First in Human Study of ChAdOx1-HBV

Study Overview
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Brief Summary
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This is a Phase 1, first in human study of ChAdOx1-HBV. The study will be conducted in 40 healthy participants and 12 participants with CHB and virally suppressed with oral antiviral medication. This will be an open-label, non randomised dose escalation study comparing the safety, tolerability and immunogenicity of 2 different doses of ChAdOx1 HBV vaccine. T cell responses in healthy participants who have received a prior two-dose series of AZD1222 will be compared with those who have received either the Pfizer COVID 19 vaccine or the Moderna mRNA COVID 19 vaccine.

Detailed Description
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This is a first in man human study of a therapeutic vaccine for chronic hepatitis B infection(ChAdOx1-1HBV). The vaccine will be given to participants in a dose escalation strategy (two doses). Five healthy participants will be administered the low dose first (cohort 1). Dose escalation will only be initiated in the next 5 healthy participants (cohort 2) following Safety Monitoring Committee (SMC) review. Six CHB participants will be administered the low dose (cohort 3) before the dose escalation is initiated in the remaining 6 CHB participants (cohort 4). Thirty healthy participants (15 who have received two doses of AZD1222 [cohort 5] and 15 who have received at least two prior doses of Pfizer/Moderna mRNA COVID 19 vaccine [cohort 6]) will be dosed in parallel with the high dose used in cohorts 2 and 4. Each participant will receive 1 dose of the vaccine (intramuscular injection). Participants (Volunteers & patients) in cohorts 1 to 4 will attend up to 9 study visits and cohorts 5 & 6 will attend up to 4 visits in total. The last visit will be 24 weeks after vaccination for cohorts 1 to 4 and 12 weeks for cohorts 5 & 6.

Official Title
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A Phase 1 Monotherapy Study to Evaluate the Safety, Tolerability & Immunogenicity of Vaccination With Candidate Chimpanzee Adenovirus-vectored HepB Virus Vaccine ChAdOx1 HBV in Healthy Participants & Participants With Chronic HepB Infection

Conditions
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Hepatitis B, Healthy

Intervention / Treatment
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* Biological: ChAdOx1-HBV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males or females aged ≥18 to ≤65 years at screening Body Mass Index ≤30 kg/m2 Able to provide informed consent indicating they understand the purpose of, and procedures required, for the study and are willing to participate If female, willing not to become pregnant up to 8 weeks after last dose of study vaccine, not breast feeding If female: Not pregnant, and one of the following: Of non-childbearing potential (i.e. women who have had a hysterectomy or tubal ligation or are post menopausal, as defined by no menses in ≥1 year) Sexual abstinence, only if the participant refrains from heterosexual intercourse during the entire study period and it is the usual lifestyle of the participant Of childbearing potential but agrees to practice highly effective contraception for 4 weeks prior to study vaccine and 8 weeks after study vaccine. Highly effective methods of contraception include one or more of the following: Male partner who is sterile (medically effective vasectomy) prior to the female participant's entry into the study and is the sole sexual partner for the female participant, Hormonal (oral, intravaginal, transdermal, implantable or injectable), An intrauterine hormone releasing system, An intrauterine device and Bilateral tubal occlusion Healthy participants (cohorts 1 and 2): Considered to be healthy with no current conditions that may significantly impair participant safety or influence study results, in the opinion of the Investigator Participants with well controlled CHB (cohorts 3 and 4): Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with detectable HBsAg levels at screening) Receipt of only either entecavir or tenofovir for at least 12 months before screening Virally suppressed (HBV DNA <40 IU/mL for ≥6 months) HBsAg <4000IU/mL Participants with well controlled CHB (cohorts 3 and 4): 7. Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with detectable HBsAg levels at screening) 8. Receipt of only either entecavir or tenofovir for at least 12 months before screening 9. Virally suppressed (HBV DNA <40 IU/mL for ≥6 months) 10. HBsAg <10000 IU/mL Healthy participants (cohort 5): 11. Considered to be healthy with no current conditions that may significantly impair participant safety or influence study results, in the opinion of the Investigator 12. Adult males or females aged ≥40 to ≤60 years at screening 13. Completed second dose of COVID-19 AZD1222 vaccine 10 to 18 weeks before enrolment Healthy participants (cohort 6): 14. Considered to be healthy with no current conditions that may significantly impair participant safety or influence study results, in the opinion of the Investigator 15. Adult males or females aged ≥40 to ≤60 years at screening 16. Received the latest dose of Completed of either Pfizer (Comirnaty®) or Moderna (Spikevax) mRNA COVID 19 vaccine 6 to 30 weeks before enrolment Exclusion Criteria: Presence of any significant acute or chronic, uncontrolled medical/ psychiatric illness Hepatitis C virus antibody positive. Human immunodeficiency virus antibody positive History or evidence of autoimmune disease or known immunodeficiency of any cause Prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics (e.g. monoclonal antibodies, interferon) within 3 months of screening Receipt of immunoglobulin or other blood products within 3 months prior to screening Receipt of any investigational drug or vaccine within 3 months prior to screening Cohorts 1-4: Receipt of any adenoviral vaccine within 3 months prior to administration of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-based vaccine within 3 months after Day 0 Cohorts 5 and 6: Receipt of any adenoviral vaccine (other than AZD1222 per inclusion criterion 13) within 3 months prior to administration of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-based vaccine within 3 months after Day 0 Receipt of any live vaccines within 30 days prior to screening Receipt of any inactivated vaccines within 14 days prior to screening History of allergic disease or reactions likely to be exacerbated by any component of the vaccine Any history of anaphylaxis in reaction to vaccination Malignancy within 5 years prior to screening with the exception of specific cancers that are cured by surgical resection (e.g. except basal cell skin carcinoma of the skin and cervical carcinoma). Participants under evaluation for possible malignancy are not eligible Current alcohol or substance abuse judged by the Investigator to potentially interfere with participant safety and compliance Significant cardiac disease or unstable uncontrolled cardiac disease Any laboratory test at screening which is abnormal and which is deemed by the Investigator to be clinically significant Any other finding that, in the opinion of the Investigator, deems the participant unsuitable for the study Additionally, for healthy participants (cohorts 1, 2, 5 and 6) HBsAg positive Additionally, for participants with well controlled CHB (cohorts 3 and 4) Co infection with hepatitis delta Documented cirrhosis or advanced fibrosis indicated by a liver biopsy within 6 months prior to screening. In the absence of an appropriate liver biopsy, either 1 of the following: Screening Fibroscan with a result >9 kPa within ≤6 months of screening or Screening FibroTest >0.48 and aspartate aminotransferase (AST) to platelet ratio index of >1 In the event of discordant results between non-invasive methods, the Fibroscan result will take precedence. Alanine transaminase (ALT) >3 × upper limit of normal, international normalised ratio (INR) >1.5 unless the participant was stable on an anticoagulant regimen affecting INR, albumin <35 g/L, total bilirubin >2 mg/dL, platelet count <100,000/mL A history of liver decompensation (e.g. ascites, encephalopathy or variceal haemorrhage) Prior or current hepatocellular carcinoma Chronic liver disease of a non HBV aetiology Any herbal supplements and or other medicines with potential liver toxicity within the previous 3 months prior to enrolment into this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The participants will be recruited in 6 cohorts as follows - Cohort 1 - Healthy Volunteers - Low dose Vaccine - 5 participants Cohort 2 - Healthy Volunteers - High dose Vaccine - 5 participants Cohort 3 - Participants with Chronic Hepatitis B infection - Low dose - 6 participants Cohort 4 - Participants with Chronic Hepatitis B infection - High dose - 6 participants Cohort 5 - Healthy Volunteers who have completed 2 doses of COVID-19 AZD1222 vaccine Cohort 6 - Healthy Volunteers who have completed 2 doses of either Pfizer or Moderna mRNA COVID 19 vaccine
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Volunteers with low dose vaccination<br>5 Healthy Volunteers receiving low dose vaccination | Biological: ChAdOx1-HBV<br>* chimpanzee adenovirus-vectored hepatitis B virus vaccine<br>|
| Experimental: Healthy Volunteers with high dose vaccination<br>5 Healthy Volunteers receiving high dose vaccination | Biological: ChAdOx1-HBV<br>* chimpanzee adenovirus-vectored hepatitis B virus vaccine<br>|
| Experimental: Chronic Hepatitis B participants with low dose vaccination<br>6 participants with Chronic Hepatitis B infection receiving low dose vaccination | Biological: ChAdOx1-HBV<br>* chimpanzee adenovirus-vectored hepatitis B virus vaccine<br>|
| Experimental: Chronic Hepatitis B participants with high dose vaccination<br>6 participants with Chronic Hepatitis B infection receiving high dose vaccination | Biological: ChAdOx1-HBV<br>* chimpanzee adenovirus-vectored hepatitis B virus vaccine<br>|
| Experimental: Healthy Volunteers who have had COVID-19 AZD1222 vaccine<br>15 participants who have had 2 doses of COVID-19 AZD1222 vaccine | Biological: ChAdOx1-HBV<br>* chimpanzee adenovirus-vectored hepatitis B virus vaccine<br>|
| Experimental: Healthy Volunteers who have had Pfizer/Moderna mRNA COVID 19 vaccine<br>15 participants who have had Pfizer/Moderna mRNA COVID 19 vaccine | Biological: ChAdOx1-HBV<br>* chimpanzee adenovirus-vectored hepatitis B virus vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Adverse events and/or adverse events leading to study discontinuation | From screening up to day 7 for solicited AE's, unsolicited events through study completion (on average 6 months) | 
| Serious adverse events | Serious adverse events related to the study vaccine | from day 0 to up to 6 months | 
| Grade ≥3 local and systemic reactions | Local reactogenicity - pain, induration, warmth, erythema at the vaccination site Systemic: feverishness, chills, myalgia, fatigue, headache, nausea, arthralgia, malaise | from day 0 to day 3 |