unvaccinated control group. These specific responses for envelope antigen were mediated by CD4 T cells that produced high levels of gamma interferon. The reduction of serum HBV-DNA in some of these patients suggests that induction of CD4 T cell responses could be important in controlling viremia after vaccine therapy of HBV chronic carriers.
Experiments in transgenic mice that constitutively express HBV in the liver as a model of asymptomatic chronic HBV carriers have shown that immunization can overcome functional tolerance to HBV by inducing a specific antiviral immune response. The study vaccine was tested for its ability to induce seroconversion in a HBV transgenic mouse model. The results confirmed that the vaccine induced a high titre of anti-HBsAg antibodies and suppressed HBV virus load in the liver. Importantly from a safety perspective no evidence of a flare in liver disease as reflected by elevation of liver functions tests, was seen despite evidence the vaccine suppressed liver virus. The vaccinated mice had the lowest levels of liver transaminases, consistent with the vaccine reducing virus-mediated damage to the liver.
This study will test the hypothesis that the investigational vaccine will boost HBV antibody and T cell responses in chronically infected patients and thereby improve HBV viral control and opportunity for seroconversion. As this is an exploratory study, subjects with chronic HBV infection will be enrolled whether or not they are on current antiviral treatment. This will then allow comparison of vaccine effects in subjects on and off concomitant antiviral treatment, with this data used to assist the design of future studies. The study will test the hypothesis that a potent preS HBV vaccine including Advax adjuvant will enhance both humoral and cellular immunity thereby helping to control chronic hepatitis B infection. The ultimate goal is to induce HBsAg seroconversion and effect permanent clearance of HBV or at a minimum to enable better immune control of viral replication. This pilot study will collect preliminary data on the safety and efficacy of this vaccine approach in chronically HBV infected individuals, as a precursor to larger efficacy studies in the future.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Sharen Pringle, RN
- Phone Number: 0437033400
- Email: admin@arasmi.org
Study Locations
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South Australia
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Adelaide, South Australia, Australia, 5046
- ARASMI
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Contact:
- Dimitar Sajkov, MBBS, PhD
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Principal Investigator:
- Dimitar Sajkov, MBBS, PhD
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Male or female
- 18 years of age or older
- Current evidence of HBV chronic infection (with or without cirrhosis) as indicated by detection of HBsAg and/or Hepatitis B DNA (Subjects on current nucleoside therapy may have no detectable Hep B DNA)
- If child bearing age, using contraception (barrier method, IUD or oral contraception)
- Able to provide written informed consent
- Willing and able to comply with the protocol for the duration of the study.
Exclusion Criteria:
- Positive for antibody to hepatitis B core antigen (anti-HBc) IgM with negative results for the rest of the HBV markers, indicating acute infection,
- Positive for anti-delta virus, or anti-hepatitis C virus or HIV
- Childs Pugh Score for Cirrhosis Mortality of Child grade B or greater
- Liver transaminases greater than 5 times the upper limit of normal
- History of severe allergic reaction to hepatitis B vaccine.
- Pregnancy or female of child-bearing age not using effective method of contraception.
- Presence of any other organ-specific disease that in the opinion of the investigator may result in risk to the subject from involvement in the study
- Current alcohol or drug abuse that in the opinion of the investigator may result in non-compliance.
- Participation in another clinical trial with an investigational agent within 30 days preceding initiation of treatment
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Standard vaccine
Subjects will receive regular intramuscular injections of a commercial hepatitis B vaccine (HBsAg containing aluminium hydroxide adjuvant) according to the same study schedule as the subjects in the experimental arm
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Commercially available prophylactic hepatitis B vaccine formulated with alum adjuvant
Other Names:
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Experimental: Experimental therapeutic vaccine
Subjects will receive regular intramuscular injections of the experimental therapeutic hepatitis B vaccine (preS HBsAg containing Advax-2 adjuvant) in two cycles with the first cycle of four immunisations administered on days 0, 14, 28, 42. and the second cycle of four immunisations on days 70, 84, 98, and 112.
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HBV vaccine based on unique combination of recombinant PreS hepatitis B surface antigen particles formulated with Advax-2 adjuvant
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety assessment: Frequency of vaccine-related adverse events relative to active comparator vaccine
Time Frame: 12 months post immunisation
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Frequency of vaccine-related adverse events relative to active comparator vaccine
|
12 months post immunisation
|
Viral load
Time Frame: 1 and 12 months post final immunisation
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Suppression of HBV viral load
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1 and 12 months post final immunisation
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Seroconversion
Time Frame: 1 and 12 months post final immunisation
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Seroconversion to e antigen (if anti HBe negative at baseline) and seroconversion to surface antigen
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1 and 12 months post final immunisation
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T-cell response
Time Frame: 1 and 12 months post final immunisation
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Development of memory T-cell responses to HBV
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1 and 12 months post final immunisation
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B cell response
Time Frame: 1 and 12 months post final immunisation
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Development of memory B-cell responses to HBV
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1 and 12 months post final immunisation
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Nikolai Petrovsky, MBBS/PhD, Vaxine Pty Ltd
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- RNA Virus Infections
- Infections
- Blood-Borne Infections
- Communicable Diseases
- Disease Attributes
- Liver Diseases
- Hepatitis, Viral, Human
- Hepadnaviridae Infections
- DNA Virus Infections
- Enterovirus Infections
- Picornaviridae Infections
- Chronic Disease
- Hepatitis B
- Hepatitis
- Hepatitis A
- Virus Diseases
- Hepatitis B, Chronic
- Hepatitis, Chronic
- Herpesviridae Infections
- Physiological Effects of Drugs
- Immunologic Factors
- Vaccines
Other Study ID Numbers
- HBV003
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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