The Treatment With HBIG+GM-CSF+HBV Vaccine for Chronic Hepatitis B Patients With HBeAg Seroconversion
Recruitment status was: Recruiting
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
|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|
- the rate of hepatitis B surface antigen (HBsAg) seroconversion [ Time Frame: At week 48 ]
- The rates of serum hepatitis B surface antigen (HBsAg) negative [ Time Frame: At Baseline and at week 4, 12, 24, 36 and 48 ]
- the decreased levels of serum hepatitis B surface antigen (HBsAg) [ Time Frame: At Baseline and at week 4, 12, 24, 36 and 48 ]
- Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: at baseline and up to week 48 week ]
- The frequency of hepatitis B virus (HBV)-specific T cells [ Time Frame: At baseline and at week 4, 12, 24, 36 and 48 ]
- The frequency of hepatitis B virus (HBV)-specific B cells [ Time Frame: At baseline and at week 4, 12, 24, 36 and 48 ]
- liver hepatitis B surface antigen (HBsAg) levels [ Time Frame: At baseline and week 48 ]
- plasma hepatitis B virus (HBV) DNA load [ Time Frame: At Entry and at Weeks 24 and 48 ]
- Hepatitis B virus (HBV) serum markers (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb) [ Time Frame: At baseline and at week 24 and 48 ]
|Study Start Date:||June 2013|
|Estimated Study Completion Date:||July 2015|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Drug treatment
Drug: 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, then 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.
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, then were treated with 75 μg of GM-CSF subcutaneously at day 2, 3, 4, 5 and 6, and finally were injected 20 μg of HBV vaccine subcutaneously at day 6.
Other Name: treatment group
GM-CSF was given four times as control in week 0, 4, 12 and 24. At each time of treatment, the patients will be hospitalized and treated with GM-CSF intramuscularly or subcutaneously at day 2, 3, 4, 5, 6.
Drug: GM-CSF control
Given four times in week 0, 4, 12 and 24. At each time of treatment, the patients will be hospitalized and treated with saline placebo intramuscularly or subcutaneously at day 2, 3, 4, 5, 6.
Other Name: drug control
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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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01878565
|Beijing 302 Hospital|
|Beijing, China, 100039|
|Principal Investigator:||Fu-Sheng Wang, M.D.||Research Center for Biotherapy|