The Treatment With HBIG+GM-CSF+HBV Vaccine for Chronic Hepatitis B Patients With HBeAg Seroconversion
Information source: Beijing 302 Hospital
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Chronic Hepatitis B
Intervention: Drug (Drug); GM-CSF control (Drug)
Phase: Phase 1/Phase 2
Status: Recruiting
Sponsored by: Beijing 302 Hospital Official(s) and/or principal investigator(s): Fu-Sheng Wang, M.D., Principal Investigator, Affiliation: Research Center for Biotherapy
Overall contact: Fu-Sheng Wang, M.D., Phone: 86-10-63879735, Email: fswang302@163.com
Summary
The host immunity has been generally recognized as the main factors to determine the outcome
of chronic hepatitis B virus (HBV) infection; however, previous studies have shown that
HBV-specific T cell and B cell function are exhausted in chronic hepatitis B (CHB) patients.
Recently, It is suggested that hepatitis B surface antigen (HBsAg) may play a key role in
the immune tolerance or immune exhaustion. Anti-HBV immune responses are partially recovered
when patients achieved hepatitis B e antigen (HBeAg) seroconversion during antiviral
therapy, and can be nearly recovered during HBsAg seroconversion. However, it is still
difficult to achieve the ideal terminal, HBsAg seroconversion. For this reason,
immunotherapy would be helpful to enhance the anti-HBV immunity and acquire higher HBsAg
seroconversion. Here, the investigators propose a hypothesis that hepatitis B immune globin
(HBIG)+granulocyte-macrophage colony-stimulating factor (GM-CSF)+HBV vaccine can enhance
anti-HBV immune responses and improve HBsAg seroconversion in CHB patients who has achieved
HBeAg seroconversion using nucleoside analogues treatment.
Clinical Details
Official title: The Treatment With Nucleoside Analogues in Combination With HBIG+GM-CSF+HBV Vaccine for Chronic Hepatitis B Patients With HBeAg Seroconversion: a Phase I/II, Single-blind, Randomized, GM-CSF-controlled Trial
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Primary outcome: the rate of hepatitis B surface antigen (HBsAg) seroconversion
Secondary outcome: The rates of serum hepatitis B surface antigen (HBsAg) negativethe decreased levels of serum hepatitis B surface antigen (HBsAg) Number of participants with adverse events as a measure of safety and tolerability The frequency of hepatitis B virus (HBV)-specific T cells The frequency of hepatitis B virus (HBV)-specific B cells liver hepatitis B surface antigen (HBsAg) levels
Detailed description:
The host immunity has been generally recognized as the main factors to determine the outcome
of chronic hepatitis B virus (HBV) infection. Previous studies have shown that HBV-specific
T cell and B cell function are exhausted in chronic hepatitis B (CHB) patients.
Interestingly, these impaired T and B cell functions could be partially restored by
antiviral treatment, but this recovery seemed to be uncompleted even if long-term HBV
suppression and HBeAg seroconversion. Recently, several emerging evidences have indicated
that HBV-specific immune responses could be nearly recovered after hepatitis B surface
antigen (HBsAg) seroconversion. This phenomenon suggest that HBsAg may play a key role in
the immune tolerance or immune exhaustion. Indeed, our recent studies have found that the
patients with HBsAg seroconversion display an HBV-specific T and B cell responses. Thus, the
amount of HBsAg may serve as a possible mechanism for evading the host immune response,
while anti-HBs antibody and HBV specific-T cell responses provide protective immunity.
HBsAg was the Nobel prize discovery that identified HBV about 40 years ago; to this day
HBsAg remains the hallmark of overt HBV infection. HBsAg synthesis during the HBV viral life
cycle is complex, and typically occurs at the endoplasmic reticulum. The envelope open
reading frame (ORF) contains pre-surface 1 (preS1), pre-surface 2 (preS2), and ORF-S domains
and envelope proteins are generated from two HBV messenger ribonucleic acid (mRNA)
transcripts, with subsequent translation resulting in small (ORF-S), medium (pres2 + ORF-S)
and large surface envelope proteins (preS1 + preS2 + ORF-S). These are also known as large
(L), medium (M) and small (S) surface proteins, respectively. However, HBsAg production far
exceeds that required for virion assembly, and excess surface envelope proteins are secreted
as non infectious filamentous or spherical sub-viral particles, which exceed virions by a
variable factor of 102-105 and can accumulate up to concentrations of several hundred
micrograms per milliliter of serum. These data suggested that sAg mainly derive from
sub-viral particles, and the decline of serum HBsAg means reduction of covalently closed
circular DNA (cccDNA) transcription and mRNA translation but not HBV replication. Recently,
several studies suggest a new potential role of quantitative serum HBsAg in the prediction
of virological response to antiviral therapy, at least in pegylated interferon (Peg-IFN)
treated patients. In natural history of chronic HBV infection, HBsAg levels differ
significantly during the 4 phases of HBV infection and decline progressively from immune
tolerance (IT) (5 log IU/ml) to low replication (LC) (3 log IU/ml), while HBsAg/HBV-DNA
ratios are significantly higher in LC as compared to all the others patients. These data
suggested that the quantitative HBsAg may be a promising prognostic marker during the
natural history of HBV-infection and during antiviral therapy. Thus, the loss of HBsAg and
the development of anti-HBs antibodies (HBsAg-seroconversion) is the ultimate goal of
anti-HBV therapy.
CHB patients would achieve HBV DNA replication inhibition, glutamic-pyruvic transaminase
(ALT) normalization and hepatitis B e antigen (HBeAg) seroconversion after treatment with
antiviral therapy. In addition, the antiviral immunity would be improved during the this
process. However, it is difficult for these patients to clear HBsAg and reach the idea
terminal. The major reasons are the presence of HBsAg and HBV-specific immunity was
impaired. For this reason, immunotherapy would be helpful to enhance the anti-HBV immunity
and acquire higher HBsAg seroconversion rate. The purpose of this study is to investigate
whether and how immunotherapy ie. HBIG+GM-CSF+HBV vaccine improve the rate of HBsAg
seroconversion. This study will also focus on the tolerance and safety of this treatment in
CHB patients.
Participants in this study will be randomly assigned to one of two treatment arms:
Arm A: Participants will receive 48 weeks of nucleoside analogs (NAs) treatment combined
with 24-week treatment with hepatitis B immune globin (HBIG)+granulocyte-macrophage
colony-stimulating factor (GM-CSF)+HBV vaccine.
Arm B: Participants will receive 48 weeks of NAs treatment combined with 24-week treatment
with saline placebo.
All of patients will be treated continuously with NAs for 48 weeks in combination with
HBIg+GM-CSF+HBV vaccine treatment or saline placebo for first 24-week and then followed-up
for other 24-week. In treatment period (24 weeks), the treatment of HBIg+GM-CSF+HBV vaccine
will be given four times in week 0, 4, 12 and 24. At each time of treatment, the patients
will be hospitalized and treated with 800 unit of HBIG intramuscularly at day 0, 1, 2, 3 and
4, and were treated with 75 μg of GM-CSF subcutaneously at day 2, 3, 4, 5 and 6, and finally
were injected 20μg of HBV vaccine subcutaneously at day 6. This approach allow that the
initial HBIG injection possibly reduces HBsAg, then antigen-presenting cells are activated
by GM-CSF treatment, and finally HBV vaccine is used to priming APC to induce HBV-specific
immune responses. In control group, the patients will received GM-CSF as control at each
time. After treatment has been initialized, the participants will be asked to come to the
clinic on weeks 4, 12, 24, 36 and 48. At each visit participants will receive enough study
treatment to last until the next visit. Each visit will last between 2 and 3 hours. At most
visits participants will have a physical exam, answer questions about any medications they
are taking and how they are feeling, and have blood drawn for safety and efficacy and HBsAg
quantization. Some additional blood will also be stored for HBV-specific T cell and B cell
responses. At some visits participants will be asked questions about their medication and
medical history, have pupils dilated, have a hearing test, and have an electrocardiogram
(EKG). Some visits will require participants to arrive fasting. Pregnancy tests may also be
conducted so as to avoid some participants who is able to become pregnant or if pregnancy is
suspected.
Eligibility
Minimum age: 18 Years.
Maximum age: 50 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. chronic hepatitis B patients with HBeAg seroconversion (eAg negative and eab
positive)
2. age 18-50, male or female
3. HBsAg positive for at least 6 months, quantitative HBsAg <1000 IU/ml (Abbott
Diagnostic, Wiesbaden, Germany)
4. HBeAg positive CHB patients who have received NAs (lamivudine, adefovir dipivoxil,
entecavir, alone or in combination) treatment and achieved HBeAg seroconversion
(HBeAg-, HBeAb+), HBV DNA<40 IU/ml and ALT normalization and maintained for at least
6 months.
5. Urine pregnancy test is negative in gestational age female subjects before
enrollment, who can take effective contraceptive measures and agree to contraception
during treatment and follow-up period.
6. Enrolled subjects should understand and sign the informed consent and comply with the
requirement of the research before study.
7. Enrolled subjects should agree not to participate in other studies, and not to accept
other immunomodulatory therapy during the study. Other treatments such as
corticosteroids should be informed timely
Exclusion Criteria:
1. Be allergic to HBIG, GM-CSF and HBV vaccine.
2. Coinfected with other virus. Any positive for anti-hepatitis A virus (HAV),
anti-hepatitis C virus (HCV), anti-hepatitis D virus (HDV), anti-hepatitis E virus
(HEV) and anti-HIV.
3. Advanced cirrhosis or Child-Pugh 7 scores or above.
4. Autoimmune thrombocytopenic purpura, coronary heart disease, cerebrovascular disease,
hypertension, diabetes mellitus, high myopia, history of epilepsy.
5. Other causes of liver disease, such as autoimmune liver disease, alcoholic liver
disease, nonalcoholic liver disease, drug-induced liver disease and other unknown
causes of chronic liver diseases.
6. Associated with other serious organic disease, mental illness, including any
uncontrolled urinary, respiratory, circulation, nervous, digestive, endocrine,
spirit, immune system diseases and tumor.
7. Suspected liver cancer or alpha feto protein (AFP) > 100ng/ml.
8. Neutrophil count < 2. 5×109/L, or hemoglobin < 100g/L, or platelet < 80×109/L.
9. Pregnant or lactating women.
10. Allergic constitution, allergy history for blood products, known allergy to
experimental drugs.
11. Alcohol or drug addiction, drug use history evidence within one year before enrolled
in the study.
12. Received immunosuppressive or other immune modulators (including thymosin) or
systemic cytotoxic drug 6 months before enrolled in the study.
13. Incompliance during antiviral therapy.
14. Enrolled in other clinical trials at present, and possible to be against the
treatment and observation index.
15. Unable or unwilling to provide informed consent or fails to comply with the
requirements of the study.
16. Other serious conditions that may hamper clinical trials.
Locations and Contacts
Fu-Sheng Wang, M.D., Phone: 86-10-63879735, Email: fswang302@163.com
Beijing 302 Hospital, Beijing 100039, China; Recruiting Zheng Zhang, M.D., Phone: 86-10-63879735, Email: zhangzheng1975@aliyun.com Fu-Sheng Wang, professor, Principal Investigator
Additional Information
Related publications: Xu DZ, Wang XY, Shen XL, Gong GZ, Ren H, Guo LM, Sun AM, Xu M, Li LJ, Guo XH, Zhen Z, Wang HF, Gong HY, Xu C, Jiang N, Pan C, Gong ZJ, Zhang JM, Shang J, Xu J, Xie Q, Wu TF, Huang WX, Li YG, Xu J, Yuan ZH, Wang B, Zhao K, Wen YM; YIC Efficacy Trial Study Team. Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol. 2013 Sep;59(3):450-6. doi: 10.1016/j.jhep.2013.05.003. Epub 2013 May 11. Shouval D. Focus: quantitative HBsAg measurement as a new surrogate marker for assessment of hepatic fibrosis in HBeAg+ chronic hepatitis B. J Hepatol. 2013 Jun;58(6):1063-4. doi: 10.1016/j.jhep.2013.03.002. Epub 2013 Mar 14. Seto WK, Wong DK, Fung J, Huang FY, Lai CL, Yuen MF. Reduction of hepatitis B surface antigen levels and hepatitis B surface antigen seroclearance in chronic hepatitis B patients receiving 10 years of nucleoside analogue therapy. Hepatology. 2013 Sep;58(3):923-31. doi: 10.1002/hep.26376. Epub 2013 Jul 24. Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, Hsu CA, Kuo SF, Liu CH, Chen PJ, Chen DS, Kao JH. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology. 2013 Feb;57(2):441-50. doi: 10.1002/hep.26041. Epub 2012 Dec 6.
Starting date: June 2013
Last updated: July 23, 2013
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