| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety of escalating doses of the HBV viral vector vaccines (prime-boost) and/or adjuvanted proteins vaccines in patients with chronic HBV infection who are virally suppressed on NA therapy |
|
| E.2.2 | Secondary objectives of the trial |
To assess in patients with chronic HBV infection who are virally suppressed on NA therapy:
•immunogenicity
•efficacy of the HBV viral vector vaccines (prime-boost) and/or adjuvanted proteins vaccines
and
•the long-term safety
of escalating doses of the HBV viral vector vaccines (prime-boost) and/or adjuvanted proteins vaccines
Proof-of-principle (PoP) for the efficacy objective will be achieved if
1)At least 15% of patients (i.e. lower limit of 80% CI of at least 15%) in 1 vaccine group show at least 10-fold decrease (i.e. 1-log difference) in Quantitative Hepatitis B Surface Antigen (qHBsAg) or show HBsAg loss at Day 337 versus Day 1, or
2)If there is at least 10-fold difference in mean HBsAg concentration between a vaccine group at Day 337 and the respective control group (i.e. the criterion is to observe a point estimate of at least 10-fold decrease between the groups with statistical significance, i.e., 80% CI on the ratio not including 1) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Ancillary study evaluating Chimpanzee adenovirus 155- Human Invariant chain-HBV vaccine (ChAd155-hIi-HBV) shedding in a subset of chronic hepatitis B patients enrolled in the first-time-in-human, Phase I/II, randomised, multi-centric, single-blind study TH HBV VV-001.
Protocol version & date:
Protocol Amendment 3: 24-Nov-2021
Primary Objective:
•To assess the shedding of ChAd155-hIi-HBV following intramuscular administration. |
|
| E.3 | Principal inclusion criteria |
•Patients who, in the opinion of the investigator, can and will comply with the requirements of the protocol
•Written informed consent obtained from the patient prior to performing any study specific procedure
•A male or female between, and including, 18 and 65 years of age at the time of the first vaccination
•Female patients of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as hysterectomy, bilateral ovariectomy or post-menopause
•Female patients of childbearing potential may be enrolled in the study if the patient:
-has practiced adequate contraception for 30 days prior to vaccination, and
-has a negative pregnancy test at Screening, and
-has agreed to continue adequate contraception from Screening until 12 weeks after completion of the vaccination series
•Male patients:
-with documented bilateral vasectomy and resultant azoospermia, bilateral orchiectomy or azoospermia, or
-who agree to practice abstinence from penile-vaginal intercourse (when this is their preferred and usual lifestyle) or use condoms from Screening until 12 weeks after completion of the vaccination series
•Chronic Hepatitis B (CHB) patient, under and adherent to treatment with a nucleo(s)tide analogue with high barrier to resistance given as per approved label/dosage for at least 24 months
•Documented medical history of Hepatitis B Virus.e Antigen (HBeAg)-negative CHB prior to onset of NA therapy (applicable to all patients in Step A and Step B and to some patients in Step C) or documented medical history of HBeAg-negative CHB over a period of at least 24 months prior screening (applicable to some patients in Step C only).
•Documented HBV viral suppression as per local clinical diagnosis within the previous 24 months AND at Screening test HBV DNA < 10 IU/mL. If no results are available, two Screening tests need to be performed at least 2 weeks apart. Small fluctuations of HBV DNA (≤ 10 x LLOQ; LLOQ defined by laboratory that performed testing) are allowed provided HBV DNA is < 10 IU/mL at Screening and was clearly not rising during the previous 24 months
•Documented normal level of ALT as per local clinical diagnosis within the previous 24 months AND at Screening test ALT < 48 U/L. Small fluctuations of ALT (≤ 1.5 X ULN) are allowed provided ALT< 48 U/L at Screening. If no results are available, two Screening tests need to be performed at least 2 weeks apart. ULN are to be defined according to local laboratory reference range
•No clinical diagnosis of cirrhosis (e.g. F4 by METAVIR scoring system or ≥ 6 by Ishak scoring system or FibroScan TE score > 12.5kPa) within the previous 24 months
•FibroScan Transient Elastography (TE) score < 9.6 KPa and FibroTest score < 0.59 at Screening. A patient with one of these parameters out of range, but having the liver biopsy within 12 months before screening that showed F0-2 by METAVIR scoring system or stage 0-4 by Ishak scoring system, can be included.
•HBsAg concentration > 50 IU/mL and anti-HBs negative at Screening
•Anti-HBc positive at Screening
•HBeAg-negative at Screening |
|
| E.4 | Principal exclusion criteria |
•Use of any investigational or non-registered product other than the study vaccines during the period starting 30 days before the first dose of study vaccines or planned use during the study period
•Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe
•Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone ≥ 10 mg/day or equivalent. Inhaled and topical steroids are allowed
•Administration of immunoglobulins and/or any blood products during the period starting 3 months before the first dose of study vaccines or planned administration during the study period
•Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which, in the opinion of the investigator, may have activity against HBV within the previous 6 months prior to randomization into this study. Antiviral treatment/prevention for influenza or herpes simplex virus is allowed
•Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months except for adenovirus/adenovector-based COVID-19 vaccines that could be administered up to 30 days prior to the first study vaccine dose (applicable for all patients except for the patients in France) OR Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months (applicable for the patients in France only).
•Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 14 days before each dose and ending 30 days after each dose of vaccines, with the exception of influenza vaccine that may be given at any time except within a 7-day period before or after each vaccine dose and COVID-19 vaccine that may be given at any time except within a 30-day period before or after each vaccine dose apart from COVID-19 mRNA based-vaccines that may be administered any time except for the period of 14 days before and 30 days after each study vaccine dose. Note: If the type of COVID-19 vaccine is unknown, the allowed interval of 30 days before or after each study vaccine dose should be followed
•Treatment with nephrotoxic drugs or competitors of renal excretion within 2 months prior to Screening or the expectation that patient will receive any of these during the course of the study. TAF/TDF given as NA therapy is allowed
•Concurrently participating in another clinical study, at any time during the study period, in which the patient has been or will be exposed to an investigational or a non-investigational vaccine/product
•Medical history of cirrhosis or hepatic decompensation.
•Planned for liver transplantation or previous liver transplantation
•Personal or family (first degree) history of autoimmune disease
•Family history of congenital or hereditary immunodeficiency
•History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines
•Evidence of Hepatitis C Virus and hepatitis D Virus infection
•Suspicion of or confirmed Hepatocellular Carcinoma or any other liver cancer in medical history or at Screening:
-Suspicious foci at liver imaging exam
-Elevated α-fetoprotein > 50 ng/mL
•Documented evidence of other currently active cause of hepatitis
•Hematology and biochemistry parameters outside normal clinical range at Screening:
Biochemistry:
-Glomerular filtration rate < 60 mL/min
-Bilirubin > 27.5 µmol/L unless *or the diagnosis of Gilbert Syndrome has been established and confirmed by the Investigator
-GGT > 65 U/L (males) or > 45 U/L (females)*
-ALT > 48 U/L
-AST > 42 U/L*
-ALP > 125 U/L*
Hematology:
-Hemoglobin < 12.0 g/dL (females) or < 13.5 g/dL (males)*
-Red blood cell count < 3.9 x 10^6 cells/mm^3 (females) or < 4.4 x 10^6 cells/mm^3 (males)*
-White blood cell count < 3,500 cells/mm^3 or > 12,000 cells/mm^3*
-Platelets < 140,000 cells/mm^3
-INR > 1.32 (i.e. 1.1 x ULN)
*unless it is considered as clinically not significant by the Investigator
•Known diabetes Type I
•Body Mass Index > 35 kg/m^2 at Screening
•Any serious or active medical or psychiatric illnesses other than chronic hepatitis B which, in the opinion of the investigator, would interfere with patient treatment, assessment or compliance with the protocol.
•History of or current drug abuse and/or excess of alcohol consumption as defined per local guidelines
•HIV-positive patient
•Pregnant or lactating female
•Female planning to become pregnant or planning to discontinue contraceptive precautions in the period starting from the Screening Visit up to 12 weeks post-last vaccination visit
•Fever and or acute minor illness may be enrolled for Screening at the discretion of the investigator, provided that the condition is resolved at the time of vaccination |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Number of subjects reporting solicited local adverse events (AEs)
2. Number of subjects reporting solicited general AEs
3. Number of subjects reporting unsolicited AEs
4. Number of subjects with hematological, biochemical or urinalysis laboratory abnormalities
5. Number of subjects reporting serious adverse events (SAEs)
6. Number of subjects reporting potential immune-mediated diseases (pIMDs)
7. Number of subjects reporting liver-disease-related (LDR) AEs
8. Number of subjects reporting any hematological adverse events of specific interest (AESIs)
9. Number of subjects reporting medically-attended adverse events (MAEs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Within 7 days after each vaccination (from day of vaccination to 6 days after vaccination).
2. Within 7 days after each vaccination (from day of vaccination to 6 days after vaccination).
3. Within 30 days after each vaccination (from day of vaccination to 29 days after vaccination).
4. Within 30 days after each vaccination (from day of vaccination to 29 days after vaccination).
5. From Day 1 up to Day 337 (6 months after last dose).
6. From Day 1 up to Day 337 (six months after the last dose).
7. From Day 1 up to Day 337 (six months after the last dose).
8. From Day 1 up to Day 337(six months after last dose).
9. From Day 1 up to Day 337 (six months after the last dose). |
|
| E.5.2 | Secondary end point(s) |
1. Number of seropositive subjects for anti-hepatitis B core antibody (anti-HBc)
2. Evaluation of immunogenicity in terms of Anti-HBc antibody concentration
3. Number of subjects with anti-hepatitis B surface antigen (anti-HBs) seroconversion
4. Evaluation of immunogenicity in terms of anti-HBs antibody concentration
5. Number of subjects with anti-HBs antibody concentration equal to or above 10 mIU/mL
6. Number of subjects with anti-HBs antibody concentration equal to or above 100 mIU/mL
7. Frequency of HBs-specific CD4+ T-cells
8. Frequency of HBs-specific CD8+ T-cells
9. Frequency of HBc-specific CD4+ T-cells
10. Frequency of HBc-specific CD8+ T-cells
11. Frequency of HBs- specific CD4+ T-cells responders
12. Frequency of HBc- specific CD4+ T-cells responders
13. Frequency of HBs- specific CD8+ T-cells responders
14. Frequency of HBc- specific CD8+ T-cells responders
15. Number of subjects with ≥ 0.5 log decrease of qHBsAg since pre-vaccination
16. Number of subjects with ≥ 1 log decrease of qHBsAg since pre-vaccination
17. Number of subjects with qHBsAg loss
18. Changes in qHBsAg since pre-vaccination
19. Number of subjects with HBsAg loss and anti-HBs seroconversion
20. Evaluation of qHBsAg geometric mean concentrations
21. Number of subjects reporting any SAEs and SAEs causally related to an investigational vaccine
22. Number of subjects reporting MAEs
23. Number of subjects reporting pIMDs
24. Number of subjects reporting liver-disease-related AEs
25. Number of subjects reporting spontaneous local or general bleeding with thrombocytopenia
26. Number of subjects reporting anemia
27. Number of subjects reporting AEs and SAEs leading to study withdrawal
28. Number of subjects reporting pregnancy and outcomes of reported pregnancy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoint(s) 1, 2, 3, 4, 5 and 6: At Days 1, 15, 71, 113, 127, 183, 337, 505 and 841
Endpoints 7, 8, 9, 10, 11, 12, 13 and 14: At Days 1, 15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Endpoint(s) 15, 16, 17, 18, 20: At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 253, 281, 309, 337, 421, 505, 673, 841.
Endpoint 19: At Days 1, 337, 505 and 841.
Endpoint(s) 21, 22, 23, 24, 25, 26, 27, 28: Throughout the study period (from Day 1 up to Day 841) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Investigational active comparators/experimental products (IMPs of the study), as per design |
|
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Hong Kong |
| Taiwan |
| Thailand |
| France |
| Poland |
| Spain |
| Germany |
| Belgium |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last testing results released of samples collected at Visit 26. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 9 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 9 |
Print
