| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054181 |
| E.1.2 | Term | Hepatitis B immunization |
| E.1.2 | System Organ Class | 100000004865 |
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| 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 demonstrate the manufacturing equivalence, in terms of immunogenicity, of three independent consecutive lots of the Sci-B-Vac™ 4 weeks after the third vaccination on Study Day 196.
This objective will be met if the following condition is satisfied:
• The upper and lower bound of the two sided 95% confidence interval (CI) of the geometric mean concentration (GMC) of anti-HBs ratios 4 weeks after the third injection, for all three pairwise comparisons (GMC of anti-HBs in group A/GMC of anti-HBs in group B, GMC of anti-HBs in group A/ GMC of anti-HBs in group C, GMC of anti-HBs in group B/ GMC
of anti-HBs in group C), are within [0.67, 1.5]
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| E.2.2 | Secondary objectives of the trial |
Immunogenicity
To demonstrate that the SPR 4 weeks after completion of the three-dose regiment of Sci-B-Vac™ is non-inferior to a three-dose regimen of EngerixB®, i.e. the lower bound of the 95% two-sided confidence interval (CI) of the difference between the SPR in the Sci-B-Vac™ arm minus the SPR in the Engerix-B® arm, achieved 4 weeks after the third vaccination will be > -5.
Safety
To assess the safety and reactogenicity of Sci-B-Vac™ compared to EngerixB®
Please refer to the protocol for the Exploratory objectives |
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| 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 |
| At select sites, study subjects will also participate in a clinical laboratory sub study. All subjects enrolled at these sites will be asked to come for three additional visits (denoted A1, A2, A3 in Appendix 1 Schedule of Events) 1 week after each vaccination, and to provide 4 additional blood samples, at V1 (Day 0) and at A1, A2 and A3, on Study Days 7, 35 and 175, respectively. The clinical laboratory sub study will include at least 10% of the total number of subjects enrolled to the trial and will assess hematology and biochemistry laboratory parameters over the full three dose vaccination schedule. |
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| E.3 | Principal inclusion criteria |
1. Any gender.
2. Age 18-45 years.
3. Healthy, as determined by a physical examination and values of laboratory tests.
4. If female a) either not of childbearing potential, defined as postmenopausal (12 months with no menses without an alternative medical cause) surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy),
OR
b) is of childbearing potential and must agree to use an adequate birth control method during the screening period and until the end of her participation in the study (effective birth control includes: 1) hormonal (implant, oral, vaginal, transdermal) contraceptives;
2) diaphragm with spermicide, condom (with or without spermicide); 3) intra-uterine devices; and 4) vasectomy of male partner; 5) abstinence from penile-vaginal intercourse (if the preferred and usual lifestyle of the subject)).
5. Able and willing to give informed consent.
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| E.4 | Principal exclusion criteria |
1. Previous vaccination with any HBV vaccine (licensed or experimental).
2. Treatment by immunosuppressant within 30 days of enrollment including but not limited to
corticosteroids at a dose that is higher than an oral or injected physiological dose, or > 20 mg /day
prednisolone equivalent (Inhaled and topical steroids are allowed).
3. History of immunological function impairment, including but not limited to:
a) autoimmune diseases (e.g. multiple sclerosis, type 1 diabetes, myasthenia gravis, Crohn disease and other inflammatory bowel diseases, celiac disease, systemic lupus erythematosus, scleroderma, including diffuse systemic form and CREST syndrome, systemic sclerosis, dermatomyositis polymyositis, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis - including Hashimoto thyroiditis, Grave's or Basedow’s disease, immune thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune hepatitis, psoriasis, vitiligo, vasculitis, Guillain-Barré syndrome, Addison’s Disease, Bell’s Palsy and Alopecia Areata);
b) secondary immunodeficiency disorders (e.g. Acquired Immunodeficiency Syndrome caused by Human Immunodeficiency Virus infection (HIV/AIDS), solid organ transplant, splenectomy);
c) primary immunodeficiency disorders (e.g. common variable immune deficiency (CVID), Defective phagocytic cell function and neutropenia syndromes, complement deficiency).
4.Pregnancy or breastfeeding.
5. Immunization with attenuated vaccines (e.g. MMR) within 4 weeks prior to enrollment.
6. Immunization with inactivated vaccines (e.g. influenza) within 2 weeks prior to enrolment.
7. Has received blood products or immunoglobulin within 90 days prior to study entry or likely to require blood products during the study period.
8. Subject in another clinical trial with an investigational drug or a biologic within 30 days of enrollment.
9. Has received granulocyte-macrophage stimulating factor (G/GM-CSF) or erythropoietin (EPO) within 30 days of enrollment or likely to require GM-CSF erythropoietin during the study period.
10. Any history of cancer requiring chemotherapy or radiation within 5 years of randomization or current disease. Subject with an history of low risk basal cell carcinoma will be accepted (low risk being defined by the following:
1) location on the trunk of the body, arms, legs, cheeks, forehead, temples, scalp, neck or chin and
2) less than 2 cm, and
3) nodular or superficial, and
4) primary cancer that has not come back after treatment and
5) edge of the cancerous area is clear and smooth and
6) not located in or around nerves).
11. Any skin abnormality or tattoo that would limit post-vaccination injection site assessment.
12. History of allergic reactions or anaphylactic reaction to any vaccine component.
13. Unwilling, or unable in the opinion of the investigator, to comply with study requirements, including the use of an adequate birth control method.
14. Immediate family members of study center staff (parents, sibling, children).
15. Current or past hepatitis B infection or prior vaccination as evidenced by HBV infection markers (antiHBc, anti-HBs , HBsAg) at screening.
16. Known hepatitis C infection or positive Hepatitis C serology at screening, unless treated and cured (defined as documented sustained virologic response (SVR) or negative viral load ≥ 12 weeks after cessation of antiviral therapy).
17. Known human immunodeficiency virus (HIV) infection or positive HIV serology at screening.
18. Renal impairment with glomerular filtration rate (GFR) of <60 mL/min/1.73m2
19. Body mass index (BMI) ≥ 35.
20. Uncontrolled hypertension (defined as an average SBP ≥ 150 mmHg or an average DBP ≥ 95 mmHg based on the last three measurements in people diagnosed and treated for hypertension), and in people without a diagnosis of hypertension).
21. Diagnosis of Type 1 or Type 2 diabetes or HbA1C ≥ 6.5% at screening
22. Any laboratory test abnormality that would be considered of Grade 1 severity or above as per FDA guidelines for grading clinical laboratory abnormalities (see Appendix 3 in Protocol) AND is considered as clinically significant by the investigator. Grade 3 severity or above is exclusionary, regardless of clinical assessment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Immunogenicity endpoints
Geometric Mean Concentration (GMC) of anti-HBs in serum after 2 vaccinations, just prior to receiving the third vaccination, and 4 weeks and 24 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, on Study Days 168, 196, and 336, respectively. The GMC at Study Day 196 is the basis for assessing lot-to-lot consistency of the three consecutive lots of Sci-B-Vac™.
• Seroprotection rate after 2 vaccinations, just prior to receiving the third vaccination, and 4 weeks and 24 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, on Study Days 168, 196, and 336, respectively. Seroprotection is defined as anti-HBs levels ≥ 10mIU/mL in serum. Seroprotection rate is the percentage (%) of subjects achieving seroprotection.
• Proportion of subjects achieving anti-HBs levels ≥ 100mIU/mL in serum after 2 vaccinations, just prior to receiving the third vaccination, and 4 weeks and 24 weeks after the third vaccination with Sci-BVac™ or Engerix-B® on Study Days 168, 196, and 336, respectively.
• Rate of non-response on Study Day 196, 4 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®. Rate of non-response is defined as the proportion of subjects not attaining anti-HBs levels ≥ 10mIU/mL in serum.
•SPR, GMC and rate of non-response in sub-groups of interest (e.g. BMI> 30), 4 weeks after receiving the third vaccination with Sci-B-Vac™ or Engerix®.
Safety endpoints
•Number (%) of subject-reported, solicited (on the day of vaccination and during the next 6 days), number (%) of unsolicited adverse events (AE) (on the day of vaccination and during the next 27 days), and number (%) of SAEs, medically significant event or new onset of chronic illness (through Day 336). Adverse events will be classified by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term, severity, seriousness, investigator and Sponsor causality assessment, and time since vaccination.
•Number (%) of subjects with abnormal vital signs; physical examination findings, compared to baseline.
•Number (%) of subjects with abnormal clinical laboratory parameters from baseline assessments, one week after each vaccination with either Sci-B-Vac™ or Engerix-B® (clinical laboratory sub-study).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 |
Immunogenicity.
Verification that the manufacturing process of Sci-B-Vac™ is consistent |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Belgium |
| Canada |
| Finland |
| Germany |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 22 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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