Chronic Hepatitis BPhase 2NCT01487876
Efficacy and Safety of Dual-plasmid Hepatitis B Virus DNA Vaccine in Chronic Hepatitis B Patients
A Phase 2 study testing HBV DNA vaccine in people with Chronic Hepatitis B, run by Fuqiang Yang at 1 site in China.
Trial summary
In order to study the immunotherapeutic effects of electroporation (EP)-mediated dual-plasmids Hepatitis B Virus DNA vaccine, the investigators plan to conduct a double-blind, randomized, placebo-controlled trial, approved by Chinese State Food and Drug Administration with written informed consent from each chronic… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Chronic Hepatitis B
- What is being tested?
- HBV DNA vaccine
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 240 participants
- Where
- 1 siteChina
- Study dates
- Sep 2011to Dec 2012
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Aged 18-65 years with either sex;
- HBV serology meet the following criteria:
- HBsAg-positive lasting for at least 6 months at the time of screening;
- HBeAg-positive at the time of screening;
- Serum HBV DNA≥1.0×10E5 copies/ml at the time of screening
- 80U/L<ALT<400U/L;
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- TBIL<40μmol/L;
- No YMDD mutation of the HBV drug resistance gene
- Subjects agree not to participate in any other clinical trial or take any other anti-HBV therapeutics during the study;
- Subjects understand and sign the ICF which approved by EC, and are able to comply with the study procedures and complete the study.
Who cannot join
- Was suspected with HCC by the following evidence:
- B-Ultrasound or imaging which shows occupying lesions;
- Continuingly elevating serum AFP level even if the B-Ultrasound is normal;
- AFP >100ng/ml;
- With acute hepatic decompensation caused by liver disease aggravation or with clinical symptoms of decompensated liver disease at baseline;
- Serum Cr≥1.5mg/dl (≥130μmol/l) at the time of screening;
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- Serum amylase > two-fold of the upper limit of the normal reference value;
- Hb (male<100g/ L, female<90g/L), WBC<3.5×10E9/L,PLT<60×10E9/L (except hypersplenism and cirrhosis);
- Co-infection with HCV (anti-HCV positive), HIV and anti-HAV IgM positive, anti-HDV IgM positive, anti-HEV IgM positive, anti-CMV IgM positive and autoimmune hepatitis (e.g. antinuclear antibody titer>1:160 ) or other active liver disease caused by known or unknown factors;
- Any other serious disease or active diseases other than hepatitis B that are considered by investigators to be potential factors that may interfere with the therapy, assessment or compliance with the protocol, including any uncontrolled diseases with clinical significance, e.g. kidney, heart, lung, blood vessel, neurogenic, digestive system and metabolic diseases (diabetes, hyperthyroidism, adrenal gland diseases), autoimmune dysfunctions, and tumors, etc;
- History of alcohol or drug abuse that is considered by investigators that could affect subject's compliance with the protocol or could influence the result of the analysis;
- Pregnant or breast-feeding female subjects, or those who plan to be pregnant during the course of the study or male subjects' companions who plan to be pregnant during the course of the study;
- Having used immunosuppressive agents, immunomodulators (thymosin), cytotoxic drugs within 6 months or transaminase-decreasing drugs within one month prior to the initiation of this study;
- Having used anti-HBV drugs (Lamivudine, interferon, adefovir, entecavir, or sebivo, etc.) within 6 months prior to the initiation of this study;
- Had or planning to have liver transplantation;
- Having received experimental drug treatment from any other study within 3 months prior to the screening;
- Allergic to nucleoside drugs or nucleoside analogues;
- Not agreeing to the study protocol or any other factors considered not eligible for this study by investigators.
Trial locations and contacts
1 site in 1 country.
China1 site, 1 recruiting
- Recruiting
Guiqiang Wang
Beijing, Bejing, 10000
Guiqiang Wang, PhD, 00861066551122 ext. 2597, wanggq@hotmail.com
Guiqiang Wang, PhD
About this study
Official title: A Randomized Controlled Trial of Dual-plasmid HBV DNA Vaccine Mediated by in Vivo Electroporation in Chronic Hepatitis B Patients Under Lamivudine Chemotherapy
In order to study the immunotherapeutic effects of electroporation (EP)-mediated dual-plasmids Hepatitis B Virus DNA vaccine, the investigators plan to conduct a double-blind, randomized, placebo-controlled trial, approved by Chinese State Food and Drug Administration with written informed consent from each chronic hepatitis B (CHB) patients with baseline ALT more than 2 times the ULN, for whom antiviral treatment is indicated and who were under the simultaneous lamivudine (LAM) chemotherapy.
Read the detailed description
Hepatitis B virus (HBV) affects approximately more than 350 million people worldwide, leading to a wide spectrum of clinical manifestations ranging from an asymptomatic carrier state to self-limited acute infection or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma and poses a serious public health problem in endemic counties like China. Current available therapeutic remedies such as interferons and nucleotide/nucleoside analogues are far from satisfactory, for their therapeutic efficacies are limited by the high economic cost with the less tolerable adverse effects or the lack of viral eradicative effect for its long term control of the virus in most of the patients. Viral persistence has been associated with a defect in the development of HBV-specific cellular immunity. Strategies to boost or to broaden the weak virus-specific T-cell response of patients with chronic hepatitis B have been proposed as a means of curing this persistent infection. HBV envelope- and nucleocapsid-based vaccines, new formulations for recombinant vaccines and DNA-based vaccines are currently being assessed in clinical trials, among which DNA vaccine represents a promising immunotherapeutic approach that can induce T-cell mediated antigen specific immunity, owing to its de novo intracellular antigenic protein expression and synthesis.
In clinical trials, although HBV DNA vaccination developed protective antibody responses and antigen-specific CD8 T cells in healthy hepatitis-naive human volunteers, the detectable HBV-specific IFN-γ secreting T cells and decreased serum HBV DNA levels only in some chronic HBV carriers vaccinated with HBV PreS2/S DNA vaccine were limited. One resolution for the main obstacles of the new technique development is to enhance the transfection efficiency of plasmids into host cells; the other is to improve the immunogenicity of DNA vaccine by driving the naïve T cell responses towards the Th1 profile. To tackle the first problem of low transfection rate of DNA vaccine, the investigators had applied the in vivo electroporation (EP) for potency enhancement of HBV DNA vaccine, which dramatically improved the host cell transfection of the plasmids and enabled the DNA vaccine the investigators prepared to elicit both humoral and cellular immune responses in the large body weight animals like rabbit and nonhuman primates. In order to achieve the second goal of immunogenicity improvement of HBV DNA vaccine for its therapeutic usage, the investigators had designed and constructed the Th1 type cytokines (interleukin-2 and interferon-γ) fusion protein expression gene plasmids (pFP), in attempt to direct Th1 bias in favor of cellular immunity augment when being used in combination with HBV DNA vaccine. Both tactics in the form of the dual-plasmids DNA vaccination mediated by EP have been investigated to be safe and efficient to improve the transfection and enhance the immunogenicity of DNA vaccine to the host in both animal models and in phase I,II trials of healthy volunteers and CHB patients.
In order to study the immunotherapeutic effects of EP-mediated dual-plasmids HBV DNA vaccine, the investigators plan to conduct a clinical trial, approved by Chinese State Food and Drug Administration (license number: 2006L03542) with written informed consent from each patient. The trial is a double-blind, randomized, placebo-controlled one in CHB patients with baseline ALT more than 2 times the ULN, for whom antiviral treatment is indicated and who were under the simultaneous lamivudine (LAM) chemotherapy.
- Conditions
- Chronic Hepatitis B
- Being tested
- HBV DNA vaccine, Placebo
- Keywords
- DNA vaccine, HBV, Chronic hepatitis B (CHB), T-cell
- Medical subject headings
- Hepatitis B, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HBV DNA vaccineBiological
HBV DNA vaccine means that each volunteer received 4 injections of 4 mg DNA vaccine scheduled by a prime and 3 boosts at intervals of 4, 8, 12 weeks.
PlaceboOther
Placebo means the arm in which each volunteer received 4 injections of 4 mg placebo scheduled by a prime and 3 boosts at intervals of 4, 8, 12 weeks.
| Study group | Role | What they receive |
|---|---|---|
| LAM+DNA vaccine | Experimental | lamivudine (LAM) chemotherapy and DNA vaccine Receives: Biological: HBV DNA vaccine |
| LAM+Placebo | Placebo comparator | Each volunteer received 4 injections of 4 mg placebo scheduled by a prime and 3 boosts at intervals of 4, 8, 12 weeks.
lamivudine (LAM) chemotherapy and Placebo Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
HBV DNA suppression
Suppression of HBV DNA was defined as the >2 log10 decrease of viral load from baseline level.
Measured: Before and after DNA vaccine injection: weeks 0, 60.
Loss of HBeAg
HBeAg serum titer was dropped to the detection limit by quantitative determination.
Measured: Weeks 0, 48.
Appearance of Anti-HBe
Measured: At weeks 0,48.
Secondary outcomes (4)
HBeAg seroconversion rate
loss of HBeAg, or presence of anti-HBe antibody
Measured: At weeks 0, 12, 24, 48, 72.
The occurrence of YMDD mutants
Tyrosine-methionine-aspartate-aspartae (YMDD) mutants were evaluated by means of polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) and PCR-Sequencing (Invitrogen Ltd. Shanghai,China), at baseline, week 48 and 72. The amino acid (AA) mutations were identified by comparing HBV RT sequences with the genotype-matched consensus sequence generated based on the HBV sequences obtained from genbank. A mutation type was referred to the replacement of the consensus AA of the corresponding genotype with a novel one.
Measured: At weeks 0, 48, 72.
Viral breakthrough rate
On the basis of present Guideline for Management of chronic hepatitis B (CHB), the virologic breakthrough (VBT) was defined as >1 log copies increase in HBV DNA from nadir after an initial virologic response or HBV DNA could be detected again after the previous report of "under the detection limit".
Measured: At weeks 0, 12, 24, 40, 48, 56, 60, 64, 72.
HBV Ag specific T cell immunity
The enzyme-linked immunosorbent spot (ELISPOT) assay was performed according to the manufacture's protocol in the human IFN-g ELISPOT Set (BD Biosciences, San Diego, CA, USA). The ELISPOT assay for enumeration of antigen-specific IFN-γ-secreting cells (spot forming cells, SFCs) was performed according to the manufacturer's instructions . The number of IFN-γ spots was counted by AID Elispot reader system (AID, Germany). Data are expressed as the mean SFCs/106 PBMC.
Detection of HBV-specific cytotoxic T lymphocyte (CTL) was performed by using flow cytometry (FACS) Calibur (BD Biosciences).
Measured: At weeks 0, 12, 24, 36, 52, 72.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Dec 2011 (estimated)
- Study startSep 2011
- Primary completionAug 2012 (estimated)
- Study completionDec 2012 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic Hepatitis BStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 240 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fuqiang Yang
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Fuqiang Yang, The 458 Hospital of Chinese PLA
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01487876
- Sponsor's protocol ID
- 2011005SW0101
- Status last verified
- Sep 2011
- First submitted
- 22 Sep 2011
- Last updated
- 8 Dec 2011
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 8 Dec 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Controlled Trial of Dual-plasmid HBV DNA Vaccine Mediated by in Vivo Electroporation in Chronic Hepatitis B Patients Under Lamivudine Chemotherapy
- ClinicalTrials.gov ID
- NCT01487876
- Acronym / sponsor ID
- 2011005SW0101
- Conditions
- Chronic Hepatitis B
- Keywords
- DNA vaccine, HBV, Chronic hepatitis B (CHB), T-cell
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 240 participants (estimated)
- Lead sponsor
- Fuqiang YangUniversity, hospital or other
- Study start
- Sep 2011
- Primary completion
- Aug 2012 (estimated)
- Study completion
- Dec 2012 (estimated)
- First posted
- 8 Dec 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In order to study the immunotherapeutic effects of electroporation (EP)-mediated dual-plasmids Hepatitis B Virus DNA vaccine, the investigators plan to conduct a double-blind, randomized, placebo-controlled trial, approved by Chinese State Food and Drug Administration with written informed consent from each chronic hepatitis B (CHB) patients with baseline ALT more than 2 times the ULN, for whom antiviral treatment is indicated and who were under the simultaneous lamivudine (LAM) chemotherapy.
Detailed description
Hepatitis B virus (HBV) affects approximately more than 350 million people worldwide, leading to a wide spectrum of clinical manifestations ranging from an asymptomatic carrier state to self-limited acute infection or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma and poses a serious public health problem in endemic counties like China. Current available therapeutic remedies such as interferons and nucleotide/nucleoside analogues are far from satisfactory, for their therapeutic efficacies are limited by the high economic cost with the less tolerable adverse effects or the lack of viral eradicative effect for its long term control of the virus in most of the patients. Viral persistence has been associated with a defect in the development of HBV-specific cellular immunity. Strategies to boost or to broaden the weak virus-specific T-cell response of patients with chronic hepatitis B have been proposed as a means of curing this persistent infection. HBV envelope- and nucleocapsid-based vaccines, new formulations for recombinant vaccines and DNA-based vaccines are currently being assessed in clinical trials, among which DNA vaccine represents a promising immunotherapeutic approach that can induce T-cell mediated antigen specific immunity, owing to its de novo intracellular antigenic protein expression and synthesis.
In clinical trials, although HBV DNA vaccination developed protective antibody responses and antigen-specific CD8 T cells in healthy hepatitis-naive human volunteers, the detectable HBV-specific IFN-γ secreting T cells and decreased serum HBV DNA levels only in some chronic HBV carriers vaccinated with HBV PreS2/S DNA vaccine were limited. One resolution for the main obstacles of the new technique development is to enhance the transfection efficiency of plasmids into host cells; the other is to improve the immunogenicity of DNA vaccine by driving the naïve T cell responses towards the Th1 profile. To tackle the first problem of low transfection rate of DNA vaccine, the investigators had applied the in vivo electroporation (EP) for potency enhancement of HBV DNA vaccine, which dramatically improved the host cell transfection of the plasmids and enabled the DNA vaccine the investigators prepared to elicit both humoral and cellular immune responses in the large body weight animals like rabbit and nonhuman primates. In order to achieve the second goal of immunogenicity improvement of HBV DNA vaccine for its therapeutic usage, the investigators had designed and constructed the Th1 type cytokines (interleukin-2 and interferon-γ) fusion protein expression gene plasmids (pFP), in attempt to direct Th1 bias in favor of cellular immunity augment when being used in combination with HBV DNA vaccine. Both tactics in the form of the dual-plasmids DNA vaccination mediated by EP have been investigated to be safe and efficient to improve the transfection and enhance the immunogenicity of DNA vaccine to the host in both animal models and in phase I,II trials of healthy volunteers and CHB patients.
In order to study the immunotherapeutic effects of EP-mediated dual-plasmids HBV DNA vaccine, the investigators plan to conduct a clinical trial, approved by Chinese State Food and Drug Administration (license number: 2006L03542) with written informed consent from each patient. The trial is a double-blind, randomized, placebo-controlled one in CHB patients with baseline ALT more than 2 times the ULN, for whom antiviral treatment is indicated and who were under the simultaneous lamivudine (LAM) chemotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| LAM+DNA vaccine | Experimental | Biological: HBV DNA vaccinelamivudine (LAM) chemotherapy and DNA vaccine |
| LAM+Placebo | Placebo comparator | Other: PlaceboEach volunteer received 4 injections of 4 mg placebo scheduled by a prime and 3 boosts at intervals of 4, 8, 12 weeks. lamivudine (LAM) chemotherapy and Placebo |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Aged 18-65 years with either sex;
- HBV serology meet the following criteria:
- 80U/L<ALT<400U/L;
- TBIL<40μmol/L;
- No YMDD mutation of the HBV drug resistance gene
Key exclusion criteria (18 listed)
- Was suspected with HCC by the following evidence:
- With acute hepatic decompensation caused by liver disease aggravation or with clinical symptoms of decompensated liver disease at baseline;
- Serum Cr≥1.5mg/dl (≥130μmol/l) at the time of screening;
- Serum amylase > two-fold of the upper limit of the normal reference value;
- Hb (male<100g/ L, female<90g/L), WBC<3.5×10E9/L,PLT<60×10E9/L (except hypersplenism and cirrhosis);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HBV DNA vaccineHBV DNA vaccine means that each volunteer received 4 injections of 4 mg DNA vaccine scheduled by a prime and 3 boosts at intervals of 4, 8, 12 weeks. | Biological | LAM+DNA vaccine |
| PlaceboPlacebo means the arm in which each volunteer received 4 injections of 4 mg placebo scheduled by a prime and 3 boosts at intervals of 4, 8, 12 weeks. | Other | LAM+Placebo |
Primary outcome
HBV DNA suppression
Time frame: Before and after DNA vaccine injection: weeks 0, 60.
Suppression of HBV DNA was defined as the >2 log10 decrease of viral load from baseline level.
Loss of HBeAg
Time frame: Weeks 0, 48.
HBeAg serum titer was dropped to the detection limit by quantitative determination.
Appearance of Anti-HBe
Time frame: At weeks 0,48.
4 secondary outcomes
HBeAg seroconversion rate
Time frame: At weeks 0, 12, 24, 48, 72.
The occurrence of YMDD mutants
Time frame: At weeks 0, 48, 72.
Viral breakthrough rate
Time frame: At weeks 0, 12, 24, 40, 48, 56, 60, 64, 72.
HBV Ag specific T cell immunity
Time frame: At weeks 0, 12, 24, 36, 52, 72.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Dec 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing HBV DNA vaccine in people with Chronic Hepatitis B, run by Fuqiang Yang at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 8 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Fuqiang Yang, PhD (00862087376240, yangfq23@163.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
HBV DNA suppression (time frame: Before and after DNA vaccine injection: weeks 0, 60.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Dec 2011.