An Open-label, Single Arm, Single Center Clinical Study In Healthy Subjects to Qualify an In-house Reference Standard Batch of Sci-B-Vac™
Phase: PHASE4
Conditions: Hepatitis B
Sponsor: VBI Vaccines Inc.

 
Protocol No.:  SciB018 
Version and Date: Version 1.0, March 4, 2015   
 
 
 
 
 
 
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CLINICAL STUDY PROTOCOL 
AN OPEN LABEL, SINGLE ARM, SINGLE CENTER CLINICAL STUDY IN HEALTHY 
SUBJECTS TO QUALIFY AN IN-HOUSE REFERENCE STANDARD BATCH OF SCI-B-VAC™ 
Sponsor: 
SciVac Ltd. 
Gad Feinstein Rd, Rehovot, 76100 Israel 
Tel: +972-8-9480666  Fax: +972-8-9480660 
Investigator: 
Dr. Jacob Atsmon M.D. 
Director, TASMC  Clinical Research Center (CRC) 
Research Facility: 
Tel Aviv Sourasky Medical Center,  
6 Weizmann St., Tel Aviv 64239 Israel 
Tel: +972 3 6974845  Fax: +972 3 6973935 
Protocol Number: 
SciB018 
CRC No. 
TRC 075/10217 
Institutional Review Board 
Tel Aviv Sourasky Medical Center, Tel Aviv 
Bioanalysis and Safety 
Laboratory: 
American Medical Laboratories Ltd. 
Herzliya Medical Center  
7 Ramot Yam  St., Herzliya Pituach, Israel  
Tel: +972-9-9568634  Fax : +972-9-9568128 
Sponsor Contact: 
Dr. Nathalie Machluf, Ph.D. 
Director of Regulatory and Clinical Affairs 
SciVac IL, Ltd. 
Tel: +972-54-3945326  Fax:+972-89480634 
Version and Date: 
Version 1.0, Version 1.0, March 4, 2015  
 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document contains trade secrets and proprietary or commercial information that are 
privileged or confidential and may not be disclosed to any third party without the prior written approval of 
SciVac, unless such disclosure is required by relevant ethics committees, regulatory authorities or under 
applicable law or regulations. In any event, persons to whom the information is disclosed, as permitted 
above, must be informed that the information is privileged or confidential and should be maintained in 
confidence. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential or should otherwise be regarded as confidential given the 
circumstances or nature of disclosure. 

 
Protocol No.:  SciB018 
Version and Date: Version 1.0, March 4, 2015   
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
An Open Label, Single Arm, Single Center Clinical Study in Healthy 
Subjects to Qualify an In-House Reference Standard Batch of Sci-B-Vac™ 
Protocol Number 
SciB018 
CRC Number 
TRC 075/10217 
Investigational 
Product 
Sci-B-Vac™ 
Dosage Form 
A single use vial containing 1 ml suspension. 
Mode of 
Administration: 
10 µg (in 1 ml) injected intramuscularly into the deltoid muscle. Three 
Intramuscular injections: on time-0, Month-1 and Month-6   
Clinical Phase 
IV 
Study Objectives 
Primary objective: 
To validate the new in-house reference standard vaccine for routine quality 
control purposes, in compliance with the European Pharmacopeia and the 
Israeli Ministry of Health. 
Secondary objectives: 
1. To characterize   the immunological response throughout the study. 
2. To monitor the subjects for safety throughout the study period. 
Exploratory objectives: 
1. To collect blood samples for the in vitro validation of anti-HBs, anti-preS1 
and anti-preS2 antibodies assays. 
2. To assess the anti-preS1 and anti-preS2 antibodies responses upon 
vaccination. 
Efficacy 
Endpoints 
Primary endpoint: 
Seroprotection rate (SPR), defined as the proportion of subjects with anti-
HBs antibody titer at least equal to 10mIU/ml, at Month 7 (i.e one month 
after the third immunization with Sci–B-Vac™). Subjects early terminated 
from the study for any reason at any time while having an anti-HBs 
antibody concentrations ≥ 10mIU/ml will be considered among those who 
met endpoint. 
Secondary endpoints: 
1. SPR at one month after the second injection of Sci-B-Vac™ (i.e. Month 
2/visit 4).  
2. SPR at month 6 prior to the third injection of Sci-B-Vac™ (i.e. Month 
6/visit 8). 
3. SPR at one month after the first injection of Sci-B-Vac™ (i.e. Month 
1/visit 3). 
4. The geometric mean concentration (GMC) as determined by anti-
HBsAg antibody titers at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12.  

 
Protocol No.:  SciB018 
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Exploratory endpoints: 
• The anti-preS1 antibody titers measured at Month 0, then at every 
month until Month 7 inclusive and at months 9 and 12. 
• The anti-preS2 antibody titers measured at Month 0, then at every 
month until Month 7 inclusive and at months 9 and 12. 
Study Design and 
Procedures 
 
 
 
 
 
 
 
This is an open label, single arm, single center clinical study in healthy 
subjects, who were never vaccinated against Hepatitis B and who are HBs 
antigen, anti-HBc and anti-HBsAg antibodies seronegative. 
Eligible subjects will be vaccinated 3 times with 10 mcg/ml of Sci-B-Vac™ 
according to the immunization schedule.  
The study will consist of three periods:  
• 
Screening period: Up to 4 weeks prior to first vaccination 
• 
Treatment and follow-up period: 6 months 
• 
Post-vaccination follow-up period: 6 months 
Blood samples will be collected prior to the first vaccination (Month 0), every 
month until month 7 inclusive, at Month 9 and at Month 12. 
Safety parameters will be assessed as outlined below and in Section 6.4. 
Duration of Study 
(Clinical Stage) 
The duration for an individual subject is approximately 13 months. 
Number of 
Subjects 
Up to 84 
Inclusion Criteria 1. 
Healthy males and females between 20 and 40 (inclusive) years of age. 
2. 
Subjects who provide written informed consent to participate in the study. 
3. 
Subjects in general good health in the opinion of the investigator as 
determined by medical history, vital signs and a physical examination. 
4. 
No clinically significant abnormalities in hematology, blood chemistry, or 
urinalysis lab tests at screening.  
5. 
Women of child-bearing potential must practice an acceptable method of 
birth control or practice abstinence during the study period or be 
surgically sterilized, from screening visit throughout the treatment phase 
and for 28 days after the last injection and agree to undergo repeated 
pregnancy tests. 
6. 
Subjects must be able to understand the requirements of the study and 
must be willing to comply with the requirements of the study. 
Exclusion Criteria 1. 
Known history of significant medical disorder, which in the investigator’s 
judgment contraindicates administration of the vaccine or may interfere 
with the subject's compliance or the interpretation of study assessment 
parameters. 
2. 
Any clinically significant abnormality upon physical examination or in 
the clinical laboratory tests at screening visit. 
3. 
Treatment with immune suppressive agents. 
4. 
Chronic administration (defined as more than 14 days) of 

 
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immunosuppressants or other immune-modifying drugs within six months 
prior to the first vaccine dose. 
5. 
History of HBV infection or confirmed exposure to hepatitis B virus.  
6. 
Previous vaccination against Hepatitis B. 
7. 
Positive for HBsAg, anti-HBsAg antibodies, anti-HBc antibodies, anti-
HCV antibodies or anti- HIV antibodies.  
8. 
Drug abusers 
9. 
Known hypersensitivity or allergy to any component of the study vaccine. 
10. BMI < 18.5 or ≥ 30 Kg/m2. 
11. Known concomitant disease or any other medical condition that is 
considered by the investigator likely to interfere with the subject's 
compliance or the interpretation of study assessments. 
12. Any acute illness (e.g. acute infection) within 48 hours prior to the first 
study drug administration that is considered of significance by the 
Principal Investigator. 
13. Female subjects: pregnant, lactating or planning a pregnancy. 
14. Any confirmed or suspected immunosuppressive or immunodeficient 
condition. 
15. Receipt of blood or immunoglobulin transfusion six months prior to the 
first vaccine dose and during the course of the trial.  
16. Unwilling or unable (in the judgment of the investigator) to comply with 
all the requirements of the protocol. 
17. Participate in another clinical trial within 3 months prior to first 
vaccination (calculated from the previous study's last dosing date). 
Safety 
Assessments 
The primary safety endpoint is the frequency, severity, and duration of adverse 
events (AEs), including clinically significant laboratory abnormalities after 
administration of Sci-B-Vac™. 
Safety will be evaluated on the basis of the following assessments: 
• 
AEs: continuous (starting from informed consent signature until end of 
study) 
• 
Recording of concomitant medications: continuous (starting from 
informed consent signature until end of study) 
• 
Physical examination: on screening and on study termination visit. 
• 
12-lead ECG: on screening and on study termination visit.  
• 
Vital signs (sitting BP, HR, RR, oral temperature): on screening, on each 
treatment (vaccination) visit within 60 minutes before vaccine 
administration, at 60 (± 15) minutes after vaccination and on study 
termination visit. 
• 
Safety laboratory evaluations (blood and urine): On screening, before each 
vaccine administration and on study termination visit. Safety laboratory 
variables are outlined in Appendix B. 
Statistical 
A total of 84 subjects, are expected to be recruited into study. The trial will 
follow-up eligible subject for a total duration of 12 months. Two interim 

 
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Methodology 
analyses are planned to be conducted at the time when approximately 65% 
subjects and 82.5% of the subjects will reach Month 7 or early terminated the 
study. 
Interim and Final Analyses 
Two interim analyses are planned for possible early termination of the study. 
These analyses will be performed at the time when approximately 65% 
subjects and 82.5% of the subjects will reach Month 7 or early terminated the 
study. The first interim analysis will use an alpha level of 0.0109 and the 
second interim analysis will use an alpha level of 0.0239. The final analysis 
will use an alpha level of 0.0414 representing the use of the Lan-DeMets 
correction to type-I error due to multiple testing. 
Significance Level  
The overall significance level for this study will be 5% using two-tailed tests. 
Sample Size Rationale:  
Sample size determination was performed under the following assumptions: 
• 
The primary endpoint for the study is the Seroprotection Rate (SPR), 
defined as the proportion of subjects with anti-HBs antibody titer at least 
equal to 10mIU/ml, at Month 7 (i.e. one month after the third 
immunization with Sci–B-Vac™). Subjects early terminated from the 
study for any reason at any time while having an anti-HBs antibody 
concentrations ≥ 10mIU/ml will be considered among those who met 
endpoint. 
• 
It is expected that the true rate of SPR following treatment with  
Sci–B-Vac™ is 95% or more. 
• 
The principal analysis of the primary endpoint will be a non-inferiority 
analysis testing the below hypothesis: 
✓ H0: P-p0 <= -Margin  
✓ H1: P-p0 >   -Margin  
• 
Where p0, the assumed true SPR is 95% and the non-inferiority margin is 
12.5%, employing that study will be considered successful if the lower 
bound of the 95.86% exact CI (using the alpha level at final analysis) will 
be 82.5% or more (lower non-inferiority limit). 
• 
Under these assumptions, sample of 70 subjects will provide a power of 
86.1% or more to demonstrate that the observed SPR is non-inferior to the 
rate of 95%. Sample size is adjusted to a total of 84 subjects to account for 
an anticipated withdrawal rate of approximately 20%.  
Primary Endpoint Definition: 
The primary endpoint of the study is the Seroprotection rate (SPR), defined as 
the proportion of subjects with anti-HBs antibody titer at least equal to 
10mIU/ml, at Month 7 (i.e one month after the third immunization with  
Sci–B-Vac™). Subjects early terminated from the study for any reason at any 
time while having an anti-HBs antibody concentrations ≥ 10mIU/ml will be 
considered among those who met endpoint. 
 

 
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Principal Analysis of the Primary Endpoint: 
The principal analysis of the primary endpoint will employ a non-inferiority 
analysis [SAS PROC FREQ with binomial (noninf margin=.125 p=(1-α) 
exact)] statement will be used for testing the below hypothesis: 
H0: P-p0 <= -Margin  
H1: P-p0 >   -Margin  
Where p0, the assumed true SPR is 95% and the non-inferiority margin is 
12.5%, employing that study will be considered successful if the lower bound 
of the (1-α) exact CI will be 82.5% or more.   
 

 
Protocol No.:  SciB018 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE 
2 
PROTOCOL SYNOPSIS 
3 
TABLE OF CONTENTS 
8 
ABBREVIATIONS AND DEFINITION OF TERMS 
11 
1 
INTRODUCTION 
13 
1.1 
BACKGROUND – HEPATITIS B VIRUS INFECTION ............................................. 13 
1.2 
SCI-B-VAC™ PRODUCT DESCRIPTION ............................................................ 13 
1.3 
SUMMARY OF CLINICAL STUDIES .................................................................... 14 
1.4 
STUDY RATIONALE .......................................................................................... 15 
2 
STUDY OBJECTIVES 
15 
2.1 
PRIMARY OBJECTIVE ....................................................................................... 15 
2.2 
SECONDARY OBJECTIVES ................................................................................ 15 
2.3 
EXPLORATORY OBJECTIVES ............................................................................. 15 
3 
STUDY ENDPOINTS 
15 
3.1 
PRIMARY ENDPOINT ........................................................................................ 15 
3.2 
SECONDARY ENDPOINTS .................................................................................. 15 
3.3 
EXPLORATORY OBJECTIVES ............................................................................. 16 
4 
STUDY DESIGN 
16 
4.1 
OVERALL STUDY DESIGN ................................................................................ 16 
5 
SELECTION OF STUDY POPULATION 
17 
5.1 
NUMBER OF SUBJECTS ..................................................................................... 17 
5.2 
INCLUSION CRITERIA ....................................................................................... 17 
5.3 
EXCLUSION CRITERIA ...................................................................................... 17 
5.4 
SUBJECT IDENTIFICATION ................................................................................ 18 
5.5 
SCREENING FAILURES ...................................................................................... 18 
5.6 
REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF SUBJECTS FROM 
TREATMENT OR ASSESSMENT ....................................................................... 18 
5.7 
HANDLING OF WITHDRAWALS ......................................................................... 18 
5.8 
TERMINATION OF STUDY BY SPONSOR ............................................................ 19 
5.9 
TERMINATION OF STUDY ................................................................................. 19 
6 
STUDY PROCEDURES AND SCHEDULES 
19 
6.1 
VISIT SCHEDULES ............................................................................................ 19 
6.2 
UNSCHEDULED VISIT ....................................................................................... 21 
6.3 
BLOOD SAMPLING FOR IMMUNOGENICITY ....................................................... 21 
6.4 
SAFETY ASSESSMENTS .................................................................................... 22 

 
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7 
INVESTIGATIONAL PRODUCTS 
23 
7.1 
DESCRIPTION OF INVESTIGATIONAL PRODUCT................................................. 23 
7.2 
PACKAGING AND LABELLING OF INVESTIGATIONAL PRODUCT ........................ 23 
7.3 
STUDY DRUG ADMINISTRATION ...................................................................... 24 
7.4 
SHIPMENT OF INVESTIGATIONAL PRODUCT ..................................................... 24 
7.5 
RECEIPT AND STORAGE OF INVESTIGATIONAL PRODUCT ................................. 24 
7.6 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCT ......................................... 25 
8 
STUDY RESTRICTIONS 
25 
8.1 
CONCOMITANT MEDICATIONS ......................................................................... 25 
8.2 
ADDITIONAL RESTRICTIONS ............................................................................ 25 
9 
SAFETY AND PHARMACOVIGILANCE 
25 
9.1 
ADVERSE EVENT DEFINITION .......................................................................... 25 
9.2 
SERIOUS ADVERSE EVENTS (SAES) ................................................................ 28 
9.3 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT .......................................... 29 
9.4 
NOTIFICATION OF SERIOUS OR UNEXPECTED ADVERSE EVENT ....................... 29 
9.5 
ANTICIPATED ADVERSE EVENTS ..................................................................... 31 
10 
STATISTICAL METHODOLOGY 
31 
10.1 
INTERIM AND FINAL ANALYSES ....................................................................... 31 
10.2 
SIGNIFICANCE LEVEL....................................................................................... 31 
10.3 
SAMPLE SIZE RATIONALE ................................................................................ 31 
10.4 
ANALYSES SETS............................................................................................... 32 
10.5 
SUBJECT DISPOSITION ...................................................................................... 32 
10.6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................ 32 
10.7 
EFFICACY ENDPOINTS AND ANALYSES ............................................................ 32 
10.8 
DESCRIPTIVE STATISTICS ................................................................................. 33 
10.9 
SAFETY ASSESSMENTS .................................................................................... 34 
10.10 REPORTING DEVIATIONS FROM THE STATISTICAL PLAN .................................. 35 
10.11 STATISTICAL SOFTWARE ................................................................................. 35 
11 
ETHICS 
35 
11.1 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE ......... 35 
11.2 
ETHICAL CONDUCT OF THE STUDY .................................................................. 35 
11.3 
SUBJECT INFORMATION AND CONSENT ............................................................ 35 
11.4 
SUBJECT INSURANCE ....................................................................................... 36 
11.5 
PERSONAL DATA PROTECTION ........................................................................ 36 
11.6 
INFORMING THE GENERAL PRACTITIONER ....................................................... 36 
11.7 
PROTOCOL EXCEPTIONS AND DEVIATIONS ...................................................... 36 
11.8 
PROTOCOL AMENDMENTS ............................................................................... 36 
12 
QUALITY CONTROL AND QUALITY ASSURANCE 
37 
12.1 
AUDITS AND INSPECTIONS ............................................................................... 37 
12.2 
STUDY MONITORING ....................................................................................... 37 
12.3 
QUALITY LABORATORY STANDARDS .............................................................. 38 
12.4 
STUDY DOCUMENTATION ................................................................................ 38 

 
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12.5 
CLINICAL TRIAL SUPPLIES ............................................................................... 39 
12.6 
DATA MANAGEMENT....................................................................................... 40 
13 
STUDY ADMINISTRATION 
40 
13.1 
REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION ..................................... 40 
13.2 
STUDY COMPLETION ........................................................................................ 41 
13.3 
CLINICAL STUDY REPORT ................................................................................ 41 
13.4 
RETENTION OF STUDY RECORDS ..................................................................... 41 
13.5 
CONFIDENTIALITY AND PUBLICATION OF STUDY DATA .................................. 41 
14 
REFERENCES 
43 
APPENDIX A  STUDY FLOW CHART 
45 
APPENDIX B  LABORATORY SAFETY TEST PARAMETERS 
48 
APPENDIX C  TOXICITY GRADING SCALE TABLES 
51 
APPENDIX D  SCI-B-VAC™ PRODUCT LEAFLET 
55 
 

 
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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation/Term 
Definition 
AE 
Adverse Events 
ANA 
Antinuclear antibodies 
ALT 
Alanine transaminase 
Anti-HBc        
Antibodies to hepatitis B core antigen 
Anti-HBs        
Antibodies to HBsAg 
Anti-HCV       
Antibodies to hepatitis C virus 
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
cm 
Centimeter 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GMR 
Geometric mean ratio 
GSK 
Glaxo Smith Kline 
h 
Hours 
HBsAg  
Hepatitis B Surface Antigen 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRB 
Institutional Review Board 
Kg 
Kilogram 
m 
Meter 
mg 
Milligram 

 
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Abbreviation/Term 
Definition 
min 
Minute 
mITT 
Modified intention-to-treat analysis 
ml 
Milliliter 
MOH 
Ministry of Health 
MSD 
Merck Sharp and Dome 
N/A 
Not Applicable 
ºC 
Degrees centigrade 
OTC 
Over the Counter 
OTC 
Over the counter 
PI 
Principal Investigator 
PQC 
Product Quality Complaint 
PT 
Prothrombin Time 
PT/INR 
Prothrombin time/International Normalized Ratio (for blood clotting time) 
QA 
Quality Assurance 
R&D  
Research and Development 
RBC 
Red blood cells 
RBC 
Red blood cell 
RDW 
RBC distribution width 
RR 
Respiration rate 
SAE 
Serious Adverse Event 
SOP 
Standard Operation Procedures 
SPR 
Seroprotection rate  
SUSAR 
Suspected unexpected serious adverse reaction 
TASMC 
Tel Aviv Sourasky Medical Center 
TEAE 
Treatment emergent adverse events 
WBC 
White blood cell 
WHO 
World Health Organization 
μg 
Microgram 

 
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1 
INTRODUCTION 
1.1 
BACKGROUND – HEPATITIS B VIRUS INFECTION  
Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. It can 
cause chronic liver disease and chronic infection and puts people at high risk of death from cirrhosis 
of the liver and liver cancer. More than 240 million people have chronic (long-term) liver 
infections. More than 780 000 people die every year due to the acute or chronic consequences of 
hepatitis B.   
In highly endemic areas, HBV is most commonly spread from mother to child at birth, or from 
person to person in early childhood. Perinatal or early childhood transmission may also account for 
more than one third of chronic infections in areas of low endemicity, although in those settings, 
sexual transmission and the use of contaminated needles are the major routes of infection.  
High risk groups include: people who frequently require blood or blood products, dialysis patients, 
recipients of solid organ transplantations, people interned in prisons, injecting drug users, household 
and sexual contacts of people with chronic HBV infection, people with multiple sexual partners, as 
well as health-care workers and others who may be exposed to blood and blood products through 
their work and travelers who have not completed their hepatitis B vaccination series.  
The hepatitis B virus can survive outside the body for at least 7 days. During this time, the virus can 
still cause infection if it enters the body of a person who is not protected by the vaccine. 
Most people do not experience any symptoms during the acute infection phase. However, some 
people have acute illness with symptoms that last several weeks, including yellowing of the skin 
and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain. In some 
people, the hepatitis B virus can also cause a chronic liver infection that can later develop into 
cirrhosis of the liver or liver cancer*. 
Five to ten percent of infected adults are unable to eliminate the virus following acute infection, and 
develop persistent viral infection which lasts more than 6 months; this is designated as a hepatitis B 
surface antigen (HBsAg) carrier state. It has been estimated that there are >200 million HBsAg 
carriers worldwide 1. 
The first generation, plasma-derived hepatitis B vaccines were developed in the US and France in 
the late 1970s. In the mid 1980s, second generation recombinant DNA hepatitis B vaccines were 
constructed in yeasts transfected with HBV-DNA sequences coding for the small HBV envelope 
protein. These vaccines have gradually replaced the first generation plasma derived vaccines and 
are currently used for universal vaccination of newborns and adults at risk in >170 countries 
worldwide. Third generation HBV vaccines containing one or two additional HBV envelope 
proteins (Pre-S1 and Pre-S2) have been developed in Germany, France and Israel in transfected 
mammalian cells (Chinese Hamster Ovarian cells). These vaccines have in general an enhanced 
efficacy as compared to yeast derived vaccines 2,3,4 
1.2 
SCI-B-VAC™ PRODUCT DESCRIPTION  
Sci-B-Vac™ is a recombinant hepatitis B vaccine, manufactured by SciVac Israel Ltd. It is 
produced in mammalian Chinese hamster ovary (CHO) cells, transfected with appropriate 
sequences that code for the HBV envelope proteins SHBs-S, MHBs-pre-S2, and LHBs-pre-S1. The 
gene coding for these antigens, including the native HBs promoter, enhancer, and poly a signal, was  
*World health organization, Hepatitis B, Fact sheet N°204 Updated July 2014 

 
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cloned into a plasmid vector containing the mouse dihydrofolate reductase (DHFR) expression 
cassette. The plasmid was used to establish the producer CHO cell line. Transfected cells were 
selected for DHFR+ phenotype, and gene co-amplification was done with methotrexate. The 
immunogenicity of the pre-S2 and pre-S1 antigens in the final vaccine preparation was 
demonstrated in BALB/c mice and rabbits, as well as in babies who developed appropriate anti-pre-
S1 and anti-pre-S2 antibodies following immunization with Sci-B-VacTM 5,6,7. The physical 
properties of the HBV envelope particles produced in CHO cells and the immune response to HBV 
nucleocapsid and Pre-S/S envelope proteins have been characterized5,8-13.  
Sci-B-VacTM is approved by Health Authorities for marketing in 13 countries including Israel, 
Central Africa, Ivory Coast, Georgia, Gabon, Guinea Equtorial, Hong Kong, Moldova, Niger, 
Nigeria, Philippines, Senegal and Vietnam. 
Since 2005, more than 1.5 million units of Sci-B-VacTM have been sold in Israel for vaccination 
against Hepatitis B in babies, children and adults. 
1.3 
SUMMARY OF CLINICAL STUDIES 
To date, thirteen open label clinical studies (plus three extensions ) and 4 single blinded clinical studies 
utilizing Sci-B-VacTM  (also distributed under the trade names Bio-Hep B and Hepimmune) have been 
completed16-28.  
The clinical development of Sci-B-VacTM  included: two phase I studies in adults 16,17, three phase II 
dose-range studies in adults 16-18 one in children 19 and four in neonates  20-23, two phase II and one 
phase III comparative studies in adults 24-26, one Phase II study in children27 and one Phase II study in 
neonates28.  Three of the studies (one in adults and two in children) were extended in order to increase 
the size of the group vaccinated with Sci-B-VacTM.  In the adult phase I studies, subjects received 10 
g of Sci-B-VacTM.  Sci-B-VacTM  was given once to prime the immune memory; the first dose was 
followed by two booster doses at 1 and 6 months after primary immunization16. This immunization 
schedule is set by convention. In the first adult Phase II study in Singapore16, subjects were randomized 
to receive 5 g or 10 g of Sci-B-VacTM  in three injections.  Once tolerability/safety and dose-
dependent efficacy were demonstrated, the clinical development of two more adult dose-range studies 
were performed in Thailand and Israel 17,18,followed by a dose-range study performed in Poland with 
children19 and four neonate studies in Poland, Singapore and Vietnam20-23. After seroconversion rates 
and the efficacy/dose relationship were more firmly established, five comparative studies which 
assessed the efficacy of Sci-B-VacTM relative to that of conventional yeast derived vaccines were 
performed in adults, children and neonates24-28. 
From the early phase II studies it became evident that a significant number of vaccinees develop 
high anti-HBs titers following vaccination. In study HBN014-0123, conducted in Vietnam, a dose-
response relationship could be demonstrated. More vaccinees who received the 5 µg dose/injection 
had anti-HBs titers ranging from 1001-10,000 mIU/ml as compared to those who received the 2.5 
µg dose/injection. More than 60% of the vaccinees in the 5 µg dose group developed these high 
titers within three months after the third vaccination. At the end of the study 95.6% (196/205) of the 
subjects were seroprotected. 
The high efficacy of Sci-B-VacTM  was further confirmed in adults25,26 and in  neonates28. In these 
comparative controlled studies conducted in Israel, more than 50% of adult vaccinees who received 
the 10 µg/dose and neonates who received the 2.5 µg dose had anti-HBs titers above 10,000 
mIU/ml after the third vaccination. These percentages were greater than those observed in vaccinees 
who received the yeast-derived vaccines. Furthermore, no non-responders were observed in 

 
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immunized neonates who received 2.5 µg Sci-B-Vac™. In adults, the number of non-responders 
who received Sci-B-VacTM was very small (3.5%, 18/513) as compared to vaccinees immunized 
with Engerix-B® (13.7%, 43/415). 
1.4 
STUDY RATIONALE 
Each Sci-B-VacTM lot released to the market is tested in comparison to a reference batch, which has 
to be tested in a human clinical trial.. Therefore, SciVac Ltd. is conducting this study to evaluate the 
efficacy of a Sci-B-Vac™ batch in support of its qualification as new reference standard. In 
accordance with the European Pharmacopeia (Ph.Eur. 1056), this reference standard is to elicited at 
least 95% seroprotection in young, healthy subjects 
2 
STUDY OBJECTIVES  
2.1 
PRIMARY OBJECTIVE 
To validate the new in-house reference standard vaccine for routine quality control purposes, in 
compliance with the European Pharmacopeia and the Israeli Ministry of Health 
2.2 
SECONDARY OBJECTIVES 
1. To characterize the immunological response throughout the study. 
2. To monitor the subjects for safety throughout the study period 
2.3 
EXPLORATORY OBJECTIVES  
1. To collect blood samples for the in vitro validation of anti-HBs, anti-preS1 and anti-preS2 
antibodies assays. 
2. To assess the anti-preS1 and anti-preS2 antibodies responses upon vaccination.  
3 
STUDY ENDPOINTS 
3.1 
PRIMARY ENDPOINT 
Seroprotection rate (SPR), defined as the proportion of subjects with anti-HBs antibody titer at least 
equal to 10mIU/ml, at Month 7 (i.e. one month after the third immunization with Sci-B-Vac™). 
Subjects early terminated from the study for any reason at any time while having an anti-HBs 
antibody concentrations ≥ 10mIU/ml will be considered among those who met endpoint. 
3.2 
SECONDARY ENDPOINTS 
1. SPR at one month after the second injection of Sci-B-Vac™ (i.e. Month 2/visit 4).  
2. SPR at month 6 prior to the third injection of Sci-B-Vac™ (i.e. Month 6/visit 8). 
3. SPR at one month after the first injection of Sci-B-Vac™ (i.e. Month 1/visit 3). 
4. The geometric mean concentration (GMC) as determined by anti-HBsAg antibody titers at 
Month 0, then at every month until Month 7 inclusive and at months 9 and 12. 

 
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3.3 
EXPLORATORY OBJECTIVES  
1. The anti-preS1 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12. 
2. The anti-preS2 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12.  
 
4 
STUDY DESIGN 
4.1 
OVERALL STUDY DESIGN 
This will be a post-marketing, open-label, single arm study in healthy volunteers who had never 
been vaccinated with any hepatitis B vaccine and who are HBs antigen, anti-HBc and anti-HBsAg 
antibodies seronegative. 
The study assessments will be performed as described in the study flow chart (See Appendix A). 
This study will consist of three periods:  
Screening Period (Visit 1: up to 1 month prior to first vaccination) 
After signing of the informed consent form (ICF), screening procedures will be carried out as 
specified in Section 6.1.1 and Appendix A.  
Treatment and Follow-up Period (Visits 2-8: Months 0-6) 
Subject identification number will be assigned to all eligible subjects following assessment of 
inclusion and exclusion criteria. 
All eligible subjects will receive Sci-B-VacTM vaccine.  The treatment phase will include three I.M. 
doses of Sci-B-VacTM administered in the deltoid muscle on Month 0, Month 1, and Month 6. 
Subjects will be followed up for safety evaluations and for efficacy (by anti-HBs, anti-pre-S1 and 
anti-pre-S2 testing), every month. The previous injection site will be inspected before the second 
and third administration. 
The following assessments will be performed during each treatment visit: recording of AEs and 
concomitant medications, vital signs and blood tests for quantitative anti-HBs, anti-preS1 and anti-
preS2 antibodies and safety assessment (including blood and urine laboratory tests). Female 
subjects will also undergo a urine pregnancy before each injection . Vital signs are not required on 
follow-up visits when vaccine is not administered.  
 
Post-Vaccination Follow-up Period (Visits 9-11: Months 7, 9 and 12) 
Additional subject follow- up visits will take place 1, 3 and 6 months after the last vaccine 
administration. On each visit, subjects will be inquired about AEs and concomitant medications, 
and blood samples for quantitative anti-HBs, anti-preS1 and anti-preS2 antibodies levels will be 
drawn. The last visit (Month 12) is a study termination visit in which all subjects will also undergo 
physical examination, laboratory safety assessments (CBC, blood chemistry and urinalysis), vital 
signs measurement and a 12-lead ECG. In addition, female subjects will undergo a urine pregnancy 
test. 
 

 
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5 
SELECTION OF STUDY POPULATION 
5.1 
NUMBER OF SUBJECTS 
Up to eighty four (84) healthy subjects will be enrolled in the study 
5.2 
INCLUSION CRITERIA 
1. 
Healthy males and females between 20 and 40 (inclusive) years of age. 
2. 
Subjects who provide written informed consent to participate in the study. 
3. 
Subjects in general good health in the opinion of the investigator as determined by medical 
history, vital signs and a physical examination. 
4. 
No clinically significant abnormalities in hematology, blood chemistry, or urinalysis lab 
tests at screening.  
5. 
Women of child-bearing potential must practice an acceptable method of birth control  (as 
specified in Section 8.2) or practice abstinence during the study period or be surgically 
sterilized, from screening visit throughout the treatment phase and for 28 days after the last 
injection and agree to undergo repeated pregnancy tests. 
6. 
Subjects must be able to understand the requirements of the study and must be willing 
to comply with the requirements of the study. 
5.3 
EXCLUSION CRITERIA 
1. 
Known history of significant medical disorder, which in the investigator’s judgment 
contraindicates administration of the vaccine or may interfere with the subject's 
compliance or the interpretation of study assessment parameters. 
2. 
Any clinically significant abnormality upon physical examination or in the clinical 
laboratory tests at screening visit. 
3. 
Treatment with immune suppressive agents. 
4. 
Chronic administration (defined as more than 14 days) of immunosuppressants or other 
immune-modifying drugs within six months prior to the first vaccine dose. 
5. 
History of HBV infection or confirmed exposure to hepatitis B virus.  
6. 
Previous vaccination against Hepatitis B. 
7. 
Positive for HBsAg, anti-HBsAg antibodies, anti-HBc antibodies, anti-HCV antibodies or 
anti- HIV antibodies.  
8. 
Drug abusers 
9. 
Known hypersensitivity or allergy to any component of the study vaccine. 
10. BMI < 18.5 or ≥ 30 Kg/m2. 
11. Known concomitant disease or any other medical condition that is considered by the 
investigator likely to interfere with the subject's compliance or the interpretation of study 
assessments. 
12. Any acute illness (e.g. acute infection) within 48 hours prior to the first study drug 
administration that is considered of significance by the Principal Investigator. 
13. Female subjects: pregnant, lactating or planning a pregnancy. 

 
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14. Any confirmed or suspected immunosuppressive or immunodeficient condition. 
15. Receipt of blood or immunoglobulin transfusion six months prior to the first vaccine dose 
and during the course of the trial.  
16. Unwilling or unable (in the judgment of the investigator) to comply with all the 
requirements of the protocol. 
17. Participate in another clinical trial within 3 months prior to first vaccination (calculated 
from the previous study's last dosing date). 
5.4 
SUBJECT IDENTIFICATION 
Each subject who signed the informed consent will be identified by a unique CRC internal 
identification number. Subjects who are dosed will receive an additional subject study ID number.   
5.5 
SCREENING FAILURES 
Subjects who fail to meet the entrance criteria at any stage during the screening period are defined 
as screen failures. All screen failures will be documented on the screening log, which documents 
the screening number, subject’s initials and reason(s) for screen failure. The screening log will be 
kept in the Investigators Site File.  
Screen failure subjects will be withdrawn from the study and will not count towards the total 
enrolled or total eligible subjects. 
5.6 
REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF SUBJECTS FROM TREATMENT 
OR ASSESSMENT 
Subjects are free to discontinue their participation in the study at any time and without prejudice to 
further treatment. The Investigator must withdraw any subject from the study if that subject requests 
to be withdrawn, or if it is determined that continuing in the study would result in a significant 
safety risk to the subject.   
Subjects discontinued or withdrawn from the study will not be replaced after first dosing. 
The subject's participation in this study may be discontinued due to the following reasons: 
• Request of regulatory agency, or Sponsor or Principal Investigator 
• Subject withdrew consent 
• Adverse event (AE) 
• Subject is unwilling or unable to continue the study or is lost-to-follow-up 
• Subject is non-compliant with study procedures/study protocol 
• Investigator decides that withdrawal from the study is in the best interest of the subject 
• Subject needs medication not allowed in the protocol 
• Any clinically significant change in subject’s medical condition. 
5.7 
HANDLING OF WITHDRAWALS 
If a subject is withdrawn from the study or fails to return either at his/her request or at the 
Investigator’s discretion, every effort should be made to determine the reason. This information will 

 
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be recorded on the subject’s case report form (CRF). All subjects who withdraw from the study 
prematurely, regardless of cause, should undergo all study termination assessments (see Section 
6.1.11).  It is vital to obtain follow-up data for any subject withdrawn because of an AE or abnormal 
laboratory test finding.  In any case, every effort must be made to undertake safety follow-up 
procedures. 
If withdrawal is caused by a Suspected Unexpected Serious Adverse Reaction (SUSAR), it will be 
reported to the institutional review board/independent ethics committee (IRB/IEC) and Sponsor. 
5.8 
TERMINATION OF STUDY BY SPONSOR 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such reasons 
may be any of, but not limited to, the following:  
▪ Occurrence of AEs unknown to date in respect of their nature, severity, and duration or the 
unexpected incidence of known AEs  
▪ Medical or ethical reasons affecting the continued performance of the study 
Regulatory Authorities also have the right to terminate the study for any reason. 
5.9 
TERMINATION OF STUDY  
A subject will be considered to have completed the study if he or she has completed all assessments 
at Month 12 of the study. 
 
6 
STUDY PROCEDURES AND SCHEDULES  
The schedule of activities for this study is shown in Appendix A. No protocol-related procedures 
should be performed before subjects provide written informed consent. Study related events and 
activities including specific instructions, procedures, concomitant medications, dispensing of study 
drugs, and descriptions of AEs should be recorded in the appropriate source documents and CRF.  
6.1 
VISIT SCHEDULES  
6.1.1 
Visit 1 - Screening (within 4 weeks before Visit 2)  
Subjects will sign an informed consent form and will be assessed for their eligibility to participate 
in the study.  
The following screening assessments will be performed at pre-study for each subject: 
• Medical history (including concomitant medications)   
• Demographics (gender, date of birth) 
• Vital signs: blood pressure  and heart rate - supine, respiration rate (RR), oral body 
temperature 
• Height 
• Weight 
• BMI (calculated as kg/m2) 
• Physical examination 

 
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• 12-lead ECG 
• Laboratory safety screens as outlined in Appendix B  
• For female subjects serum HCG 
• Serology tests as outlined in Appendix A 
• Compliance with inclusion/exclusion criteria 
The amount of blood drawn in this visit is approximately 31 ml. 
6.1.2 
Visit 2 - First Vaccine Administration:  Month-0 (Day 1)  
Dosing day will be designated "Month 0, Day 1". 
The subjects will be admitted to the CRC in the morning of treatment. They will be interviewed by 
the CRC study personnel regarding change in concomitant medications or changes to their health 
status since the Screening visit. Female subjects will undergo a urine pregnancy test, and eligibility 
of inclusion/exclusion criteria will be reviewed.  
Prior to dosing (within 60 min before vaccination), the following activities will be completed:  
• Vital signs, measured following 3 min rest (sitting BP, HR, RR and oral temperature); 
• A blood sample for serology and safety laboratory testing (18 ml) will be drawn. 
• Urine sample will be collected for safety testing. 
Vaccine administration: Each subject will receive the injection as described in Section 7.3. The 
time and date of vaccination will be documented in the CRFs and on the CRC Drug Administration 
Records.  
After vaccination: Subjects remain in the CRC for approximately 1 hour after injection. Vital signs 
(sitting BP, HR, respiratory rate, and oral body temperature) will be measured at 60 (± 15) minutes 
after treatment, and recorded as appropriate.  
Before discharge from the CRC a study physician will examine the injection site using a grading 
score (Appendix C). 
The subjects will then be released from the CRC following a study physician's approval. 
6.1.3 
Visit 3 - Second Vaccine Administration:  Month 1, (Week 4± 3 days) 
The second vaccination will take place 28 (±3) days after the first vaccination (Visit 2). The 
previous injection site will be inspected before the second administration. Procedures will be 
identical to Visit 2. 
6.1.4 
Visit 4 – Follow-up: Month 2 (Week 8± 3 days) 
Subjects will arrive in the CRC and will be will be interviewed by the CRC study personnel 
regarding change in concomitant medications or changes to their health status since the last visit. A 
10 ml blood sample for serology will be drawn and the subject will be released from the CRC. 
6.1.5 
Visit 5 – Follow-up: Month 3 (Week 12± 3 days) 
Procedures will be identical to Visit 4. 

 
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6.1.6 
Visit 6 – Follow-up: Month 4 (Week 16± 3 days) 
Procedures will be identical to Visit 4. 
6.1.7 
Visit 7 – Follow-up: Month 5 (Week 20± 3 days) 
Procedures will be identical to Visit 4. 
6.1.8 
Visit 8 - Third Vaccine Administration:  Month 6, (Week 24± 3 days) 
The third (last) vaccination will take place 5 months after the second vaccination (Visit 3). The 
previous injection site will be inspected before the second administration. Procedures will be 
identical to Visit 2. 
6.1.9 
Visit 9 – Follow-up: Month 7 (Week 28± 3 days) 
Procedures will be identical to Visit 4. 
6.1.10 Visit 10 – Follow-up: Month 9 (Week 36± 8 days) 
Procedures will be identical to Visit 4. 
6.1.11 Visit 11 – Study Termination: Month 12 (Week 48± 8 days) 
The following assessments will be performed: 
• Physical examination 
• Vital signs: (sitting BP, HR, RR, oral temperature)  
• 12-lead ECG 
• Laboratory safety tests (See Appendix B) 
• Serology tests  
• AE and concomitant medication recording 
The amount of blood drawn in this visit is approximately 23 ml. 
The total amount of blood drawn for serology and routine safety laboratory tests will be about 168 
ml over a period of 13 months.  
6.2 
UNSCHEDULED VISIT 
An unscheduled visit may be performed at any time during the study at the subject's request or as 
deemed necessary by the Investigator due to medical considerations. The date and reason for the 
unscheduled visit will be recorded. AE monitoring and concomitant medication recording will be 
performed by the Investigator. Other procedures and evaluations will be completed as deemed 
necessary by the Investigator and may include (but not limited to) safety laboratory tests, ECG, vital 
signs and physical examination. 
6.3 
BLOOD SAMPLING FOR IMMUNOGENICITY  
6.3.1 
Serology Tests 
The immunogenicity of the vaccine will be assessed by the anti-HBsAg, anti-preS1 and anti-preS2 
antibody levels at each visit, from visit 2 till visit 11, as presented in Appendix A. 

 
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6.3.2 
Blood Sampling and Processing. 
Approximately 10 ml of blood will be collected in SST Gel tubes.  
Processing and storage of the samples are detailed in the lab manual provided by the Sponsor. 
6.3.3 
Shipment of Samples to the Bioanalytical Laboratory 
Samples will be shipped in a cold pack to the central laboratory on the same day it is drawn from 
the subject, as detailed in the lab manual provided by the Sponsor.  
6.4 
SAFETY ASSESSMENTS 
Safety assessments will be based on AEs reported by the subject or observed by the Investigator, 
concomitant medication use, clinically significant changes from baseline of vital signs, ECG, 
physical examination, and safety laboratory tests (hematology, chemistry, and urinalysis). 
6.4.1 
Adverse Events (AEs) 
AEs will be recorded continuously starting from the signing of the ICF through the Study 
Termination visit, in those subjects who have been actually dosed.  
AEs reported prior to dosing will be recorded in the CRF and considered non-treatment emergent 
AEs. Any new systemic effect that occurs between scheduled visits should be brought to the 
attention of the Investigator and recorded in the subject’s medical file and in the CRF. 
6.4.2 
Local reaction at injection site 
Local reaction at injection site, based on the FDA Guidance to Industry29 (see grading scale in 
Appendix C) will be assessed by a study physician on treatment visits.  
6.4.3 
Vital Signs 
Vital signs (sitting systolic and diastolic blood pressure, heart rate, respiratory rate and oral 
temperature) will be measured after at least 3 minutes rest as per standard practice at the 
investigational site at the following time points:  
- 
On screening,  
- 
On each treatment visits (Visits 2, 3 and 8): within 60 minutes before vaccination, 60 (± 15) 
minutes after vaccination. 
- 
On Study Termination visit 
Changes in vital signs determined by the Investigator to be clinically significant will be noted as an 
AE on the appropriate CRF and in the subject’s file. Such abnormalities will be closely monitored 
until stabilized or resolved.  
6.4.4 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed at the following time points:   
- On screening,  
- On Study Termination visit  
 

 
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6.4.5 
Physical Examination 
Complete physical examination will be performed at the following time points: 
- 
On screening,  
- 
On Study Termination visit 
Significant changes from baseline examination on screening will be recorded as AEs in the CRF 
and in the subject’s file.  
6.4.6 
Safety Laboratory Tests 
Safety laboratory tests including biochemistry, hematology and urinalysis (see details in Appendix 
B) will be performed at the following times:  
- On screening;  
- On each treatment visits (Visits 2, 3 and 8): within 60 minutes before vaccination 
- On Study Termination visit (without the screening serology tests) 
All safety (chemistry, hematology urinalysis, serology and urine tests will be carried out by AML 
Laboratories, except urine test for pregnancy which will be performed at the trial site by the CRC 
staff.  
Clinically significant laboratory tests or tests of unknown significance which are outside the normal 
range may be repeated as clinically indicated until the values return to normal, or until the etiology 
has been determined and the condition considered stable. Abnormal laboratory test results that are 
considered to be clinically significant by the investigator will be reported as an AE in the CRF. 
 
7 
INVESTIGATIONAL PRODUCTS 
7.1 
DESCRIPTION OF INVESTIGATIONAL PRODUCT 
Sci-B-VacTM is a recombinant Hepatitis B vaccine, produced by SciVac Israel Ltd. It contains the 3 
surface antigens of the HBV: HBs, preS1 and preS2 antigens. Each 1ml dose contains sterile 10µg 
HBs antigen. It is formulated for intramuscular injection supplied in a single use vials containing 1 
ml suspension. The components of the investigational vaccine are produced under aseptic 
conditions and according to the rules of current Good Manufacturing Practice and guidelines 
applicable to IMPs (investigational medicinal products). The vaccine lot used in this trial will be 
tested and released by the Quality Assurance Department of the Sponsor. 
7.2 
PACKAGING AND LABELLING OF INVESTIGATIONAL PRODUCT 
All clinical supplies will be provided from the designated commercial batch packed and labeled in 
compliance with the Good Manufacturing Practices of drugs used in clinical trials and with the 
Israeli Ministry of Health Guidelines for Clinical Trials in Human Subjects. All study vaccines 
provided will be appropriately documented. 

 
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7.3 
STUDY DRUG ADMINISTRATION 
Sci-B-VacTM Vaccine will be administered intramuscularly in the deltoid area of the arm, 10 μg/ml, 
on Month 0, 1 and 6.  
Vaccine administration will be documented in the Case Report Forms and on the Drug 
Administration Records. 
Upon loading the syringe by the nurse, with the vaccine, it should be administered to the subjects 
immediately.  
7.4 
SHIPMENT OF INVESTIGATIONAL PRODUCT 
Prior to study start, study medications will be supplied to the CRC by the Sponsor. It is the 
responsibility of the Sponsor to ensure the vaccine is kept at 2-8C during the shipment. 
 
The Sponsor must notify the Investigator/study staff prior to dispatch of drug supplies, with the 
anticipated date of their arrival, addressed to: 
Clinical Trials Unit 
TASMC Pharmacy 
Tel-Aviv Sourasky Medical Center 
6 Weizmann Street,  
Tel-Aviv 64239, Israel 
Shipment of study drug supplies for the study will be accompanied by a shipment form describing 
the contents of the shipment drug information, acknowledgement of receipt and other appropriate 
documentation. The shipment form will assist in maintaining current and accurate inventory 
records.  
7.5 
RECEIPT AND STORAGE OF INVESTIGATIONAL PRODUCT 
All study supplies should arrive at the Pharmacy in sufficient quantity and in time to enable dosing 
as scheduled.   
The investigational product will be accompanied by a shipment form and appropriate 
documentation.   
Vaccines will be stored at the hospital pharmacy in an appropriate locked room until dosing, 
refrigerated at an average temperature between 2ºC to 8ºC. During the storage at the pharmacy, the 
temperature of the refrigerator will be monitored continuously and recorded by a pharmacist or 
another member of study staff who will record refrigerator temperature log. The Sponsor should be 
notified for any deviation from the storage conditions. Vaccine vials should never be exposed to 
freezing temperatures. 
The Investigator will issue a prescription, and the vaccines will be picked up from the pharmacy 
before administration. The vaccines will be transferred from the pharmacy to the CRC in an icebox. 
The time during which the vaccines will be out of the refrigerator should not exceed 15 min. 

 
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7.6 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCT 
The TASMC pharmacy will be responsible for recording the receipt of all drug supplies and for 
ensuring the supervision of the storage and allocation of these supplies. When a shipment is 
received, the pharmacist verifies the quantities received and the accompanying documentation and 
returns the acknowledgment of receipt to the Sponsor.   
Drug administration will be recorded in the source documents, in the CRFs and in the Drug 
Administration Record form. The latter includes the subject identification, quantity (volume) and 
date of administration. The containers from which the drug was administered to the subjects will be 
retained for dose confirmation. 
At the end of the study, delivery records of study drug will be reconciled with used / unused stocks 
and appropriate forms will be filled in, to verify that all used, unused or partially used supplies have 
been returned and that no study supplies remain in the Investigator’s possession.  
All unused drug supplies, partially used and empty containers will be returned to the Sponsor or 
disposed of according to the Sponsor's instructions. 
8 STUDY RESTRICTIONS 
8.1 
CONCOMITANT MEDICATIONS 
The following medications are prohibited for use by the subject throughout the study: 
• Systemic corticosteroid treatment less than 14 days before first vaccination and throughout 
the study. 
• Immunosuppressant medications (e.g. mycofenolate mofetil, cyclosporine, 
cyclophosphamide etc.) 
• Biological immune-modifying agents (e.g. anti TNF alfa, anti CD20)  
8.2 
ADDITIONAL RESTRICTIONS 
Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-
HCG) test on screening (and negative consecutive urine tests during the study) and be willing and 
able to use an acceptable method of birth control (acceptable methods of birth control include: 
intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive or 
double-barrier method - condom or diaphragm with spermicide) from the screening visit through 
the EOS visit, or declare that they are abstaining from sexual intercourse, or be surgically sterile 
(bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or post-menopausal. 
 
9 
SAFETY AND PHARMACOVIGILANCE 
9.1 
ADVERSE EVENT DEFINITION 
An AE is defined as “Adverse event means any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related”. 

 
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An AE (also referred to as an adverse experience) can therefore be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a drug, without any judgment about causality or seriousness. An adverse event can arise from any 
use of the drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
An abnormal result of diagnostic procedures including abnormal laboratory findings will be 
considered an AE if it fulfills one or more of the following:  
• 
Results in subject's withdrawal by the Investigator 
• 
Is associated with a serious adverse event (SAE) 
• 
Is associated with clinical signs or symptoms 
• 
Is considered by the physician to be of clinical significance (a laboratory abnormality that is 
not clinically significant will not be considered an AE) 
A new condition or the worsening of a pre-existing condition will be considered an AE.  
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Suspected adverse reaction is “any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event.”  
AEs do not include the following: 
• 
Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to  study entry and recorded in the subject's file and do not worsen during the 
study 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion). The 
condition that leads to the procedure is an AE if not present at baseline 
• 
Overdose of either study drug or concomitant medication without any signs or symptoms 
unless the subject is hospitalized for observation 
• 
Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred) 
• 
Pregnancy alone is not considered an AE. Elective abortions without complications should 
not be handled as AEs.  
All AEs, whether observed by the Investigator or designee or volunteered by or elicited from the 
subject, should be recorded individually in the CRF. AEs will be recorded from the time a subject 
has signed the ICF and throughout the study, including the follow up period, in those subjects who 
have been dosed at least once.  
Severity of the AE will be assessed by the investigating physician in accordance with the definitions 
in Appendix C. An SAE must fulfill the requirements listed in the Section 9.2. 
The Investigator will document in his/her opinion the relationship of the AE to the study drug using 
the criteria outlined in definition of adverse events relationship to study drug (Table 1).  
 
 

 
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Table 1: Definition of adverse events relationship to study drug 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated In general, this category can 
be considered applicable to 
those adverse events, which 
after 
careful 
medical 
consideration at the time they 
are evaluated, are judged to 
be unrelated to the test drug. 
An adverse experience may be considered unlikely 
related if or when (must have two): 
• It does not follow a reasonable temporal 
sequence from the administration of the test 
drug. 
• It could readily have been produced by the 
subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered 
to the subject. 
• It does not follow a known pattern of response 
to the test drug.   
• It does not reappear or worsen when the drug is 
re-administered. 
Possibly 
Related 
This category applies to those 
adverse events for which, 
after 
careful 
medical 
consideration at the time they 
are evaluated, a connection 
with 
the 
test 
drug 
administration 
appears 
unlikely but cannot be ruled 
out with certainty. 
An adverse experience may be considered possibly 
related if or when (at least two of the following): 
• It follows a reasonable temporal sequence from 
administration of the drug. 
• It could not readily have been produced by the 
subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered 
to the subject. 
• It follows a known pattern of response to the test 
drug. 
Probably 
Related 
This category applies to those 
adverse events which, after 
careful medical consideration 
at the time they are evaluated, 
are felt with a high degree of 
certainty to be related to the 
test drug. 
An adverse experience may be considered probably 
related if or when (at least three of the following): 
• It follows a reasonable temporal sequence from 
administration of the drug. 
• It could not be reasonably explained by the 
known characteristics of the subject’s clinical 
state, environmental or toxic factors or other 
modes of therapy administered to the subject. 
• It disappears or decreases on cessation or 
reduction in dose. There are important 
exceptions when an adverse event does not 
disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists. 
• It follows a known pattern of response to the test 
drug. 
 
 
 
 

 
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Outcomes to Date are classified as follows: 
• Recovered – The subject has fully recovered from the adverse event with no residual 
effects observable 
• Recovered with sequelae – The subject has recovered from the adverse event with 
residual effects observable 
• Recovering – the subject status improved but has been recovered 
• Ongoing – AE is not recovered 
• Fatal 
• Unknown 
AEs will be coded by Data Management using the using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
9.2 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any AE occurring at any dose that suggest a significant hazard or side effect, regardless 
of the Investigator or Sponsor's opinion on the relationship to the investigational product and that 
results in, but may not be limited to, any of the following outcomes: 
• death (regardless of the cause) 
• a life-threatening adverse event or suspected adverse reaction  
• inpatient hospitalization or prolongation of existing hospitalization (any inpatient 
hospital admission that includes a minimum of an overnight stay in a health care facility) 
• a persistent or significant disability/incapacity or a substantial disruption of the ability to 
conduct normal life functions 
• a congenital anomaly or birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, or that 
they occurred as a consequence of the event. 
Hospitalization for elective treatment of a pre-study condition that did not worsen while on study 
and optional hospitalizations not associated with a clinical adverse event (e.g., elective cosmetic 
surgery) are not considered SAEs.  
Significant medical events are those which may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
resulting in an AE will normally be considered serious by this criterion. 

 
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A life-threatening adverse drug experience is any adverse event that places the subject, in the view 
of the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death.  
9.3 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT 
An unexpected adverse event is any adverse event, the specificity or severity of which is not 
consistent with information in the clinical protocol or current Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for an 
approved product (package inserts are available separately at the participating center). 
Serious Unexpected Suspected Adverse Reaction (SUSAR) is a serious adverse reaction assessed 
as unexpected by the Sponsor and that is judged by either the reporting investigator or the Sponsor 
to have a reasonable causal relationship to a medical product. 
9.4 
NOTIFICATION OF SERIOUS OR UNEXPECTED ADVERSE EVENT 
Per FDA new safety reporting requirements (US Department of Health and Human Services 
September 2010)30 a sponsor must continue to “promptly” review all safety information obtained 
from foreign or domestic sources.  However, the sources of information listed in the regulation has 
expanded to include “any clinical or epidemiological investigations, animal or in vitro studies, 
reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign 
regulatory authorities and reports of foreign commercial marketing experience for drugs that are not 
marketed in the United States. 
If the Investigator identifies a SAE or Unexpected AE, an SAE report form must be completed and 
sent within 24 hours of the Investigator’s knowledge of the event to the sponsor. The names (and 
corresponding telephone numbers) of the individuals who should be contacted regarding safety 
issues or questions regarding the study are listed on the Contact Information page(s), which will be 
provided as a separate document. 
These preliminary reports will be followed within 24 hours by more detailed descriptions that will 
include a completed SAE form, copies of hospital case reports (i.e., hospital progress notes, results 
of applicable diagnostic tests, lab results and biopsy results), autopsy reports, and other documents, 
when requested and applicable.   
For regulatory purposes, initial SAE reports submitted to SciVac immediately and should include: 
a) a suspected investigational medicinal product 
b)  an identifiable subject (e.g., study subject code number) 
c)  an adverse event with a seriousness and the Investigator’s assessment of the relationship to study 
drug 
d)  an identifiable reporting source (investigator contact details) 
Once faxed or emailed, the printed SAE form and accompanying documentation should be placed 
in the SAE section of the Investigator’s site file. 
In addition, all AEs/SAEs/SUSARs will be reported to the IRB/IEC and regulatory authorities as 
required by local regulations and ICH-GCP guidelines.  

 
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Follow-up of SAEs/SUSARs  
Follow-up of SAEs/SUSARs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, it may be defined as “ongoing without further 
follow-up” by the Investigator and Sponsor’s decision. 
When supplementary information is available, a follow-up SAE Report Form must be completed by 
the site (marked as “follow-up report”) and reported as indicated above. 
Information to include on SAE form 
The following information should be provided in the SAE form to accurately and completely 
record the event: 
Investigator name and site address 
Subject study identification number 
Subject’s initials 
Subject demographics (gender, date of birth or age, weight, height) 
Clinical Event: 
▪ Description 
▪ Date and time of onset, stop date, or duration  
▪ Severity 
▪ Treatment (including hospitalization) 
▪ Relationship to study drug (causality) 
▪ Action taken regarding study drug 
▪ Information on recovery and any sequelae 
▪ If the AE resulted in death 
- 
Cause of death (whether or not the death was related to study drug) 
- 
Autopsy findings (if available) 
▪ Medical History case report form (copy) 
▪ Concomitant Medication case report form (copy) 
▪ Any relevant reports (laboratory, discharge, etc.) 
Accompanying documentation, such as copies of hospital case reports, autopsy report, and other 
documents when applicable, should be sent as soon as they are available.   
Subsequent additional information (follow-up) about any SAE unavailable at the initial reporting 
should be forwarded by the site to the Sponsor representative and study monitor within 24 hours of 
the information becoming available.  
SAEs should also be reported to the IRB/IEC according to local regulations. 
Subjects who have had an SAE during the treatment period must be followed clinically until all 
parameters (including laboratory) have either returned to normal or have stabilized or are otherwise 
explained.  
Any newly emergent SAE after treatment is discontinued or the subject has completed the study 
and is considered to be related to the study drug or study participation should be recorded and 
reported immediately. The post-study period for the purpose of SAE reporting is up to 30 days 
following last visit of the study. 

 
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Follow-up Reports for non-serious AEs 
All AEs, that do not meet any of the criteria for serious, should be regarded as non-SAEs. All AEs 
must be followed until resolution or stabilization and will be recorded on the Adverse Event Record 
in the CRF and if relevant, the Concomitant Medications Record in the CRF. Severity and 
relationship to study drug will be assigned by the Investigator as described in the section above.   
9.5 
ANTICIPATED ADVERSE EVENTS 
Previous human experience and known adverse effects of the test product are detailed in the 
Product Information leaflet.  
 
10 
STATISTICAL METHODOLOGY 
A total of 84 subjects, are expected to be recruited into study. The trial will follow-up eligible 
subject for a total duration of 12 months. Two interim analyses are planned to be conducted at the 
time when approximately 65% subjects and 82.5% of the subjects will reach Month 7 or early 
terminated the study. 
10.1 
INTERIM AND FINAL ANALYSES 
Two interim analyses are planned for possible early termination of the study. These analyses will be 
performed at the time when approximately 65% subjects and 82.5% of the subjects will reach 
Month 7 or early terminated the study. The first interim analysis will use an alpha level of 0.0109 
and the second interim analysis will use an alpha level of 0.0239. The final analysis will use an 
alpha level of 0.0414 representing the use of the Lan-DeMets correction to type-I error due to 
multiple testing. 
10.2 
SIGNIFICANCE LEVEL 
The overall significance level for this study will be 5% using two-tailed tests. 
10.3 
SAMPLE SIZE RATIONALE  
Sample size determination was performed under the following assumptions: 
• 
The primary endpoint for the study is the Seroprotection Rate (SPR), defined as the proportion 
of subjects with anti-HBs antibody titer at least equal to 10mIU/ml, at Month 7 (i.e. one month 
after the third immunization with Sci-B-Vac™). Subjects early terminated from the study for 
any reason at any time while having an anti-HBs antibody concentrations ≥ 10mIU/ml will be 
considered among those who met endpoint. 
• 
It is expected that the true rate of SPR following treatment with Sci–B-Vac™ is 95% or more. 
• 
The principal analysis of the primary endpoint will be a non-inferiority analysis testing the 
below hypothesis: 
✓ H0: P-p0 <= -Margin  
✓ H1: P-p0 >   -Margin  

 
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• 
Where p0, the assumed true SPR is 95% and the non-inferiority margin is 12.5%, employing 
that study will be considered successful if the lower bound of the 95.86% exact CI (using the 
alpha level at final analysis) will be 82.5% or more (lower non-inferiority limit). 
• 
Under these assumptions, sample of 70 subjects will provide a power of 86.1% or more to 
demonstrate that the observed SPR is non-inferior to the rate of 95%. Sample size is adjusted to 
a total of 84 subjects to account for an anticipated withdrawal rate of approximately 20%.  
10.4 
ANALYSES SETS 
10.4.1 Modified Intent-to-Treat (mITT) Analysis Set  
The Modified Intent-to-Treat (mITT) analysis set is a subset of the ITT set. This set will consist of 
all enrolled subjects who were vaccinated at least once with Sci-B-Vac™ and had at least one post 
study IP administration follow-up visit. This analysis set will serve as the primary analysis set for 
efficacy and safety inference. 
10.4.2 
Full Treatment (FT) Analysis Set 
The Full Treatment (FT) analysis set is a subset of the mITT analysis set and will consist of all 
subjects who were vaccinated 3 times with Sci-B-Vac™ and had at least one visit following the 3rd 
vaccination.  
10.5 
SUBJECT DISPOSITION 
Data from subjects who are screened but not treated, subjects in the mITT, FT analysis sets, as well 
as study withdrawal data will be summarized using descriptive statistics. This summary will include 
all subjects screened into the study. The denominator for calculating the percentages will be the set 
of the mITT. 
10.6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic and baseline data as well as disease prognostic factors, medical history and prior 
medications will be summarized for the mITT analysis set using descriptive statistics. For 
continuous variables, descriptive statistics (number [n], mean, standard deviation (SD), standard 
error, median, minimum, and maximum) will be provided. For categorical variables, subject counts 
and percentages will be provided. Categories for missing data will be presented if necessary. 
Missing categories will be presented if necessary. 
 
10.7 
EFFICACY ENDPOINTS AND ANALYSES  
Analyses of primary and secondary efficacy endpoints will use the mITT Analysis Set including all 
enrolled subjects who were vaccinated at least once with Sci-B-Vac™ and had at least one post first 
Sci-B-Vac™ administration follow-up visit.  
10.7.1 Primary Endpoint Definition and Analysis  
The primary endpoint of the study is the Seroprotection rate (SPR), defined as the proportion of 
subjects with anti-HBs antibody titer at least equal to 10mIU/ml, at Month 7 (i.e. one month after 
the third immunization with Sci-B-Vac™). Subjects early terminated from the study for any reason 

 
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at any time while having an anti-HBs antibody concentrations ≥ 10mIU/ml will be considered 
among those who met endpoint. 
The principal analysis of the primary endpoint will employ a non-inferiority analysis [SAS PROC 
FREQ with binomial (noninf margin=.125 p=(1-α) exact)] statement will be used for testing the 
below hypothesis: 
H0: P-p0 <= -Margin  
H1: P-p0 >   -Margin  
Where p0, the assumed true SPR is 95% and the non-inferiority margin is 12.5%, employing that 
study will be considered successful if the lower bound of the (1-α) exact CI will be 82.5% or more. 
10.7.2 Secondary Endpoints and Analyses  
The secondary endpoints for the study are: 
• SPR at one month after the second injection of Sci-B-Vac™ (i.e. Month 2/visit 4).  
• SPR at month 6 prior to the third injection of Sci-B-Vac™ (i.e. Month 6/visit 8). 
• SPR at one month after the first injection of Sci-B-Vac™ (i.e. Month 1/visit 3). 
• The geometric mean concentration (GMC) as determined by anti-HBsAg antibody titers at 
Month 0, then at every month until Month 7 inclusive and at months 9 and 12.  
SPR at all time points as above defined will be analyzed using the principal analysis method as 
above defined. The geometric mean concentration (GMC) as determined by anti-HBsAg 
antibody titers at Month 0, then at every month until Month 7 inclusive and at months 9 and 12 
will be displayed across time in order to establish the kinetic of the immunological response 
during the study. 
10.7.3 Exploratory Endpoints and analyses  
The exploratory endpoints for the study are: 
• The anti-preS1 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12. 
• The anti-preS2 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12. 
The geometric mean concentration (GMC) at Month 0, then at every month until Month 7 inclusive 
and at months 9 and 12 will be displayed across time in order to establish the kinetic of the 
immunological response during the study. 
10.8 
DESCRIPTIVE STATISTICS  
All measured variables and derived parameters will be listed individually and tabulated and 
descriptive statistics will be provided. For categorical variables summary tables will be provided 
displaying sample size, absolute and relative frequency and percentages. For continuous variables 
summary tables providing sample size, mean value or geometric means where appropriate, median, 
standard deviation (SD), standard error, minimum and maximum values. Summary statistics of 
Anti-HBs antibody concentrations and Anti-PreS1 and Anti-PreS2 antibodies concentrations will 
use geometric means due to the expected dispersion and skewness of the data. 

 
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Descriptive statistics for each of the study endpoints will be provided for the mITT Analysis Set and 
for both mITT and FT analyses set for the primary endpoint only. 
10.9 
SAFETY ASSESSMENTS  
10.9.1  Treatment Emergent Adverse Events  
Adverse events will be recorded from the time when a subject has signed the Informed Consent 
Form and throughout the study, including the follow-up period. The MedDRA dictionary will be 
used to standardize the terms used by the investigator to describe the Adverse Events. The 
following were incorporated into the analyses which will include only Treatment Emergent Adverse 
Events (TEAEs), namely, events that were started on the day of first study dose or afterwards. 
• 
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down by SOC 
and by SOC and Preferred Term according to MedDRA dictionary. 
• 
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down by events 
attributes.  
• 
The derived dictionary used in the analyses. 
• 
Listing of SAEs (regardless if started before or after first study dose) of randomized and dosed 
subjects captured in the clinical database until database drop date.  
• 
Listing of Non-Treatment Emergent AEs. 
10.9.2  Vital Signs  
Vital signs will be measured at each treatment visit including at unscheduled or early termination 
visits. Analyses of vital signs were performed in the following manner: 
• 
Box-Plots of vital signs before first study dose and afterwards by scheduled visit will be 
generated.  
• 
Descriptive statistics of vital signs before first study dose and afterwards as well as the changes 
from baseline by scheduled visit will be generated.  
• 
The incidence (no. of subjects) of potentially clinically significant (PCS) abnormal values will 
be summarized in a frequency table and will be listed. 
10.9.3 Laboratory Evaluations  
Analyses of safety laboratory data will be performed in the following manner: 
• 
Box-Plots of laboratory measurements first study dose and afterwards by scheduled visit will 
be provided.  
• 
Descriptive statistics of quantitative tests results and changes from baseline by scheduled visit. 
• 
Quantitative laboratory measurements will be categorized with reference to the normal ranges 
as Low, Normal or High. Shift analysis of the categorical change form baseline to each 
scheduled visit and to the last observed assessment will also be presented. 
• 
Incidence tables of PCS lab values as well as the individual subject listing will also be 
provided. 
 

 
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10.9.4 Other Safety Outcome Measures  
Summary statistics of other safety evaluations including assessment of local safety evaluations and 
pain evaluations will be tabulated and listed. Kaplan-Meier curves will be used to describe time to 
study withdrawal. 
10.10 
REPORTING DEVIATIONS FROM THE STATISTICAL PLAN  
Deviations from the statistical plan, along with the reasons for the deviations, will be described in 
protocol amendments, the clinical study report, or any combination of these, as appropriate. 
10.11 
STATISTICAL SOFTWARE   
Study accumulated data will be analyzed and summarized using the SAS® version 9.4 (SAS 
Institute, Cary North Carolina) or higher. 
 
11 
ETHICS 
11.1 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE 
Prior to initiation of the study, the Investigator will submit the study protocol and amendments, 
sample ICF, and any other documents that may be requested to the IRB/IEC for review and 
approval.  The Investigator will request that the IRB/IEC provide written approval of the study and 
will keep on file records of approval of all documents pertaining to this study. The Investigator will 
not begin the study until the protocol and ICF have been approved by the IRB/IEC. The Investigator 
must agree to make any required progress reports to the IRB/IEC, as well as reports of SAEs, life-
threatening conditions, or death. 
11.2 
ETHICAL CONDUCT OF THE STUDY 
All clinical work conducted under this protocol is subject to GCP guidelines. This includes an 
inspection by Sponsor or its designee, health authority or IRB/IEC representatives at any time.  The 
Investigator must agree to the inspection of study-related records by health authority representatives 
and/or Sponsor or its designee.  
The study will be conducted in accordance with Sponsor’s standards operating procedures and the 
following guidelines: 
• GCP: Consolidated Guideline (International Conference on Harmonisation of Technical 
Requirements for the Registration of Pharmaceuticals for Human Use, May 1996). 
• Declaration of Helsinki: Seoul, 2008 
• Israeli Guidelines, Laws and Regulations for the conduct of clinical trials (2006) 
11.3 
SUBJECT INFORMATION AND CONSENT 
Prior to screening for the study each subject will be informed in detail about the study drugs to be 
administered, and the nature of the clinical investigation with its risks and discomforts to be 
expected. The basic elements of informed consent as specified by the FDA (21 CFR 50.25) and 
ICH-GCP will be followed.  The subjects will also be instructed that they are free to withdraw their 

 
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consent and discontinue their participation in the study at any time without prejudice. Written 
consent will be obtained from each subject to be involved in the clinical trial by using the IRB/IEC-
approved ICF prior to the conduct of any study-related activity.  A copy of the ICF will be 
submitted together with this protocol and must be approved by the IRB/IEC prior to study 
commencement. Each subject will be given a copy of the written ICF, and each subject’s chart will 
include the signed ICF for study participation. The original subject signed and dated ICFs will be 
maintained by the site for 15 years.  Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the study.   
11.4 
SUBJECT INSURANCE 
A product liability to cover against injury and damages arising from the use of products in this 
project is provided by SciVac for the total duration of the study covering the subjects and 
Investigators in respect of the risks involved in conducting this study according to this protocol.  
The insurance policy will be filed in the Investigator’s site file or can be made available to the 
Investigator and to the IRB/IEC upon request. 
Where applicable, subjects will be insured through contract between an insurance company and the 
Sponsor. 
11.5 
PERSONAL DATA PROTECTION 
SciVac complies with the principle of subject’s right to protection against invasion of privacy. 
Throughout this trial, all subject data will be identified only by a subject identification number and 
subject initials and date of birth. The data will be blinded in all data analyses. The subject must be 
informed and consent as required that authorized personnel on behalf of SciVac such as study 
monitor, auditor etc. and relevant health regulatory agency will have direct access to personal 
medical data to assure a high quality standard of the study.  
At the subject's request, medical information may be given to his or her personal physician or other 
appropriate medical personnel responsible for his or her welfare.   
11.6 
INFORMING THE GENERAL PRACTITIONER 
The Investigator will inform the subject's primary care physician of the subject’s participation in the 
study, by sending a letter to the physician as required by the Israeli Guidelines for the Conduct of 
Clinical Trials. 
11.7 
PROTOCOL EXCEPTIONS AND DEVIATIONS 
It is expected that subjects will meet all eligibility criteria as specified in the protocol.  Deviations 
from the protocol should be avoided, unless required for the safety of the subject.  Protocol 
deviations, and if possible the reason for occurrence, will be documented by the study monitor and 
will be included in the final clinical study report.  The Investigator must report any protocol 
deviation to the Sponsor and if required, to the IRB/IEC in accordance with local regulations, 
within reasonable time. 
11.8 
PROTOCOL AMENDMENTS 
All protocol modifications must be submitted to the site IRB/IEC in accordance with local 
requirements and, if required, to the Regulatory Authority, either as an amendment or a notification. 

 
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Approval for amendments must be awaited before any changes can be implemented, except for 
changes necessary to eliminate an immediate hazard to trial subjects, or when the changes involve 
only logistical or administrative aspects of the trial. No approval is required for notifications. 
 
12 
QUALITY CONTROL AND QUALITY ASSURANCE  
The study will be conducted according to GCP as outlined by ICH Topic E6 step 5 guidelines. The 
Sponsor maintains a quality assurance system with written SOPs to ensure that clinical trials are 
conducted and data are generated, documented and reported in compliance with the protocol, GCP 
and applicable regulatory requirements. 
12.1 
AUDITS AND INSPECTIONS 
The study may be audited according to the Sponsor's QA inspection program. The purpose of the 
audit is to determine whether or not the study is being conducted and monitored in compliance with 
study protocol and ICH GCP guideline. Audit visit(s) will be arranged in advance with site 
personnel at a mutually acceptable time. 
The Investigator should understand that source documents for this trial should be made available to 
appropriately qualified personnel from the Sponsor quality assurance or its designees or to 
regulatory authority inspectors after appropriate notification. The verification of the CRF data must 
be by direct inspection of source documents. These audits or inspections may take place at any time, 
during or after the study, and are based on the national regulations, as well as ICH guidelines.  
12.2 
STUDY MONITORING 
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a CRO or a 
contract monitor. The study monitor will advise the Investigator regarding the practical conduct of 
the study and maintaining compliance with the protocol, GCP and all applicable regulatory 
requirements.   
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a CRO representative 
will review the protocol and CRFs with the Investigator and his staff. 
Throughout the course of the study, the study monitor will oversee the conduct and the progress of 
the study by frequent contacts with the Investigator.  This will include telephone calls and on-site 
visits.  During the on-site visits, the CRF will be reviewed for completeness with corresponding 
source documents.  As part of the data audit, source documents will be made available for review 
by the study monitor.  The study monitor will also perform drug accountability checks and may 
periodically request review of the Investigator study file to ensure completeness of documentation 
in all respects of clinical study conduct.  
Periodically, some or all of the facilities used in the study (e.g., local laboratory, pharmacy) may be 
reviewed. Monitoring visits will be arranged in advance with site personnel at a mutually acceptable 
time. Sufficient time must be allowed by the site personnel for the monitor to review CRFs and 
relevant source documents. The Investigator should be available to answer questions or resolve data 
clarifications. The Investigator or appointed delegate will receive the study monitor during these on-
site visits, cooperate in providing the documents for inspection, and respond to inquiries.   
The Investigator will ensure that the study participants are aware of and consent that personal 
information may be scrutinized during the data verification process as part of study-related 

 
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monitoring and auditing by properly authorized persons associated with SciVac or inspection by 
domestic and/or foreign regulatory authority(ies). However, participation and personal information 
should be treated as strictly confidential to the extent that the applicable law permits and not be 
publicly available.  
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period.   
12.3 
QUALITY LABORATORY STANDARDS 
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the local institution laboratory and central 
laboratories. 
Before the study begins, the laboratories to be used in the study will provide a list of the reference 
ranges for all laboratory tests to be undertaken and details of the method used for quality control. 
These will be held in the Investigator file and the trial master file. The methods employed for each 
assay should be available on request. Any change in the laboratory, its procedures, references, 
values, etc. during the study must be notified promptly to the Sponsor. 
12.4 
STUDY DOCUMENTATION 
Study documents will include the following: 
▪ Signed ICFs 
▪ Source documents (e.g., subject files, medical notes, study worksheets) 
▪ Investigator copies of the CRFs and SAE reports 
▪ Investigator site file + contents 
▪ Laboratory manual 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period.   
12.4.1 Source Document 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents.  
Source documents are original records in which raw data are first recorded.  These may be 
office/clinic/hospital records, charts, diaries, ultrasound images, and laboratory results, ECG 
printouts, pharmacy records, care records, completed scales for each study participant and/or 
worksheets provided by the Sponsor.  Source documents should be kept in a secure and limited 
access area.  All source documents must be accurate, clear, unambiguous, permanent and capable of 
being audited. They should be made using a permanent form of recording (ink, typing, printing, 
optical disc, etc.).  They should not be obscured by correcting fluid or have temporary attachments 
(such as removable self-stick notes).  Source documents that are computer generated and stored 
electronically must be printed, signed and dated by the Investigator.  
Source data for subjects registered to the study should indicate date ICF was signed, participation in 
clinical protocol number and title, treatment number, evidence that inclusion/exclusion criteria have 
been met. 
 

 
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12.4.2 Recording of Data on Case Report Form (CRF) 
Case report forms are provided for each subject in electronic format.  
The study data will be transcribed by study personnel from the source documents onto an electronic 
CRF, and transmitted in a secure manner to the sponsor within the timeframe agreed upon between 
the sponsor and the site. The electronic file will be considered to be the CRF. 
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any such 
worksheets will become part of the subject's source documentation. All data relating to the study 
must be recorded in CRF prepared by the sponsor. Data must be entered into CRF in English. 
Designated site personnel must complete the CRF as soon as possible after a subject visit, and the 
forms should be available for review at the next scheduled monitoring visit. 
Every effort should be made to ensure that all subjective measurements (eg, pain scale information 
or other questionnaires) to be recorded in the CRF are completed by the same individual who made 
the initial baseline determinations. The investigator must verify that all data entries in the CRF are 
accurate and correct. 
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or an 
authorized member of the study staff must adjust the CRF and complete the query.  
If corrections to CRF are needed after the initial entry into the CRF, this can be done in 3 different 
ways: 
• Site manager can generate a query for resolution by the study staff 
• Clinical data manager can generate a query for resolution by the study staff 
12.4.3 Investigator Site File 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines will be 
maintained by the Investigator in an orderly manner and made available for monitoring and/or 
auditing by the Sponsor and regulatory agencies. 
12.5 
CLINICAL TRIAL SUPPLIES 
The Sponsor will be responsible for the supplying, administrating, inventory, and accountability of 
all clinical trial supplies, exercising accepted medical and pharmaceutical practices.  An accurate 
and timely record of the disposition of all clinical supplies must be maintained.  The supplies and 
inventory record must be made available for inspection upon request.  Upon completion or 
termination of the study, the Investigator will keep the remaining clinical supplies along with a copy 
of the inventory record and a record of the clinical supplies returned.  Under no circumstances will 
the Investigator allow the study drugs to be used other than as directed by this protocol. 
Clinical trial supplies include, however, not limited to: CRF, study worksheets, lab supplies and 
study drug. 

 
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12.6 
DATA MANAGEMENT 
The CRF data will be captured within a clinical data management system (CDMS) that is 21 CFR 
part 11 compliant. The CDMS will be fully validated prior to use on the study to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study. All CDMS users 
will be provided system and study specific training prior to use. Once trained, users will be 
provided with individual system access rights. 
 
13 
STUDY ADMINISTRATION 
13.1 
REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION 
Prior to the start of this study, all pre-investigational requirements must be met by the Investigator 
and study site. These may include: 
▪ Appropriate local health authority documentation properly signed and dated by the required 
Investigator (i.e.,  the submission package) 
▪ Signed copy (original) of the approved protocol 
▪ Completed and signed statement of Investigator 
▪ A signed Clinical Trial Agreement 
▪ Curriculum vitae for the Investigator and sub-Investigator (can be collected at site initiation 
visit) 
▪ IRB/IEC name and address; and membership list (can be collected at site initiation visit) 
▪ Letter of approval from the IRB/IEC for both protocol (identified by protocol title and 
number) and ICF (identified by protocol title and number) 
▪ Copy of the IRB/IEC-approved written ICF to be used in the study (that has also been 
approved by the Sponsor) 
▪ Provisions for direct access to source/data documents if necessary for trial-related 
monitoring, audits, IRB/IEC review, and regulatory inspection 
▪ Name and location of the laboratory utilized for laboratory assays, and other facilities 
conducting tests, as well as a copy of the laboratory certificate and list of normal laboratory 
values (can be collected at site initiation visit) 
In case a laboratory certification is not available, a written statement as to how the laboratory 
complies with quality assurance should be provided.   
Upon satisfactory receipt of all required regulatory documents, Sponsor will arrange that study 
drugs be delivered to the study site.  Supply of all other study materials will be the responsibility of 
SciVac and/or designee. Subject entry should not begin until after the required regulatory 
documents are confirmed as received and the Investigator Meeting/Initiation Meeting has occurred. 
All personnel expected to be involved in the conduct of the study will undergo orientation to 
include review of study protocol, instructions for CRF completion, AE reporting, and overall 
responsibilities including those for drug accountability and study file maintenance. 
The Investigator and/or designee (study monitor) will prepare an Investigator's site file.  This file 
should be used for all trial related documents.  The Investigator will be responsible for keeping the 

 
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Investigator's site file updated and ensuring that all required documents are filed. The file will be 
inspected during monitoring visits. 
13.2 
STUDY COMPLETION 
This study is expected to end when all required subjects have been enrolled and the last subject has 
completed the study and the query resolution has been completed. 
Data and materials that are required before the study can be considered complete and/or terminated 
are: 
▪ Laboratory findings, clinical data, and all special test results from screening through the end 
of the follow-up period 
▪ CRF (including correction forms) properly completed by appropriate study personnel and 
electronically signed by the Investigator 
▪ Completed Drug Accountability Records 
▪ Statement of outcome for each SAE reported 
▪ Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable) 
13.3 
CLINICAL STUDY REPORT 
A clinical study report will be issued by the Sponsor at completion of data analysis. This report will 
be a clinical and statistical integrated report, according to the ICH E3 guidelines. 
13.4 
RETENTION OF STUDY RECORDS 
The Investigator will retain copies of the approved protocol, completed CRF, ICFs, relevant source 
documents, and all other supporting documentation related to the project for 15 years in a secure 
and safe facility with limited access. If the Investigator is unable to retain the study documents for 
the required amount of time, Sponsor or designee must be informed of the individual who will be 
assuming this responsibility. 
Further retention, if required, will be negotiated at the end of this 15 year period. In that case, 
SciVac will notify, in writing, the Investigator when the clinical study data may be discarded. The 
Investigator will take measures to prevent accidental or premature destruction of these documents.  
These files must be made available for inspection upon reasonable request by authorized 
representatives of Sponsor and/or the relevant regulatory agencies. 
13.5 
CONFIDENTIALITY AND PUBLICATION OF STUDY DATA 
All information, including but not limited to information regarding Sci-B-Vac™ or the sponsor's 
operations (e.g., patent applications, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by or on behalf of the sponsor to the investigator 
and not previously published, and any data and results, generated as a result of this study, are 
considered confidential and remain the sole property of the sponsor. The investigator agrees to 
maintain this information in confidence and use this information only to accomplish this study, and 
will not use it for other purposes or disclose it to others without the sponsor's prior written consent. 

 
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The investigator understands that the information developed in the clinical study will be used by the 
sponsor in connection with the continued development of Sci-B-Vac™, and thus may be disclosed 
as required to other clinical investigators and regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to provide the sponsor with 
all data and results generated in the study. 
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data generated in the study. Recruitment performance or specific expertise related 
to the nature and the key assessment parameters of the study will be used to determine a 
coordinating investigator. Results of analyses performed after the Clinical Study Report has been 
issued will be reported in a separate report and will not require a revision of the Clinical Study 
Report. Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data, results or reports that can 
benefit from copyright protection (except any publication by the investigator as provided for below) 
shall be the property of the sponsor as author and owner of copyright in such work.  
The sponsor shall have the right to publish such data, results and information without approval from 
the investigator. If an investigator wishes to publish information from the study, a copy of the 
manuscript must be provided to the sponsor for review at least 60 days before submission for 
publication or presentation. Expedited reviews will be arranged for abstracts, poster presentations, 
or other materials. If requested by the sponsor in writing, the investigator will delete confidential or 
proprietary information of the sponsor (except for the results) and shall withhold such publication 
for up to an additional 60 days to allow for filing of a patent application. In the event that issues 
arise regarding scientific integrity or regulatory compliance, the sponsor will review these issues 
with the investigator. The sponsor may suggest reasonable changes to the publication but will not 
mandate modifications to scientific content and does not have the right to suppress publication of 
the results of the study. Authorship of publications resulting from this study will be based on the 
guidelines on authorship, such as those described in the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version. The publication shall adequately 
acknowledge and appropriately reflect the contribution of the researchers and employees of each of 
the sponsor and the trial site and the source of the information included therein, in accordance with 
customary scientific practice. 
 
 
 
 
 
 
 
 
 

 
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14 
REFERENCES 
1 
Ott, J. J., Stevens, G. A., Groeger, J. & Wiersma, S. T. Global epidemiology of hepatitis B 
virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. 
Vaccine 30, 2212-2219, doi:10.1016/j.vaccine.2011.12.116 (2012). 
2 
Zanetti, A. R., Van Damme, P. & Shouval, D. The global impact of vaccination against 
hepatitis B: a historical overview. Vaccine 26, 6266-6273, doi:10.1016/j.vaccine.2008.09.056 
(2008). 
3 
Shouval, D. Hepatitis B vaccines. J Hepatol 39 Suppl 1, S70-76 (2003). 
4 
Adkins, J. C. & Wagstaff, A. J. Recombinant hepatitis B vaccine: a review of its efficacy 
and protective efficacy against hepatitis B. BioDrugs 10, 137-158 (1998). 
5 
Shouval, D. et al. Improved efficacy in mice of a mammalian cell-derived recombinant 
hepatitis B vaccine containing pre-S1 and pre-S2 antigens as compared with conventional 
yeast-derived vaccines. Vaccine 12, 1453-1459 (1994). 
6 
Hellstrom, U. B., Madalinski, K. & Sylvan, S. P. PreS1 epitope recognition in newborns 
after vaccination with the third-generation Sci-B-Vac vaccine and their relation to the 
antibody response to hepatitis B surface antigen. Virol J 6, 7, doi:10.1186/1743-422X-6-7 
(2009). 
7 
Sylvan, S. P., Madalinski, K. & Hellstrom, U. B. Anti-preS responses influence the anti-
HBs response in newborns after vaccination with the third generation Sci-B-Vac vaccine. 
Vaccine 28, 446-451, doi:10.1016/j.vaccine.2009.10.023 (2009). 
8 
Milich, D. R. et al. Enhanced efficacy of the pre-S region of hepatitis B surface antigen. 
Science 228, 1195-1199 (1985). 
9 
Milich, D. R., McLachlan, A., Chisari, F. V., Kent, S. B. & Thorton, G. B. Immune response 
to the pre-S(1) region of the hepatitis B surface antigen (HBsAg): a pre-S(1)-specific T cell 
response can bypass nonresponsiveness to the pre-S(2) and S regions of HBsAg. J Immunol 
137, 315-322 (1986). 
10 
Petit, M. A., Maillard, P., Capel, F. & Pillot, J. Immunochemical structure of the hepatitis B 
surface antigen vaccine--II. Analysis of antibody responses in human sera against the 
envelope proteins. Mol Immunol 23, 511-523 (1986). 
11 
Milich, D. R., Hughes, J. L., McLachlan, A., Thornton, G. B. & Moriarty, A. Hepatitis B 
synthetic immunogen comprised of nucleocapsid T-cell sites and an envelope B-cell epitope. 
Proc Natl Acad Sci U S A 85, 1610-1614 (1988). 
12 
Diminsky, D., Moav, N., Gorecki, M. & Barenholz, Y. Physical, chemical and 
immunological stability of CHO-derived hepatitis B surface antigen (HBsAg) particles. 
Vaccine 18, 3-17 (1999). 
13 
Diminsky, D., Schirmbeck, R., Reimann, J. & Barenholz, Y. Comparison between hepatitis 
B surface antigen (HBsAg) particles derived from mammalian cells (CHO) and yeast cells 
(Hansenula polymorpha): composition, structure and efficacy. Vaccine 15, 637-647 (1997). 
14 
FDA Guidance for Industry Considerations for Developmental Toxicity Studies for 
Preventive and Therapeutic Vaccines for Infectious Disease Indications, 2006.pdf. 
15 
Shouval D, Sci-B-VacTM  clinical expert opinion , 2001.pdf. 

 
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16 
Clinical Report Safety and Efficacy of Recombinant HB Vaccine (Sci-B-Vac™ ) in Healthy 
Adults (Protocol HB-88002). (Singapore).pdf. 
17 
Clinical Report The Efficacy of Recombinant HB Vaccine (Bio-Hep-B Sci-B-Vac ™) in 
Healthy Adults (Protocol HBV-003-89).pdf. 
18 
Clinical Report Safety and Efficacy of Recombinant HB Vaccine (Sci-B-Vac™ ) in Healthy 
Adults (Protocol HB-88002). (Thailand).pdf. 
19 
Clinical Report Safety and Efficacy of Recombinant HB Vaccine (Bio-Hep-B™Sci-B-Vac 
™) in High Risk Children (Protocol 38-91-027).pdf. 
20 
Clinical Report Efficacy and Protective Efficacy of Recombinant HB Vaccine Bio-Hep-B™ 
in Healthy Neonates (Protocol 38-92-005).pdf. 
21 
Clinical Report Safety and Efficacy of Recombinant HB Vaccine (Sci-B-VacT™ ) in 
Healthy Newborns Born to Healthy or Carrier Mothers (Protocol HBN002-01HBN002-
01A).pdf. 
22 
Clinical Report Safety and Efficacy of Recombinant HB Vaccine (Sci-B-Vac™) in Healthy 
Newborns to Hepatitis B e Antigen Negative Mothers (Protocol No. HBN018-01).pdf. 
23 
Clinical Report Safety and Efficacy of Recombinant HB Vaccine (Sci-B-Vac™) in Healthy 
Newborns Born to Healthy or Carrier Mothers (Protocol No. HBN014-01).pdf. 
24 
Clinical Report Comparison of Recombinant Hepatitis B Vaccine, Sci-B-Vac™, with 
Engerix-B®  and Hepavac II™ (Protocol HBA9006-S).pdf. 
25 
Clinical Report Comparison of Safety and Efficacy of Recombinant HB Vaccines in Healthy 
Adults Bio-Hep-B™Sci-B-Vac™ and Engerix-B®  (Protocol 38-92-001).pdf. 
26 
Clinical Report Comparison of Safety and Efficacy of Recombinant HB Vaccines in Healthy 
Adults Bio-Hep-B™Sci-B-Vac™ and Engerix-B®  (Protocol 38-96-040).pdf. 
27 
Clinical Report Comparison of Safety and Efficacy of Recombinant HB Vaccines in Healthy 
Children Bio-Hep-B™Sci-B-Vac™ and Engerix-B® (Protocol 38-92-004).pdf. 
28 
Clinical Report Comparison of Safety and Efficacy of Recombinant HB Vaccines in 
Neonates Bio-Hep-B™Sci-B-Vac™ and Engerix-B® ™ (Protocol No. 38-93-011).pdf 
29 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials. Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007. 
30. 
US Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER) (September 2010). Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE Studies (draft guidance) 
retrieved from:   
  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 

 
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APPENDIX A 
 
STUDY FLOW CHART  
 

 
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Visit  Number 
1 
2 
3 
4 
5 
6  
7 
8 
9  
10 
11 
Visit Name  
Screening 
Treatment 
1 
Treatment 
2 
Follow-
up 
Follow-
up 
Follow-
up 
Follow-
up 
Treatment 
3 
Follow-
up 
Follow-
up 
Study 
Termination 
Month (Week )  of the 
Study 
-1 ((-)4) - 0  
0 (0) 
1(41) 
2(81) 
3(121) 
4(161) 
 5(201) 
6(241() 
7(281) 
9(362) 
12(482) 
Activity 
 
 
 
 
 
 
 
 
 
 
 
ICF 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Vital signs3 
X 
X4 
X4 
 
 
 
 
X4 
 
 
X 
Weight, height, BMI 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Blood safety tests5 
X 
X6 
X6 
 
 
 
 
X6 
 
 
X 
Screening serology7 
X8 
 
 
 
 
 
 
 
 
 
 
General urinalysis 
X 
X6 
X6 
 
 
 
 
X6 
 
 
X 
Serum β-HCG 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X6 
X6 
 
 
 
 
X6 
 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Sci-B-Vac™ injection9  
 
X 
X 
 
 
 
 
X 
 
 
 
Local reaction grading 
 
X6 
X6 
 
 
 
 
X6 
 
 
 
Serologic markers  for 
hepatitis B infection 
X8,10 
X6,11 
X6,11 
X11 
X11 
X11 
X11 
X6, 11 
X11 
X11 
X12 
Serologic response to 
immunization13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Recorded throughout the study 
Concomitant 
Medications 
Recorded throughout the study 
 
1  ± 3 days 
2  ± 8 days 
3  Sitting BP, HR, RR, oral temperature 

 
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4  Within 60 min before vaccine administration and at 60 (± 15) min after vaccination  
5  CBC, blood chemistry, PT/INR (screening only) - see Appendix B 
6  Prior to vaccine administration 
7  Anti HIV (Ab type 1&2), anti-HCV Ab, anti-HAV IgM antibodies, ANA (See Appendix B) 
8 Positive serology excludes from participation in the study 
9  One IM injections of 1.0 ml into the deltoid muscle. The previous injection site will be inspected before the second and third administration.Subjects will remain for 
observation in the CRC for at least 1 hour after injections. 
10  HBsAg, anti-HBs antibodies,  total anti-HBc antibodies and  IgM anti-HBc antibodies. 
11 HBsAg only. 
12 HBsAg, Total anti-HBc antibodies and IgM anti-HBc antibodies 
13 Anti-HBsAg, anti-preS1 and anti-preS2 antibodies 
 

 
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APPENDIX B 
 
LABORATORY SAFETY TEST 
PARAMETERS  
 
 
 
 
 

 
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LABORATORY SAFETY TEST PARAMETERS - SCREENING 
 
 
SERUM BIOCHEMISTRY 
• Total Protein 
• Albumin 
• Total bilirubin 
• ALT 
• AST 
• GGT 
• LDH 
• CPK 
• Alkaline phosphatase 
• Glucose 
• Sodium 
• Potassium 
• BUN 
• Creatinine 
HAEMATOLOGY 
• Red Blood Cell Count 
• Hemoglobin (HGB) 
• Hematocrit (HCT) 
• Mean Cell Hemoglobin (MCH) 
• Mean Cell Hemoglobin Concentration (MCHC) 
• Mean Corpuscular Volume (MCV) 
• White Blood Cell (WBC) Count and Differential 
• Platelet Count 
• PT/INR 
URINALYSIS 
• Protein 
• Nitrates 
• Glucose 
• Specific Gravity 
• Ketones 
• Urobilinogen 
• Bilirubin 
• pH 
• Blood (Hemoglobin) 
• Leukocytes 
• Erythrocytes 
SEROLOGY 
• Human immunodeficiency virus (anti HIV Ab type 1&2) 
• Hepatitis C virus (anti-HCV Ab) 
• Hepatitis A virus (anti-HAV IgM antibodies)  
• Antinuclear antibodies (ANA) 
• Anti-HBs antibodies 
• HBsAg 
• Total anti-HBc,  IgM anti-HBc antibodies 
BLOOD PREGNANCY TEST  

 
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LABORATORY SAFETY TEST PARAMETERS – INTERIM AND STUDY TERMINATION  
 
 
 
SERUM BIOCHEMISTRY 
• Total Protein 
• Albumin 
• Total bilirubin 
• ALT 
• AST 
• GGT 
• LDH 
• CPK 
• Alkaline phosphatase 
• Glucose 
• Sodium 
• Potassium 
• BUN 
• Creatinine 
 
HAEMATOLOGY 
• Red Blood Cell Count 
• Hemoglobin (HGB) 
• Hematocrit (HCT) 
• Mean Cell Hemoglobin (MCH) 
• Mean Cell Hemoglobin Concentration (MCHC) 
• Mean Corpuscular Volume (MCV) 
• White Blood Cell (WBC) Count and Differential 
• Platelet Count 
 
URINALYSIS 
• Protein 
• Nitrates 
• Glucose 
• Specific Gravity 
• Ketones 
• Urobilinogen 
• Bilirubin 
• pH 
• Blood (Hemoglobin) 
• Leukocytes 
• Erythrocytes 
 
URINE PREGNANCY TEST  
  
 
 
 

 
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APPENDIX C 
 
TOXICITY GRADING SCALE TABLES 

 
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The following tables are based on the " FDA Guidance to Industry:   Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials"29   
 
TABLE 1: GRADING OF LOCAL REACTION 
 
Local Reaction to 
Injectable Product 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Pain  
Does not interfere with 
activity  
Repeated use of non-narcotic 
pain reliever > 24 hours or 
interferes with activity  
Any use of narcotic pain 
reliever or prevents daily  
activity  
Emergency room (ER) visit or  
hospitalization  
Tenderness  
Mild discomfort to touch  
Discomfort with movement  
Significant discomfort at rest  
ER visit or hospitalization  
Erythema/Redness *  
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or exfoliative dermatitis  
Induration/Swelling **  
2.5 – 5 cm and does not 
interfere with activity  
5.1 – 10 cm or            
interferes with activity  
> 10 cm or            prevents 
daily activity  
Necrosis  
*  In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous variable.  
**  Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  
 
 

 
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TABLE 2: GRADING OF VITAL SIGNS 
 
Vital Signs *  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Fever (°C) **  
(°F) **  
38.0 – 38.4  
100.4 – 101.1  
38.5 – 38.9  
101.2 – 102.0  
39.0 – 40  
102.1 – 104  
> 40  
> 104  
Tachycardia - beats per minute  
101 – 115  
116 – 130  
> 130  
ER visit or hospitalization for  arrhythmia  
Bradycardia - beats per minute***  
50 – 54  
45 – 49  
< 45  
ER visit or hospitalization for arrhythmia  
Hypertension (systolic) - mm Hg  
141 – 150  
151 – 155  
> 155  
ER visit or hospitalization for  malignant hypertension  
Hypertension (diastolic) - mm Hg  
91 – 95  
96 – 100  
> 100  
ER visit or hospitalization for malignant hypertension  
Hypotension (systolic) – mm Hg  
85 – 89  
80 – 84  
< 80  
ER visit or hospitalization for  hypotensive shock  
Respiratory Rate – breaths per minute  
17 – 20  
21 – 25  
> 25  
Intubation  
 
* Subject should be at rest for all vital sign measurements.  
** Oral temperature; no recent hot or cold beverages or smoking.  
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when characterizing bradycardia among some healthy subject 
populations, for example, conditioned athletes. 
 
 

 
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TABLE 3: GRADING OF SYSTEMIC SYMPTOMS 
 
Systemic (General)  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Nausea/vomiting  
No interference with activity or 
1 – 2 episodes/24 hours  
Some interference with 
activity or > 2 episodes/24 
hours  
Prevents daily activity, 
requires outpatient IV  
hydration  
ER visit or  hospitalization for  
hypotensive shock  
Diarrhea  
2 – 3 loose stools or < 400 
gms/24 hours 
4 – 5 stools or  
400 – 800 gms/24  
hours  
6 or more watery stools or > 
800gms/24 hours or requires 
outpatient IV hydration  
ER visit or hospitalization  
Headache  
No interference with activity  
Repeated use of non-  
narcotic pain reliever > 24 
hours or some interference 
with activity  
Significant; any use of 
narcotic pain reliever or  
prevents daily activity  
ER visit or  
hospitalization  
Fatigue  
No interference with activity  
Some interference with 
activity  
Significant; prevents daily 
activity  
ER visit or hospitalization  
Myalgia  
No interference with activity  
Some interference with 
activity  
Significant; prevents daily 
activity  
ER visit or hospitalization  
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations)  
No interference with activity  
Some interference with 
activity not requiring medical 
intervention  
Prevents daily activity and 
requires medical  
intervention  
ER visit or hospitalization  
 

 
Protocol No.:  SciB018 
Version and Date: Version 1.0, March 4, 2015   
 
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APPENDIX D 
 
Sci-B-Vac™ PRODUCT LEAFLET  
 
 

 
Protocol No.:  SciB018 
Version and Date: Version 1.0, March 4, 2015   
 
SciVac Ltd.                                                   Page 56 of 57                                  
Confidential and Proprietary  
Sci-B-Vac
™  
Hepatitis B Vaccine (rDNA)
   
Description  
Sci-B-Vac [Hepatitis B Vaccine (rDNA)] is a third generation vaccine produced by culture in Chinese hamster ovary cells.  It consists of 22 
nm particles isolated and purified from culture medium.  The particles contain all three epitopes of hepatitis B surface antigen (HBsAg), 
namely S, pre-S1 and pre-S2, in their glycosylated and non-glycosylated forms, embedded in a phospholipid matrix, thus resembling the 
authentic plasma derived HBsAg.  The antigen is formulated by adsorption onto aluminum hydroxide.  The final preparation is virtually free 
of DNA and contains less than 3% protein contaminants.  It does not contain any known animal viruses, bacteria or Mycoplasma.  
Composition:  
Active ingredient:  
Sci-B-Vac 10µg/ml contains hepatitis B surface antigen 10µg/ml  
Sci-B-Vac 5µg/0.5ml contains hepatitis B surface antigen 5µg/0.5ml   
Sci-B-Vac 2.5µg/0.5ml contains hepatitis B surface antigen 2.5µg/0.5ml  
Other ingredients:  
Al(OH)3 (2% solution) 0.5ml/1ml equivalent to dry weight of 1.5mg Al(OH)3 per mL,  
NaCl, KCl, Na2HPO4×12H2O, KH2PO4, WFI.  
Each batch of the vaccine is rigorously tested for purity, safety, sterility and potency.  
In each formulation, the HBsAg is adsorbed onto approximately 0.5 mg of aluminum per ml of vaccine.  
Indications and Usage  
Sci-B-Vac is indicated for active immunization against hepatitis B virus (HBV) infection.  
Immunization against hepatitis B is expected, in the long term, to reduce not only the incidence of the disease,,but also its chronic 
complications such as massive hepatic necrosis, cirrhosis of the liver and hepatocellular carcinoma.  
Vaccination with Sci-B-Vac is recommended for all ages in those subjects who are or will be at increased risk of infection with HBV.  In 
areas of high prevalence of infection, the majority of the population is at high risk, especially neonates and children.  In high risk areas, 
infection occurs primarily through mother to child and horizontal transmission.  Therefore, vaccination should be targeted to prevent such 
transmission.  In areas of intermediate and low prevalence, vaccination is recommended for neonates, infants and adolescents, as well as 
subjects who are or will be at increased risk of infection, such as:  
 • Health care personnel  
• Frequent recipients of blood products  
• Infants born to HBsAg-positive mothers  
 • Personnel and residents of public health institutions  
 • Persons at increased risk of the disease due to their sexual practices  
• Travelers to areas with high endemicity of HBV  
• Persons originating from areas of high endemicity  
• Users of illicit injectable drugs  
 • Military personnel, police personnel and anybody who through their work or personal lifestyle may be exposed to HBV  
 • Family members and others in intimate contact with persistent HBsAg-positive individuals.  
 
Persons who develop anti-HBs antibodies following active infection with the hepatitis B vaccine are protected against the disease if they are 
re-exposed to the virus.  
Clinical trials have shown that Sci-B-Vac induced protective levels of antibody in up to 100% of healthy adults who received the 
recommended three-dose regimen of 10 μg/dose.  
Sci-B-Vac is highly immunogenic in children.  The specific antibody titers tend to be an order of magnitude higher in children than in adults 
when the recommended doses are administered.  Children tend to achieve seroprotection more frequently than adults.  
Contraindications  
Sci-B-Vac should not be administered to subjects with known hypersensitivity to any components of the vaccine or to subjects who 
developed symptoms suggestive of hypersensitivity after the injection of Sci-B-Vac.  
As with other vaccines, the administration of Sci-B-Vac should be postponed in subjects suffering from acute severe illness.  The presence of 
a minor infection, however, is not a contraindication for immunization..   
Warnings  
Due to the long incubation period for hepatitis B, it is possible for unrecognized infection to be present at the time of vaccination.  
Vaccination may not prevent hepatitis B in such individuals.  The vaccine will not prevent infection caused by other agents such as hepatitis 
A, hepatitis C and hepatitis E or other pathogens known to infect the liver.  
Precautions  
General: As with any vaccine, epinephrine should be available for immediate use should an anaphylactic reaction occur.  

 
Protocol No.:  SciB018 
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Caution and appropriate care should be exercised in administering the vaccine to individuals with severe compromised cardiopulmonary 
status or to others in whom a febrile or systemic reaction could pose a significant risk.  
Sci-B-Vac should under no circumstances be administered intravenously.  
Pregnancy and Nursing Mothers: Animal reproduction studies have not been conducted with the vaccine.  It is also not known whether the 
vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.  The vaccine should be given to a 
pregnant woman only if clearly needed.  It is not known whether the vaccine is excreted in human milk. Since many drugs are excreted in 
human milk, caution should be exercised when the vaccine is administered to a nursing woman.  
Pediatric Use: Sci-B-Vac has been shown to be well tolerated and highly immunogenic in infants and children of all ages.  Newborns also 
respond well; maternally transferred antibodies do not interfere with the active immune response to the vaccine.  
Adverse Reactions  
Sci-B-Vac is generally well tolerated. No serious adverse reactions attributable to the vaccine have been reported during the course of 
clinical trials.  As with any vaccine, there is the possibility that broad use of the vaccine could reveal adverse reactions not observed in 
clinical trials.  
In a series of studies, 2313 doses of Sci-B-Vac were administered to 771 healthy adults who were monitored for 5 days after each dose.  The 
following adverse reactions were reported:  
Incidence Equal to or Greater Than 1% of Injections:   
Local Reaction (Injection Site): Injection site reactions consist of soreness and include pain, tenderness, pruritus, erythema, ecchymosis, 
swelling, warmth and nodule formation.  These reactions were mild and resolved within two days after vaccination.  
Additional complaints included fatigue/weakness, headache, fever (37.8ºC), malaise, nausea, diarrhea pharyngitis and upper respiratory 
infection.  
Incidence Less Than 1% of Injections:  
Sweating, aching, sensation of warmth, light-headedness, chills, flushing, vomiting, abdominal pains/cramps, dyspepsia, diminished appetite, 
rhinitis, influenza, cough, vertigo/dizziness, paresthesia, pruritus, rash (non-specified), angioedema, urticaria, arthralgia including 
monarticular, myalgia, back pain, neck pain, shoulder pain, neck stiffness, lymphadenopathy, insomnia/disturbed sleep, earache, dysuria and 
hypotension.  
Dosage and Administration  
Sci-B-Vac is a sterile suspension for intramuscular injection.    
Adult Formulation, 10 μg/ml: each 1 ml dose contains 10 μg hepatitis B surface antigen; recommended for children above the age of 10 years 
and adults.  
Pediatric Formulation (option 1) 2.5 μg/0.5 ml: each 0.5 ml dose contains 2.5 μg hepatitis B surface antigen; recommended for neonates, 
infants and young children.  
Pediatric Formulation (option 2) 5 μg/0.5 ml: each 0.5 ml dose contains 5 μg hepatitis B surface antigen; recommended for neonates, infants 
and young children in highly endemic areas.  
In each formulation, the hepatitis B surface antigen is adsorbed onto approximately 0.5 mg of aluminum per ml of vaccine. 
Method of Administration: Sci-B-Vac should be injected intramuscularly into the deltoid muscle in adults and children or in the anterolateral 
thigh in neonates, infants and young children. The vaccine may be administered subcutaneously to persons who are at high risk of 
hemorrhage due to thrombocytopenia or bleeding disorders. Do not inject into the gluteal muscle.  
Vaccination Schedule: The vaccination regimen for all subjects consists of three (3) doses of vaccine given according to the following 
schedule: first dose at elected date; second dose 1 month after the first dose; third dose 6 months after the first dose.  
Booster Dose: The duration of the protective effect of Sci-B-Vac against HBV is unknown at present. A booster dose may be considered 
when the anti-HBs titer falls below 10 mlU/ml.  
As with all parenteral drug products, the vaccine should be inspected visually for any particulate matter and/or discoloration prior to 
administration.  
Before use of Sci-B-Vac, the vaccine should be shaken well to obtain a slightly opaque, white suspension. Discard if the contents of the vial 
appear otherwise. As with other vaccines, a dose of vaccine should be withdrawn under aseptic conditions and precautions taken to avoid 
contamination of the contents.  
 
Recommended Storage Conditions:  
The vaccine should be stored in the dark at +2°C to +8°C. Do Not Freeze.  
 
Manufactured and Distributed by:  
SciVac  
Gad Feinstein Rd, Rehovot, Israel 7610303, P.O.Box 580 Tel: 972-8-9480666, Fax: 972-8-9480660  
 
The format of this leaflet was determined by the Israeli Ministry of Health and its contents checked and approved.  
Approved leaflet February, 2009. 

SciVac Ltd. 
Clinical Study Report SciB018 
95 
CONFIDENTIAL 
 
16.1.1.2 
Protocol V2 amendment 1 

 
Protocol No.:  SciB018 
Version and Date: Version 2.0, September 9, 2015 
Amendment 1  
 
 
 
 
 
 
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CLINICAL STUDY PROTOCOL 
AN OPEN LABEL, SINGLE ARM, SINGLE CENTER CLINICAL STUDY IN HEALTHY 
SUBJECTS TO QUALIFY AN IN-HOUSE REFERENCE STANDARD BATCH OF SCI-B-VAC™ 
Sponsor: 
SciVac Ltd. 
Gad Feinstein Rd, Rehovot, 7610303 Israel 
Tel: +972-8-9480666  Fax: +972-8-9480660 
Investigator: 
Dr. Jacob Atsmon M.D. 
Director, TASMC  Clinical Research Center (CRC) 
Research Facility: 
Tel Aviv Sourasky Medical Center,  
6 Weizmann St., Tel Aviv 64239 Israel 
Tel: +972 3 6974845  Fax: +972 3 6973935 
Protocol Number: 
SciB018 
CRC No. 
TRC 075/10217 
Institutional Review Board 
Tel Aviv Sourasky Medical Center, Tel Aviv 
Bioanalysis and Safety 
Laboratory: 
American Medical Laboratories Ltd. 
Herzliya Medical Center  
7 Ramot Yam  St., Herzliya Pituach, Israel  
Tel: +972-9-9568634  Fax : +972-9-9568128 
Sponsor Contact: 
Dr. Nathalie Machluf, Ph.D. 
Director of Regulatory and Clinical Affairs 
SciVac IL, Ltd. 
Tel: +972-54-3945326  Fax:+972-89480634 
Version and Date: 
Version 2.0, September 9  , 2015  
Amendment 1  
 
 
 
 
 
 
Confidentiality Statement 
The information in this document contains trade secrets and proprietary or commercial information that are 
privileged or confidential and may not be disclosed to any third party without the prior written approval of 
SciVac, unless such disclosure is required by relevant ethics committees, regulatory authorities or under 
applicable law or regulations. In any event, persons to whom the information is disclosed, as permitted 
above, must be informed that the information is privileged or confidential and should be maintained in 
confidence. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential or should otherwise be regarded as confidential given the 
circumstances or nature of disclosure. 

 
Protocol No.:  SciB018 
Version and Date: Version 2.0, September 9, 2015 
Amendment 1  
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
An Open Label, Single Arm, Single Center Clinical Study in Healthy 
Subjects to Qualify an In-House Reference Standard Batch of Sci-B-Vac™ 
Protocol Number 
SciB018 
CRC Number 
TRC 075/10217 
Investigational 
Product 
Sci-B-Vac™ 
Dosage Form 
A single use vial containing 1 ml suspension. 
Mode and 
schedule of 
Administration: 
10 µg (in 1 ml) injected intramuscularly into the deltoid muscle. Three 
Intramuscular injections: on time-0, Month-1 and Month-6   
Clinical Phase 
IV 
Study Objectives 
Primary objective: 
To validate the new in-house reference standard vaccine for routine quality 
control purposes, in compliance with the European Pharmacopeia and the 
Israeli Ministry of Health. 
Secondary objectives: 
1. To characterize   the immunological response throughout the study. 
2. To monitor the subjects for safety throughout the study period. 
Exploratory objectives: 
1. To collect blood samples for the in vitro validation of anti-HBs, anti-preS1 
and anti-preS2 antibodies assays. 
2. To assess the anti-preS1 and anti-preS2 antibodies responses upon 
vaccination. 
3. To investigate additional protective mechanisms of action and the type of 
immune response triggered by the vaccination. No genetic tests will be 
performed. 
Efficacy 
Endpoints 
Primary endpoint: 
Seroprotection rate (SPR), defined as the proportion of subjects with anti-
HBs antibody titer at least equal to 10mIU/ml, at Month 7 (i.e. one month 
after the third immunization with Sci–B-Vac™). Subjects early terminated 
from the study for any reason at any time while having an anti-HBs 
antibody concentrations ≥ 10mIU/ml will be considered among those who 
met endpoint. 
Secondary endpoints: 
1. SPR one  month after the first injection and at every month until Month 
6 inclusive and at months 9 and 12.  
2. Percentage of subjects with anti-HBs antibodies titer ≥ 100mIU/ml at 
Month 0, and then at every month until Month 7 inclusive and at 
months 9 and 12.                                                                                               

 
Protocol No.:  SciB018 
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3. The geometric mean concentration (GMC) as determined by anti-
HBsAg antibody titers at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12.  
Exploratory endpoints: 
• The anti-preS1 antibody titers measured at Month 0, then at every 
month until Month 7 inclusive and at months 9 and 12. 
• The anti-preS2 antibody titers measured at Month 0, then at every 
month until Month 7 inclusive and at months 9 and 12. 
Study Design and 
Procedures 
 
 
 
 
 
 
 
This is an open label, single arm, single center clinical study in healthy 
subjects, who were never vaccinated against Hepatitis B and who are HBs 
antigen, anti-HBc and anti-HBsAg antibodies seronegative. 
Eligible subjects will be vaccinated 3 times with 10 mcg/ml of Sci-B-Vac™ 
according to the immunization schedule.  
The study will consist of three periods:  
• 
Screening period: Up to 4 weeks prior to first vaccination 
• 
Treatment and follow-up period: 6 months 
• 
Post-vaccination follow-up period: 6 months 
Blood samples will be collected prior to the first vaccination (Month 0), every 
month until month 7 inclusive, at Month 9 and at Month 12. 
Safety parameters will be assessed as outlined below and in Section 6.4. 
Duration of Study 
(Clinical Stage) 
The duration for an individual subject is approximately 13 months. 
Number of 
Subjects 
Up to 84 
Inclusion Criteria 1. 
Healthy males and females between 20 and 40 (inclusive) years of age. 
2. 
Subjects who provide written informed consent to participate in the study. 
3. 
Subjects in general good health in the opinion of the investigator as 
determined by medical history, vital signs and a physical examination. 
4. 
No clinically significant abnormalities in hematology, blood chemistry, or 
urinalysis lab tests at screening.  
5. 
Women of child-bearing potential must practice an acceptable method of 
birth control or practice abstinence during the study period or be 
surgically sterilized, from screening visit throughout the treatment phase 
and for 28 days after the last injection and agree to undergo repeated 
pregnancy tests. 
6. 
Subjects must be able to understand the requirements of the study and 
must be willing to comply with the requirements of the study. 
Exclusion Criteria  
 
 
 
 
1. 
Known history of significant medical disorder, which in the investigator’s 
judgment contraindicates administration of the vaccine or may interfere 
with the subject's compliance or the interpretation of study assessment 
parameters. 
 

 
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2. 
Any clinically significant abnormality upon physical examination or in 
the clinical laboratory tests at screening visit. 
3. 
Treatment with immune suppressive agents. 
4. 
Chronic administration (defined as more than 14 days) of 
immunosuppressants or other immune-modifying drugs within six months 
prior to the first vaccine dose. 
5. 
History of HBV infection or confirmed exposure to hepatitis B virus.  
6. 
Previous vaccination against Hepatitis B. 
7. 
Positive for HBsAg, anti-HBsAg antibodies, anti-HBc antibodies, anti-
HCV antibodies or anti- HIV antibodies.  
8. 
Drug abusers 
9. 
Known hypersensitivity or allergy to any component of the study vaccine. 
10. BMI < 18.5 or ≥ 30 Kg/m2. 
11. Known concomitant disease or any other medical condition that is 
considered by the investigator likely to interfere with the subject's 
compliance or the interpretation of study assessments. 
12. Any acute illness (e.g. acute infection) within 48 hours prior to the first 
study drug administration that is considered of significance by the 
Principal Investigator. 
13. Female subjects: pregnant, lactating or planning a pregnancy. 
14. Any confirmed or suspected immunosuppressive or immunodeficient 
condition. 
15. Receipt of blood or immunoglobulin transfusion six months prior to the 
first vaccine dose and during the course of the trial.  
16. Unwilling or unable (in the judgment of the investigator) to comply with 
all the requirements of the protocol. 
17. Participate in another clinical trial within 3 months prior to first 
vaccination (calculated from the previous study's last dosing date). 
Safety 
Assessments 
The primary safety endpoint is the frequency, severity, and duration of adverse 
events (AEs), including clinically significant laboratory abnormalities after 
administration of Sci-B-Vac™. 
Safety will be evaluated on the basis of the following assessments: 
• 
AEs: continuous (starting from informed consent signature until end of 
study) 
• 
Recording of concomitant medications: continuous (starting from 
informed consent signature until end of study) 
• 
Physical examination: on screening and on study termination visit. 
• 
12-lead ECG: on screening and on study termination visit.  
• 
Vital signs (sitting BP, HR, RR, oral temperature): on screening, on each 
treatment (vaccination) visit within 60 minutes before vaccine 
administration, at 60 (± 15) minutes after vaccination and on study 
termination visit. 
 

 
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• 
Safety laboratory evaluations (blood and urine): On screening, before each 
vaccine administration and on study termination visit. Safety laboratory 
variables are outlined in Appendix B. 
Statistical 
Methodology   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A total of 84 subjects, are expected to be recruited into study. The trial will 
follow-up eligible subject for a total duration of 12 months. One interim 
analysis is planned to be conducted at the time when approximately  50% of 
the subjects will reach Month 7 or early terminated the study. 
Interim and Final Analyses 
One interim analysis is planned for possible early termination of the study. The 
interim analysis will be performed at the time when approximately 50% of the 
subjects will reach Month 7 (1 month after the 3rd vaccine) or early terminated 
the study.   
Significance Level  
The overall significance level for this study will be 5% using two-tailed tests. 
Sample Size Rationale:  
Sample size determination was performed under the following assumptions: 
• The primary endpoint for the study is the Seroprotection Rate 
(SPR), defined as the proportion of subjects with anti-HBs antibody 
titer at least equal to 10mIU/ml, at Month 7 (i.e. one month after 
the third immunization with Sci–B-Vac™). Subjects early 
terminated from the study for any reason at any time while having 
an anti-HBs antibody concentrations ≥ 10mIU/ml will be 
considered among those who met endpoint. 
• It is expected that the true rate of SPR following treatment with  
Sci–B-Vac™ is 95% or more. 
• The principal analysis of the primary endpoint will be a non-
inferiority analysis testing the below hypothesis: 
• H0: P-p0 <= -Margin  
• H1: P-p0 >   -Margin  
• Where p0, the assumed true SPR is 95% and the non-inferiority 
margin is 9.0%, employing that study will be considered successful 
if the lower bound of the 95.0% exact CI will be 86.0% or more 
(lower non-inferiority limit). 
• The rational for sample size calculation is based on demonstrating 
an expected SPR rate of 95%. The lower bound of a calculated 95% 
confidence interval (CI) using Exact binomial method ensures that 
the actual SPR rate will not exceed the calculated lower limit (will 
not be lower than the lower bound). 
• The sample size is adjusted to a total of 84 subjects to account for 
an anticipated withdrawal rate of approximately 20%.  
 
 

 
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Sample Size Justification:  
When the sample size is 70, a one-sided 95.0% confidence interval (CI) for 
a single proportion using Exact binomial method will demonstrate a lower 
bound of 86.0% or more for an expected proportion of 0.95. 
Primary Endpoint Definition: 
The primary endpoint of the study is the Seroprotection rate (SPR), defined as 
the proportion of subjects with anti-HBs antibody titer at least equal to 
10mIU/ml, at Month 7 (i.e. one month after the third immunization with  
Sci–B-Vac™). Subjects early terminated from the study for any reason at any 
time while having an anti-HBs antibody concentrations ≥ 10mIU/ml will be 
considered among those who met endpoint. 
 
Principal Analysis of the Primary Endpoint: 
The principal analysis of the primary endpoint will employ a non-inferiority 
analysis [SAS PROC FREQ with binomial (noninf margin=0.09 p=(1-α) 
exact)] statement will be used for testing the below hypothesis: 
H0: P-p0 <= -Margin  
H1: P-p0 >   -Margin  
Where p0, the assumed true SPR is 95% and the non-inferiority margin is 
9.0%, employing that study will be considered successful if the lower bound of 
the (1-α) exact CI will be 86.0% or more.   
 

 
Protocol No.:  SciB018 
Version and Date: Version 2.0, September 9, 2015 
Amendment 1  
 
 
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE 
2 
PROTOCOL SYNOPSIS 
3 
TABLE OF CONTENTS 
8 
ABBREVIATIONS AND DEFINITION OF TERMS 
11 
1 
INTRODUCTION 
13 
1.1 
BACKGROUND – HEPATITIS B VIRUS INFECTION ............................................. 13 
1.2 
SCI-B-VAC™ PRODUCT DESCRIPTION ............................................................ 13 
1.3 
SUMMARY OF CLINICAL STUDIES .................................................................... 14 
1.4 
STUDY RATIONALE .......................................................................................... 15 
2 
STUDY OBJECTIVES 
15 
2.1 
PRIMARY OBJECTIVE ....................................................................................... 15 
2.2 
SECONDARY OBJECTIVES ................................................................................ 15 
2.3 
EXPLORATORY OBJECTIVES ............................................................................. 15 
3 
STUDY ENDPOINTS 
15 
3.1 
PRIMARY ENDPOINT ........................................................................................ 15 
3.2 
SECONDARY ENDPOINTS .................................................................................. 15 
3.3 
EXPLORATORY ENDPOINTS .............................................................................. 16 
4 
STUDY DESIGN 
16 
4.1 
OVERALL STUDY DESIGN ................................................................................ 16 
5 
SELECTION OF STUDY POPULATION 
17 
5.1 
NUMBER OF SUBJECTS ..................................................................................... 17 
5.2 
INCLUSION CRITERIA ....................................................................................... 17 
5.3 
EXCLUSION CRITERIA ...................................................................................... 17 
5.4 
SUBJECT IDENTIFICATION ................................................................................ 18 
5.5 
SCREENING FAILURES ...................................................................................... 18 
5.6 
REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF SUBJECTS FROM 
TREATMENT OR ASSESSMENT ....................................................................... 18 
5.7 
HANDLING OF WITHDRAWALS ......................................................................... 19 
5.8 
TERMINATION OF STUDY BY SPONSOR ............................................................ 19 
5.9 
TERMINATION OF STUDY ................................................................................. 19 
6 
STUDY PROCEDURES AND SCHEDULES 
19 
6.1 
VISIT SCHEDULES ............................................................................................ 19 
6.2 
UNSCHEDULED VISIT ....................................................................................... 22 
6.3 
BLOOD SAMPLING FOR IMMUNOGENICITY ....................................................... 22 
6.4 
SAFETY ASSESSMENTS .................................................................................... 22 

 
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7 
INVESTIGATIONAL PRODUCT 
24 
7.1 
DESCRIPTION OF INVESTIGATIONAL PRODUCT................................................. 24 
7.2 
PACKAGING AND LABELLING OF INVESTIGATIONAL PRODUCT ........................ 24 
7.3 
STUDY DRUG ADMINISTRATION ...................................................................... 24 
7.4 
SHIPMENT OF INVESTIGATIONAL PRODUCT ..................................................... 25 
7.5 
RECEIPT AND STORAGE OF INVESTIGATIONAL PRODUCT ................................. 25 
7.6 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCT ......................................... 25 
8 
STUDY RESTRICTIONS 
26 
8.1 
CONCOMITANT MEDICATIONS ......................................................................... 26 
8.2 
ADDITIONAL RESTRICTIONS ............................................................................ 26 
9 
SAFETY AND PHARMACOVIGILANCE 
26 
9.1 
ADVERSE EVENT DEFINITION .......................................................................... 26 
9.2 
SERIOUS ADVERSE EVENTS (SAES) ................................................................ 29 
9.3 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT .......................................... 29 
9.4 
NOTIFICATION OF SERIOUS OR UNEXPECTED ADVERSE EVENT ....................... 30 
9.5 
ANTICIPATED ADVERSE EVENTS ..................................................................... 32 
10 
STATISTICAL METHODOLOGY 
32 
10.1 
INTERIM AND FINAL ANALYSES ....................................................................... 32 
10.2 
SIGNIFICANCE LEVEL....................................................................................... 32 
10.3 
SAMPLE SIZE RATIONALE ................................................................................ 32 
10.4 
ANALYSES SETS............................................................................................... 33 
10.5 
SUBJECT DISPOSITION ...................................................................................... 33 
10.6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................ 33 
10.7 
EFFICACY ENDPOINTS AND ANALYSES ............................................................ 33 
10.8 
DESCRIPTIVE STATISTICS ................................................................................. 34 
10.9 
SAFETY ASSESSMENTS .................................................................................... 35 
10.10 REPORTING DEVIATIONS FROM THE STATISTICAL PLAN .................................. 36 
10.11 STATISTICAL SOFTWARE ................................................................................. 36 
11 
ETHICS 
36 
11.1 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE ......... 36 
11.2 
ETHICAL CONDUCT OF THE STUDY .................................................................. 36 
11.3 
SUBJECT INFORMATION AND CONSENT ............................................................ 36 
11.4 
SUBJECT INSURANCE ....................................................................................... 37 
11.5 
PERSONAL DATA PROTECTION ........................................................................ 37 
11.6 
INFORMING THE GENERAL PRACTITIONER ....................................................... 37 
11.7 
PROTOCOL EXCEPTIONS AND DEVIATIONS ...................................................... 37 
11.8 
PROTOCOL AMENDMENTS ............................................................................... 37 
12 
QUALITY CONTROL AND QUALITY ASSURANCE 
38 
12.1 
AUDITS AND INSPECTIONS ............................................................................... 38 
12.2 
STUDY MONITORING ....................................................................................... 38 
12.3 
QUALITY LABORATORY STANDARDS .............................................................. 39 

 
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12.4 
STUDY DOCUMENTATION ................................................................................ 39 
12.5 
CLINICAL TRIAL SUPPLIES ............................................................................... 40 
12.6 
DATA MANAGEMENT....................................................................................... 41 
13 
STUDY ADMINISTRATION 
41 
13.1 
REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION ..................................... 41 
13.2 
STUDY COMPLETION ........................................................................................ 42 
13.3 
CLINICAL STUDY REPORT ................................................................................ 42 
13.4 
RETENTION OF STUDY RECORDS ..................................................................... 42 
13.5 
CONFIDENTIALITY AND PUBLICATION OF STUDY DATA .................................. 42 
14 
REFERENCES 
43 
APPENDIX A  STUDY FLOW CHART 
46 
APPENDIX B  LABORATORY SAFETY TEST PARAMETERS 
49 
APPENDIX C  TOXICITY GRADING SCALE TABLES 
52 
APPENDIX D  SCI-B-VAC™ PRODUCT LEAFLET 
56 
 

 
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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation/Term 
Definition 
AE 
Adverse Events 
ANA 
Antinuclear antibodies 
ALT 
Alanine transaminase 
Anti-HBc        
Antibodies to hepatitis B core antigen 
Anti-HBs        
Antibodies to HBsAg 
Anti-HCV       
Antibodies to hepatitis C virus 
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
cm 
Centimeter 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GMR 
Geometric mean ratio 
GSK 
Glaxo Smith Kline 
h 
Hours 
HBsAg  
Hepatitis B Surface Antigen 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRB 
Institutional Review Board 
Kg 
Kilogram 
m 
Meter 
mg 
Milligram 

 
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Abbreviation/Term 
Definition 
min 
Minute 
mITT 
Modified intention-to-treat analysis 
ml 
Milliliter 
MOH 
Ministry of Health 
MSD 
Merck Sharp and Dome 
N/A 
Not Applicable 
ºC 
Degrees centigrade 
OTC 
Over the Counter 
OTC 
Over the counter 
PI 
Principal Investigator 
PQC 
Product Quality Complaint 
PT 
Prothrombin Time 
PT/INR 
Prothrombin time/International Normalized Ratio (for blood clotting time) 
QA 
Quality Assurance 
R&D  
Research and Development 
RBC 
Red blood cells 
RBC 
Red blood cell 
RDW 
RBC distribution width 
RR 
Respiration rate 
SAE 
Serious Adverse Event 
SOP 
Standard Operation Procedures 
SPR 
Seroprotection rate  
SUSAR 
Suspected unexpected serious adverse reaction 
TASMC 
Tel Aviv Sourasky Medical Center 
TEAE 
Treatment emergent adverse events 
WBC 
White blood cell 
WHO 
World Health Organization 
μg 
Microgram 

 
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1 
INTRODUCTION 
1.1 
BACKGROUND – HEPATITIS B VIRUS INFECTION  
Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. It can 
cause chronic liver disease and chronic infection and puts people at high risk of death from cirrhosis 
of the liver and liver cancer. More than 240 million people have chronic (long-term) liver 
infections. More than 780 000 people die every year due to the acute or chronic consequences of 
hepatitis B.   
In highly endemic areas, HBV is most commonly spread from mother to child at birth, or from 
person to person in early childhood. Perinatal or early childhood transmission may also account for 
more than one third of chronic infections in areas of low endemicity, although in those settings, 
sexual transmission and the use of contaminated needles are the major routes of infection.  
High risk groups include: people who frequently require blood or blood products, dialysis patients, 
recipients of solid organ transplantations, people interned in prisons, injecting drug users, household 
and sexual contacts of people with chronic HBV infection, people with multiple sexual partners, as 
well as health-care workers and others who may be exposed to blood and blood products through 
their work and travelers who have not completed their hepatitis B vaccination series.  
The hepatitis B virus can survive outside the body for at least 7 days. During this time, the virus can 
still cause infection if it enters the body of a person who is not protected by the vaccine. 
Most people do not experience any symptoms during the acute infection phase. However, some 
people have acute illness with symptoms that last several weeks, including yellowing of the skin 
and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain. In some 
people, the hepatitis B virus can also cause a chronic liver infection that can later develop into 
cirrhosis of the liver or liver cancer*. 
Five to ten percent of infected adults are unable to eliminate the virus following acute infection, and 
develop persistent viral infection which lasts more than 6 months; this is designated as a hepatitis B 
surface antigen (HBsAg) carrier state. It has been estimated that there are >200 million HBsAg 
carriers worldwide 1. 
The first generation, plasma-derived hepatitis B vaccines were developed in the US and France in 
the late 1970s. In the mid 1980s, second generation recombinant DNA hepatitis B vaccines were 
constructed in yeasts transfected with HBV-DNA sequences coding for the small HBV envelope 
protein. These vaccines have gradually replaced the first generation plasma derived vaccines and 
are currently used for universal vaccination of newborns and adults at risk in >170 countries 
worldwide. Third generation HBV vaccines containing one or two additional HBV envelope 
proteins (Pre-S1 and Pre-S2) have been developed in Germany, France and Israel in transfected 
mammalian cells (Chinese Hamster Ovarian cells). These vaccines have in general an enhanced 
efficacy as compared to yeast derived vaccines 2,3,4 
1.2 
SCI-B-VAC™ PRODUCT DESCRIPTION  
Sci-B-Vac™ is a recombinant hepatitis B vaccine, manufactured by SciVac Israel Ltd. It is 
produced in mammalian Chinese hamster ovary (CHO) cells, transfected with appropriate 
sequences that code for the HBV envelope proteins SHBs-S, MHBs-pre-S2, and LHBs-pre-S1. The 
gene coding for these antigens, including the native HBs promoter, enhancer, and poly a signal, was  
*World health organization, Hepatitis B, Fact sheet N°204 Updated July 2014 

 
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cloned into a plasmid vector containing the mouse dihydrofolate reductase (DHFR) expression 
cassette. The plasmid was used to establish the producer CHO cell line. Transfected cells were 
selected for DHFR+ phenotype, and gene co-amplification was done with methotrexate. The 
immunogenicity of the pre-S2 and pre-S1 antigens in the final vaccine preparation was 
demonstrated in BALB/c mice and rabbits, as well as in babies who developed appropriate anti-pre-
S1 and anti-pre-S2 antibodies following immunization with Sci-B-VacTM 5,6,7. The physical 
properties of the HBV envelope particles produced in CHO cells and the immune response to HBV 
nucleocapsid and Pre-S/S envelope proteins have been characterized5,8-13.  
Sci-B-VacTM is approved by Health Authorities for marketing in 13 countries including Israel, 
Central Africa, Ivory Coast, Georgia, Gabon, Guinea Equtorial, Hong Kong, Moldova, Niger, 
Nigeria, Philippines, Senegal and Vietnam. 
Since 2005, more than 1.5 million units of Sci-B-VacTM have been sold in Israel for vaccination 
against Hepatitis B in babies, children and adults. 
1.3 
SUMMARY OF CLINICAL STUDIES 
To date, thirteen open label clinical studies (plus three extensions ) and 4 single blinded clinical studies 
utilizing Sci-B-VacTM  (also distributed under the trade names Bio-Hep B and Hepimmune) have been 
completed16-28.  
The clinical development of Sci-B-VacTM  included: two phase I studies in adults 16,17, three phase II 
dose-range studies in adults 16-18 one in children 19 and four in neonates  20-23, two phase II and one 
phase III comparative studies in adults 24-26, one Phase II study in children27 and one Phase II study in 
neonates28.  Three of the studies (one in adults and two in children) were extended in order to increase 
the size of the group vaccinated with Sci-B-VacTM.  In the adult phase I studies, subjects received 10 
g of Sci-B-VacTM.  Sci-B-VacTM  was given once to prime the immune memory; the first dose was 
followed by two booster doses at 1 and 6 months after primary immunization16. This immunization 
schedule is set by convention. In the first adult Phase II study in Singapore16, subjects were randomized 
to receive 5 g or 10 g of Sci-B-VacTM  in three injections.  Once tolerability/safety and dose-
dependent efficacy were demonstrated, the clinical development of two more adult dose-range studies 
were performed in Thailand and Israel 17,18,followed by a dose-range study performed in Poland with 
children19 and four neonate studies in Poland, Singapore and Vietnam20-23. After seroconversion rates 
and the efficacy/dose relationship were more firmly established, five comparative studies which 
assessed the efficacy of Sci-B-VacTM relative to that of conventional yeast derived vaccines were 
performed in adults, children and neonates24-28. 
From the early phase II studies it became evident that a significant number of vaccinees develop 
high anti-HBs titers following vaccination. In study HBN014-0123, conducted in Vietnam, a dose-
response relationship could be demonstrated. More vaccinees who received the 5 µg dose/injection 
had anti-HBs titers ranging from 1001-10,000 mIU/ml as compared to those who received the 2.5 
µg dose/injection. More than 60% of the vaccinees in the 5 µg dose group developed these high 
titers within three months after the third vaccination. At the end of the study 95.6% (196/205) of the 
subjects were seroprotected. 
The high efficacy of Sci-B-VacTM  was further confirmed in adults25,26 and in  neonates28. In these 
comparative controlled studies conducted in Israel, more than 50% of adult vaccinees who received 
the 10 µg/dose and neonates who received the 2.5 µg dose had anti-HBs titers above 10,000 
mIU/ml after the third vaccination. These percentages were greater than those observed in vaccinees 
who received the yeast-derived vaccines. Furthermore, no non-responders were observed in 

 
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immunized neonates who received 2.5 µg Sci-B-Vac™. In adults, the number of non-responders 
who received Sci-B-VacTM was very small (3.5%, 18/513) as compared to vaccinees immunized 
with Engerix-B® (13.7%, 43/415). 
1.4 
STUDY RATIONALE 
Each Sci-B-VacTM lot released to the market is tested in comparison to a reference batch, which has 
to be tested in a human clinical trial. Therefore, SciVac Ltd. is conducting this study to evaluate the 
efficacy of a Sci-B-Vac™ batch in support of its qualification as new reference standard. In 
accordance with the European Pharmacopeia (Ph.Eur. 1056), this reference standard is to elicited at 
least 95% seroprotection in young, healthy subjects. 
 
2 
STUDY OBJECTIVES  
2.1 
PRIMARY OBJECTIVE 
To validate the new in-house reference standard vaccine for routine quality control purposes, in 
compliance with the European Pharmacopeia and the Israeli Ministry of Health. 
2.2 
SECONDARY OBJECTIVES 
1. To characterize the immunological response throughout the study. 
2. To monitor the subjects for safety throughout the study period 
2.3 
EXPLORATORY OBJECTIVES  
1. To collect blood samples for the in vitro validation of anti-HBs, anti-preS1 and anti-preS2 
antibodies assays. 
2. To assess the anti-preS1 and anti-preS2 antibodies responses upon vaccination.  
3. To investigate additional protective mechanisms of action and the type of immune response 
triggered by the vaccination.  No genetic tests will be performed. 
3 
STUDY ENDPOINTS 
3.1 
PRIMARY ENDPOINT 
Seroprotection rate (SPR), defined as the proportion of subjects with anti-HBs antibody titer at least 
equal to 10mIU/ml, at Month 7 (i.e. one month after the third immunization with Sci-B-Vac™). 
Subjects early terminated from the study for any reason at any time while having an anti-HBs 
antibody concentrations ≥ 10mIU/ml will be considered among those who met endpoint. 
3.2 
SECONDARY ENDPOINTS 
1. SPR one month after the first injection and at every month until Month 6 inclusive and 
at months 9 and 12.  
2. Percentage of subjects with anti-HBs antibodies titer ≥ 100mIU/ml at Month 0, and then 
at every month until Month 7 inclusive and at months 9 and 12.  

 
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3. The geometric mean concentration (GMC) as determined by anti-HBsAg antibody titers 
at Month 0, then at every month until Month 7 inclusive and at months 9 and 12. 
3.3 
EXPLORATORY ENDPOINTS  
1. The anti-preS1 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12. 
2. The anti-preS2 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12.  
 
4 
STUDY DESIGN 
4.1 
OVERALL STUDY DESIGN 
This will be a post-marketing, open-label, single arm study in healthy volunteers who had never 
been vaccinated with any hepatitis B vaccine and who are HBs antigen, anti-HBc and anti-HBsAg 
antibodies seronegative. 
The study assessments will be performed as described in the study flow chart (See Appendix A). 
This study will consist of three periods:  
Screening Period (Visit 1: up to 1 month prior to first vaccination) 
After signing of the informed consent form (ICF), screening procedures will be carried out as 
specified in Section 6.1.1 and Appendix A.  
Treatment and Follow-up Period (Visits 2-8: Months 0-6) 
Subject identification number will be assigned to all eligible subjects following assessment of 
inclusion and exclusion criteria. 
All eligible subjects will receive Sci-B-VacTM vaccine.  The treatment phase will include three I.M. 
doses of Sci-B-VacTM administered in the deltoid muscle on Month 0, Month 1, and Month 6. 
Subjects will be followed up for safety evaluations and for efficacy (by anti-HBs, anti-pre-S1 and 
anti-pre-S2 testing), every month. The previous injection site will be inspected before the second 
and third administration. 
The following assessments will be performed during each treatment visit: recording of AEs and 
concomitant medications, vital signs and blood tests for quantitative anti-HBs, anti-preS1 and anti-
preS2 antibodies and safety assessment (including blood and urine laboratory tests). Female 
subjects will also undergo a urine pregnancy before each injection. Vital signs are not required on 
follow-up visits when vaccine is not administered.  
Post-Vaccination Follow-up Period (Visits 9-11: Months 7, 9 and 12) 
Additional subject follow- up visits will take place 1, 3 and 6 months after the last vaccine 
administration. On each visit, subjects will be inquired about AEs and concomitant medications, 
and blood samples for quantitative anti-HBs, anti-preS1 and anti-preS2 antibodies levels will be 
drawn. The last visit (Month 12) is a study termination visit in which all subjects will also undergo 
physical examination, laboratory safety assessments (CBC, blood chemistry and urinalysis), vital 

 
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signs measurement and a 12-lead ECG. In addition, female subjects will undergo a urine pregnancy 
test. 
 
5 
SELECTION OF STUDY POPULATION 
5.1 
NUMBER OF SUBJECTS 
Up to eighty four (84) healthy subjects will be enrolled in the study 
5.2 
INCLUSION CRITERIA 
1. 
Healthy males and females between 20 and 40 (inclusive) years of age. 
2. 
Subjects who provide written informed consent to participate in the study. 
3. 
Subjects in general good health in the opinion of the investigator as determined by medical 
history, vital signs and a physical examination. 
4. 
No clinically significant abnormalities in hematology, blood chemistry, or urinalysis lab 
tests at screening.  
5. 
Women of child-bearing potential must practice an acceptable method of birth control  (as 
specified in Section 8.2) or practice abstinence during the study period or be surgically 
sterilized, from screening visit throughout the treatment phase and for 28 days after the last 
injection and agree to undergo repeated pregnancy tests. 
6. 
Subjects must be able to understand the requirements of the study and must be willing 
to comply with the requirements of the study. 
5.3 
EXCLUSION CRITERIA 
1. 
Known history of significant medical disorder, which in the investigator’s judgment 
contraindicates administration of the vaccine or may interfere with the subject's 
compliance or the interpretation of study assessment parameters. 
2. 
Any clinically significant abnormality upon physical examination or in the clinical 
laboratory tests at screening visit. 
3. 
Treatment with immune suppressive agents. 
4. 
Chronic administration (defined as more than 14 days) of immunosuppressants or other 
immune-modifying drugs within six months prior to the first vaccine dose. 
5. 
History of HBV infection or confirmed exposure to hepatitis B virus.  
6. 
Previous vaccination against Hepatitis B. 
7. 
Positive for HBsAg, anti-HBsAg antibodies, anti-HBc antibodies, anti-HCV antibodies or 
anti- HIV antibodies.  
8. 
Drug abusers 
9. 
Known hypersensitivity or allergy to any component of the study vaccine. 
10. BMI < 18.5 or ≥ 30 Kg/m2. 
11. Known concomitant disease or any other medical condition that is considered by the 
investigator likely to interfere with the subject's compliance or the interpretation of study 
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12. Any acute illness (e.g. acute infection) within 48 hours prior to the first study drug 
administration that is considered of significance by the Principal Investigator. 
13. Female subjects: pregnant, lactating or planning a pregnancy. 
14. Any confirmed or suspected immunosuppressive or immunodeficient condition. 
15. Receipt of blood or immunoglobulin transfusion six months prior to the first vaccine dose 
and during the course of the trial.  
16. Unwilling or unable (in the judgment of the investigator) to comply with all the 
requirements of the protocol. 
17. Participate in another clinical trial within 3 months prior to first vaccination (calculated 
from the previous study's last dosing date). 
5.4 
SUBJECT IDENTIFICATION 
Each subject who signed the informed consent will be identified by a unique CRC internal 
identification number and a screening number that will be a unique identifier of the subject through 
the study. The screening number will include the letter "S", the site number and a sequential 
chronological order per site of three digits. 
Subjects who are dosed will be assigned a recruitment number which will include the letter "R", the 
site number and a sequential chronological order per site of three digits. 
5.5 
SCREENING FAILURES 
Subjects who fail to meet the entrance criteria at any stage during the screening period are defined 
as screen failures. All screen failures will be documented on the screening log, which documents 
the screening number, subject’s initials and reason(s) for screen failure. The screening log will be 
kept in the Investigators Site File.  
Screen failure subjects will be withdrawn from the study and will not count towards the total 
enrolled or total eligible subjects. 
5.6 
REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF SUBJECTS FROM TREATMENT 
OR ASSESSMENT 
Subjects are free to discontinue their participation in the study at any time and without prejudice to 
further treatment. The Investigator must withdraw any subject from the study if that subject requests 
to be withdrawn, or if the subject present positive serological marker of hepatitis B infection, or it is 
determined that continuing in the study would result in a significant safety risk to the subject.   
Subjects discontinued or withdrawn from the study will not be replaced after first dosing. If 
insufficient number of subjects are expected to complete the study, recruitment of additional 
volunteers will be considered. Approval by the IRB will be required.  
The subject's participation in this study may be discontinued due to the following reasons: 
• Positive serological marker for hepatitis B infection  
• Request of regulatory agency, or Sponsor or Principal Investigator 
• Subject withdrew consent 
• Adverse event (AE) 
• Subject is unwilling or unable to continue the study or is lost-to-follow-up 

 
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• Subject is non-compliant with study procedures/study protocol 
• Investigator decides that withdrawal from the study is in the best interest of the subject 
• Subject needs medication not allowed in the protocol 
• Any clinically significant change in subject’s medical condition. 
5.7 
HANDLING OF WITHDRAWALS 
If a subject is withdrawn from the study or fails to return either at his/her request or at the 
Investigator’s discretion, every effort should be made to determine the reason. This information will 
be recorded on the subject’s case report form (CRF). All subjects who withdraw from the study 
prematurely, regardless of cause, should undergo all study termination assessments (see Section 
6.1.11).  It is crucial  to obtain follow-up data for any subject withdrawn because of an AE or 
abnormal laboratory test finding.  In any case, every effort must be made to undertake safety 
follow-up procedures. 
If withdrawal is caused by a Suspected Unexpected Serious Adverse Reaction (SUSAR), it will be 
reported to the institutional review board/independent ethics committee (IRB/IEC) and Sponsor. 
5.8 
TERMINATION OF STUDY BY SPONSOR 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such reasons 
may be any of, but not limited to, the following:  
▪ Occurrence of AEs unknown to date in respect of their nature, severity, and duration or the 
unexpected incidence of known AEs  
▪ Medical or ethical reasons affecting the continued performance of the study 
Regulatory Authorities also have the right to terminate the study for any reason. 
5.9 
TERMINATION OF STUDY  
A subject will be considered to have completed the study if he or she has completed all assessments 
at Month 12 of the study. 
 
6 
STUDY PROCEDURES AND SCHEDULES  
The schedule of activities for this study is shown in Appendix A. No protocol-related procedures 
should be performed before subjects provide written informed consent. Study related events and 
activities including specific instructions, procedures, concomitant medications, dispensing of study 
drugs, and descriptions of AEs should be recorded in the appropriate source documents and CRF.  
6.1 
VISIT SCHEDULES  
6.1.1 
Visit 1 - Screening (within 4 weeks before Visit 2)  
Subjects will sign an informed consent form and will be assessed for their eligibility to participate 
in the study.  
The following screening assessments will be performed at pre-study for each subject: 

 
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• Medical history (including concomitant medications)   
• Demographics (gender, date of birth) 
• Vital signs: blood pressure  and heart rate - sitting, respiration rate (RR), oral body 
temperature 
• Height 
• Weight 
• BMI (calculated as kg/m2) 
• Physical examination 
• 12-lead ECG 
• Laboratory safety screens as outlined in Appendix B  
• For female subjects serum HCG 
• Serology tests as outlined in Appendix A 
• Compliance with inclusion/exclusion criteria 
The amount of blood drawn in this visit is approximately 26 ml. 
6.1.2 
Visit 2 - First Vaccine Administration:  Month-0 (Day 1)  
Dosing day will be designated "Month 0, Day 1". 
The subjects will be admitted to the CRC in the morning of treatment. They will be interviewed by 
the CRC study personnel regarding change in concomitant medications or changes to their health 
status since the Screening visit. Female subjects will undergo a urine pregnancy test, and eligibility 
of inclusion/exclusion criteria will be reviewed.  
Prior to dosing (within 60 min before vaccination), the following activities will be completed:  
• Vital signs, measured following 3 min rest (sitting BP, HR, RR and oral temperature); 
• A blood sample for serology,  safety laboratory testing and for further investigational 
purposes ( 55 ml) will be drawn. 
• Urine sample will be collected for safety testing. 
Vaccine administration: Each subject will receive the injection as described in Section 7.3. The 
time, date of vaccination and side of injection (i.e. left or right arm) will be documented in the 
CRFs and on the CRC Drug Administration Records.  
After vaccination: Subjects remain in the CRC for approximately 1 hour after injection. Vital signs 
(sitting BP, HR, respiratory rate, and oral body temperature) will be measured at 60 (± 15) minutes 
after treatment, and recorded as appropriate.  
Before discharge from the CRC a study physician will examine the injection site using a grading 
score (Appendix C). 
The subjects will then be released from the CRC following a study physician's approval. 
6.1.3 
Visit 3 - Second Vaccine Administration:  Month 1, (Week 4± 3 days) 

 
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The second vaccination will take place 28 (±3) days after the first vaccination (Visit 2). The 
previous injection site will be inspected before the second administration. Procedures will be 
identical to Visit 2,. except the volume of blood drawn for serology, safety laboratory testing and 
for further investigational purposes, which will be lower (40 ml). 
 
6.1.4 
Visit 4 – Follow-up: Month 2 (Week 8± 3 days) 
Subjects will arrive in the CRC and will be will be interviewed by the CRC study personnel 
regarding change in concomitant medications or changes to their health status since the last visit. 
Blood samples for serology and for exploratory purposes (35 mL) will be drawn and the subject will 
be released from the CRC. 
6.1.5 
Visit 5 – Follow-up: Month 3 (Week 12± 3 days) 
Procedures will be identical to Visit 4. 
6.1.6 
Visit 6 – Follow-up: Month 4 (Week 16± 3 days) 
Procedures will be identical to Visit 4. 
6.1.7 
Visit 7 – Follow-up: Month 5 (Week 20± 3 days) 
Procedures will be identical to Visit 4. 
6.1.8 
Visit 8 - Third Vaccine Administration:  Month 6, (Week 24± 3 days) 
The third (last) vaccination will take place 5 months after the second vaccination (Visit 3). The 
previous injection site will be inspected before the third administration. Procedures will be identical 
to Visit 2, except the volume of blood drawn for serology, safety laboratory testing and for further 
investigational purposes, which will be lower (35 ml).  
6.1.9 
Visit 9 – Follow-up: Month 7 (Week 28± 3 days) 
Subjects will arrive in the CRC and will be will be interviewed by the CRC study personnel 
regarding change in concomitant medications or changes to their health status since the last visit. 
Blood samples (50 ml) for serology and for further investigational purposes will be drawn and the 
subject will be released from the CRC. 
6.1.10 Visit 10 – Follow-up: Month 9 (Week 36± 8 days) 
Procedures will be identical to Visit 9. 
6.1.11 Visit 11 – Study Termination: Month 12 (Week 48± 8 days) 
The following assessments will be performed: 
• Physical examination 
• Vital signs: (sitting BP, HR, RR, oral temperature)  
• 12-lead ECG 
• Laboratory safety tests (See Appendix B) 
• Serology tests  

 
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• Blood samples for additional investigational purposes 
• AE and concomitant medication recording 
The amount of blood drawn in this visit is approximately 28 ml 
The total amount of blood drawn for serology and routine safety laboratory tests will be about 424 
ml over a period of 13 months.  
6.2 
UNSCHEDULED VISIT 
An unscheduled visit may be performed at any time during the study at the subject's request or as 
deemed necessary by the Investigator due to medical considerations. The date and reason for the 
unscheduled visit will be recorded. AE monitoring and concomitant medication recording will be 
performed by the Investigator. Other procedures and evaluations will be completed as deemed 
necessary by the Investigator and may include (but not limited to) safety laboratory tests, ECG, vital 
signs and physical examination. 
6.3 
BLOOD SAMPLING FOR IMMUNOGENICITY  
6.3.1 
Serology Tests 
The immunogenicity of the vaccine will be assessed by the anti-HBsAg, anti-preS1 and anti-preS2 
antibody levels at each visit, from visit 2 till visit 11, as presented in Appendix A. 
6.3.2 
Blood Sampling and Processing. 
Processing and storage of the samples are detailed in the lab manual provided by the Sponsor. 
6.3.3 
Shipment of Samples to the Bioanalytical Laboratory 
Samples will be shipped in a cold pack to the central laboratory on the same day it is drawn from 
the subject, as detailed in the lab manual provided by the Sponsor.  
6.4 
SAFETY ASSESSMENTS 
Safety assessments will be based on AEs reported by the subject or observed by the Investigator, 
concomitant medication use, clinically significant changes from baseline of vital signs, ECG, 
physical examination, and safety laboratory tests (hematology, chemistry, and urinalysis). 
6.4.1 
Adverse Events (AEs) 
AEs will be recorded continuously starting from the signing of the ICF through the Study 
Termination visit, in those subjects who have been actually dosed.  
AEs reported prior to dosing will be recorded in the CRF and considered non-treatment emergent 
AEs. Any new systemic effect that occurs between scheduled visits should be brought to the 
attention of the Investigator and recorded in the subject’s medical file and in the CRF. 
The systemic symptoms will be graded according to the FDA Guidance to Industry29 (see grading 
scale in Appendix C Table 3). 
 

 
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6.4.2 
Local reaction at injection site 
Local reaction at injection site, based on the FDA Guidance to Industry29 (see grading scale in 
Appendix C Table 1) will be assessed by a study physician on treatment visits.  
6.4.3 
Vital Signs 
Vital signs (sitting systolic and diastolic blood pressure, heart rate, respiratory rate and oral 
temperature) will be measured after at least 3 minutes rest as per standard practice at the 
investigational site at the following time points:  
- 
On screening,  
- 
On each treatment visits (Visits 2, 3 and 8): within 60 minutes before vaccination, 60 (± 15) 
minutes after vaccination. 
- 
On Study Termination visit 
Changes in vital signs determined by the Investigator to be clinically significant will be noted as an 
AE on the appropriate CRF and in the subject’s file. Such abnormalities will be closely monitored 
until stabilized or resolved.  
Vital Signs will be graded according to the FDA Guidance to Industry29 (see grading scale in 
Appendix C Table 2). 
6.4.4 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed at the following time points:   
- On screening,  
- On Study Termination visit  
6.4.5 
Physical Examination 
Complete physical examination will be performed at the following time points: 
- 
On screening,  
- 
On Study Termination visit 
Significant changes from baseline examination on screening will be recorded as AEs in the CRF 
and in the subject’s file.  
6.4.6 
Safety Laboratory Tests 
Safety laboratory tests including biochemistry, hematology and urinalysis (see details in Appendix 
B) will be performed at the following times:  
- On screening;  
- On each treatment visits (Visits 2, 3 and 8): within 60 minutes before vaccination 
- On Study Termination visit (without the screening serology tests) 
All safety (chemistry, hematology urinalysis, serology and urine tests will be carried out by AML 
Laboratories, except urine test for pregnancy which will be performed at the trial site by the CRC 
staff.  

 
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Clinically significant laboratory tests or tests of unknown significance which are outside the normal 
range may be repeated as clinically indicated until the values return to normal, or until the etiology 
has been determined and the condition considered stable. Abnormal laboratory test results that are 
considered to be clinically significant by the investigator will be reported as an AE in the CRF. 
 
7 
INVESTIGATIONAL PRODUCT 
7.1 
DESCRIPTION OF INVESTIGATIONAL PRODUCT 
Sci-B-VacTM is a recombinant Hepatitis B vaccine, produced by SciVac Israel Ltd. It contains the 3 
surface antigens of the HBV: HBs, preS1 and preS2 antigens. Each 1ml dose contains sterile 10µg 
HBs antigen. It is formulated for intramuscular injection supplied in a single use vials containing 1 
ml suspension. The components of the investigational vaccine are produced under aseptic 
conditions and according to the rules of current Good Manufacturing Practice and guidelines 
applicable to IMPs (investigational medicinal products). The vaccine lot used in this trial will be 
tested and released by the Quality Assurance Department of the Sponsor. 
7.2 
PACKAGING AND LABELLING OF INVESTIGATIONAL PRODUCT 
All clinical supplies will be provided from the designated commercial batch packed and labeled in 
compliance with the Good Manufacturing Practices of drugs used in clinical trials and with the 
Israeli Ministry of Health Guidelines for Clinical Trials in Human Subjects. All study vaccines 
provided will be appropriately documented. 
7.3 
STUDY DRUG ADMINISTRATION 
7.3.1 
Vaccination Regimen:  
One ml of a single Sci-B-VacTM Vaccine vial  (i.e. 10 μg) will be administered intramuscularly in 
the deltoid area of the arm, on Month 0, 1 and 6, according to common immunization practice. 
7.3.2  
Preparation of the Vaccine. 
Prepare vaccine just prior to administration. Agitate the vial to mix the vaccine thoroughly and 
obtain a uniform suspension prior to withdrawing each dose. Whenever solution and container 
permit, inspect the vaccine visually for discoloration, precipitation or if it cannot be re-suspended 
prior to administration. If problems are noted (e.g., vaccine cannot be re-suspended), the vaccine 
should not be administered. 
A separate vial should be used for each subject. 
7.3.3  
Administration of the Vaccine. 
The vaccine should be administered while wearing gloves. Once loaded  into the syringe with a 22–
25 gauge needle, the vaccine should be administered to the subjects immediately.  
 

 
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Vaccine administration information including date, time and side of the injection (i.e. left or right 
arm) will be documented in the Case Report Forms and on the Drug Administration Records. 
7.4 
SHIPMENT OF INVESTIGATIONAL PRODUCT 
Prior to study start, study medications will be supplied to the CRC by the Sponsor. It is the 
responsibility of the Sponsor to ensure the vaccine is kept at 2-8C during the shipment. 
The Sponsor must notify the Investigator/study staff prior to dispatch of drug supplies, with the 
anticipated date of their arrival, addressed to: 
Clinical Trials Unit 
TASMC Pharmacy 
Tel-Aviv Sourasky Medical Center 
6 Weizmann Street,  
Tel-Aviv 64239, Israel 
Shipment of study drug supplies for the study will be accompanied by a shipment form describing 
the contents of the shipment drug information, acknowledgement of receipt and other appropriate 
documentation. The shipment form will assist in maintaining current and accurate inventory 
records.  
7.5 
RECEIPT AND STORAGE OF INVESTIGATIONAL PRODUCT 
All study supplies should arrive at the Pharmacy in sufficient quantity and in time to enable dosing 
as scheduled.   
The investigational product will be accompanied by a shipment form and appropriate 
documentation.   
Vaccines will be stored at the hospital pharmacy in an appropriate locked room until dosing, 
refrigerated at an average temperature between 2ºC to 8ºC. During the storage at the pharmacy, the 
temperature of the refrigerator will be monitored continuously and recorded by a pharmacist or 
another member of study staff who will record refrigerator temperature log. The Sponsor should be 
notified for any deviation from the storage conditions. Vaccine vials should never be exposed to 
freezing temperatures. 
The Investigator will issue a prescription, and the vaccines will be picked up from the pharmacy 
before administration. The time at which the vaccine exits the pharmacy will be recorded. The 
vaccines will be transferred from the pharmacy to the CRC in a closed icebox without ice, 
according to the Sponsor’s instructions, and time limitation until vaccine administration will be 
provided based on stability prior to first dosing. The icebox will be provided by the Sponsor 
7.6 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCT 
The TASMC pharmacy will be responsible for recording the receipt of all drug supplies and for 
ensuring the supervision of the storage and allocation of these supplies. When a shipment is 
received, the pharmacist verifies the quantities received and the accompanying documentation and 
returns the acknowledgment of receipt to the Sponsor.   
Drug administration will be recorded in the source documents, in the CRFs and in the Drug 
Administration Record form. The latter includes the subject identification, quantity (volume) and 

 
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date of administration. The containers from which the drug was administered to the subjects will be 
retained for dose confirmation. 
At the end of the study, delivery records of study drug will be reconciled with used / unused stocks 
and appropriate forms will be filled in, to verify that all used, unused or partially used supplies have 
been returned and that no study supplies remain in the Investigator’s possession.  
All unused drug supplies, partially used and empty containers will be returned to the Sponsor or 
disposed of according to the Sponsor's instructions. 
 
8 STUDY RESTRICTIONS 
8.1 
CONCOMITANT MEDICATIONS 
The following medications are prohibited for use by the subject throughout the study: 
• Systemic corticosteroid treatment less than 14 days before first vaccination and throughout 
the study. 
• Immunosuppressant medications (e.g. mycofenolate mofetil, cyclosporine, 
cyclophosphamide etc.) 
• Biological immune-modifying agents (e.g. anti TNF alfa, anti CD20)  
8.2 
ADDITIONAL RESTRICTIONS 
Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-
HCG) test on screening (and negative consecutive urine tests during the study) and be willing and 
able to use an acceptable method of birth control (acceptable methods of birth control include: 
intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive or 
double-barrier method - condom or diaphragm with spermicide) from the screening visit through 
the EOS visit, or declare that they are abstaining from sexual intercourse, or be surgically sterile 
(bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or post-menopausal. 
 
9 
SAFETY AND PHARMACOVIGILANCE 
9.1 
ADVERSE EVENT DEFINITION 
An AE is defined as “Adverse event means any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related”. 
An AE (also referred to as an adverse experience) can therefore be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a drug, without any judgment about causality or seriousness. An adverse event can arise from any 
use of the drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
An abnormal result of diagnostic procedures including abnormal laboratory findings will be 
considered an AE if it fulfills one or more of the following:  

 
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• 
Results in subject's withdrawal by the Investigator 
• 
Is associated with a serious adverse event (SAE) 
• 
Is associated with clinical signs or symptoms 
• 
Is considered by the physician to be of clinical significance (a laboratory abnormality that is 
not clinically significant will not be considered an AE) 
A new condition or the worsening of a pre-existing condition will be considered an AE.  
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Suspected adverse reaction is “any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event.”  
AEs do not include the following: 
• 
Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to  study entry and recorded in the subject's file and do not worsen during the 
study 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion). The 
condition that leads to the procedure is an AE if not present at baseline 
• 
Overdose of either study drug or concomitant medication without any signs or symptoms 
unless the subject is hospitalized for observation 
• 
Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred) 
• 
Pregnancy alone is not considered an AE. Elective abortions without complications should 
not be handled as AEs.  
All AEs, whether observed by the Investigator or designee or volunteered by or elicited from the 
subject, should be recorded individually in the CRF. AEs will be recorded from the time a subject 
has signed the ICF and throughout the study, including the follow up period, in those subjects who 
have been dosed at least once.  
Severity of the AE will be assessed by the investigating physician in accordance with the definitions 
in Appendix C. An SAE must fulfill the requirements listed in the Section 9.2. 
The Investigator will document in his/her opinion the relationship of the AE to the study drug using 
the criteria outlined in definition of adverse events relationship to study drug (Table 1).  
 
 
 
 
 
 
 
 

 
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Table 1: Definition of adverse events relationship to study drug 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated In general, this category can 
be considered applicable to 
those adverse events, which 
after 
careful 
medical 
consideration at the time they 
are evaluated, are judged to 
be unrelated to the test drug. 
An adverse experience may be considered unlikely 
related if or when (must have two): 
• It does not follow a reasonable temporal 
sequence from the administration of the test 
drug. 
• It could readily have been produced by the 
subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered 
to the subject. 
• It does not follow a known pattern of response 
to the test drug.   
• It does not reappear or worsen when the drug is 
re-administered. 
Possibly 
Related 
This category applies to those 
adverse events for which, 
after 
careful 
medical 
consideration at the time they 
are evaluated, a connection 
with 
the 
test 
drug 
administration 
appears 
unlikely but cannot be ruled 
out with certainty. 
An adverse experience may be considered possibly 
related if or when (at least two of the following): 
• It follows a reasonable temporal sequence from 
administration of the drug. 
• It could not readily have been produced by the 
subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered 
to the subject. 
• It follows a known pattern of response to the test 
drug. 
Probably 
Related 
This category applies to those 
adverse events which, after 
careful medical consideration 
at the time they are evaluated, 
are felt with a high degree of 
certainty to be related to the 
test drug. 
An adverse experience may be considered probably 
related if or when (at least three of the following): 
• It follows a reasonable temporal sequence from 
administration of the drug. 
• It could not be reasonably explained by the 
known characteristics of the subject’s clinical 
state, environmental or toxic factors or other 
modes of therapy administered to the subject. 
• It disappears or decreases on cessation or 
reduction in dose. There are important 
exceptions when an adverse event does not 
disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists. 
• It follows a known pattern of response to the test 
drug. 
Outcomes to Date are classified as follows: 
• Recovered – The subject has fully recovered from the adverse event with no residual 
effects observable 
• Recovered with sequelae – The subject has recovered from the adverse event with 
residual effects observable 

 
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• Recovering – the subject status improved but has been recovered 
• Ongoing – AE is not recovered 
• Fatal 
• Unknown 
AEs will be coded by Data Management using the using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
9.2 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any AE occurring at any dose that suggest a significant hazard or side effect, regardless 
of the Investigator or Sponsor's opinion on the relationship to the investigational product and that 
results in, but may not be limited to, any of the following outcomes: 
• death (regardless of the cause) 
• a life-threatening adverse event or suspected adverse reaction  
• inpatient hospitalization or prolongation of existing hospitalization (any inpatient 
hospital admission that includes a minimum of an overnight stay in a health care facility) 
• a persistent or significant disability/incapacity or a substantial disruption of the ability to 
conduct normal life functions 
• a congenital anomaly or birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, or that 
they occurred as a consequence of the event. 
Hospitalization for elective treatment of a pre-study condition that did not worsen while on study 
and optional hospitalizations not associated with a clinical adverse event (e.g., elective cosmetic 
surgery) are not considered SAEs.  
Significant medical events are those which may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
resulting in an AE will normally be considered serious by this criterion. 
A life-threatening adverse drug experience is any adverse event that places the subject, in the view 
of the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death.  
9.3 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT 
An unexpected adverse event is any adverse event, the specificity or severity of which is not 
consistent with information in the clinical protocol or current Investigator’s Brochure for an 

 
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unapproved investigational product or package insert/summary of product characteristics for an 
approved product (package inserts are available separately at the participating center). 
Suspected Unexpected Serious Adverse Reaction (SUSAR) is a serious adverse reaction assessed 
as unexpected by the Sponsor and that is judged by either the reporting investigator or the Sponsor 
to have a reasonable causal relationship to a medical product. 
9.4 
NOTIFICATION OF SERIOUS OR UNEXPECTED ADVERSE EVENT 
Per FDA new safety reporting requirements (US Department of Health and Human Services 
September 2010)30 a sponsor must continue to “promptly” review all safety information obtained 
from foreign or domestic sources.  However, the sources of information listed in the regulation has 
expanded to include “any clinical or epidemiological investigations, animal or in vitro studies, 
reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign 
regulatory authorities and reports of foreign commercial marketing experience for drugs that are not 
marketed in the United States. 
If the Investigator identifies an SAE or Unexpected AE, an SAE report form must be completed and 
sent within 24 hours of the Investigator’s knowledge of the event to the sponsor. The names (and 
corresponding telephone numbers) of the individuals who should be contacted regarding safety 
issues or questions regarding the study are listed on the Contact Information page(s), which will be 
provided as a separate document. 
These preliminary reports will be followed within 24 hours by more detailed descriptions that will 
include a completed SAE form, copies of hospital case reports (i.e., hospital progress notes, results 
of applicable diagnostic tests, lab results and biopsy results), autopsy reports, and other documents, 
when requested and applicable.   
For regulatory purposes, initial SAE reports submitted to SciVac immediately and should include: 
a) a suspected investigational medicinal product 
b)  an identifiable subject (e.g., study subject code number) 
c)  an adverse event with a seriousness and the Investigator’s assessment of the relationship to study 
drug 
d)  an identifiable reporting source (investigator contact details) 
Once faxed or emailed, the printed SAE form and accompanying documentation should be placed 
in the SAE section of the Investigator’s site file. 
In addition, all AEs/SAEs/SUSARs will be reported to the IRB/IEC and regulatory authorities as 
required by local regulations and ICH-GCP guidelines.  
Follow-up of SAEs/SUSARs  
Follow-up of SAEs/SUSARs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, it may be defined as “ongoing without further 
follow-up” by the Investigator and Sponsor’s decision. 
When supplementary information is available, a follow-up SAE Report Form must be completed by 
the site (marked as “follow-up report”) and reported as indicated above. 

 
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Information to include on SAE form 
The following information should be provided in the SAE form to accurately and completely 
record the event: 
Investigator name and site address 
Subject study identification number 
Subject’s initials 
Subject demographics (gender, date of birth or age, weight, height) 
Clinical Event: 
▪ Description 
▪ Date and time of onset, stop date, or duration  
▪ Severity 
▪ Treatment (including hospitalization) 
▪ Relationship to study drug (causality) 
▪ Action taken regarding study drug 
▪ Information on recovery and any sequelae 
▪ If the AE resulted in death 
- 
Cause of death (whether or not the death was related to study drug) 
- 
Autopsy findings (if available) 
▪ Medical History case report form (copy) 
▪ Concomitant Medication case report form (copy) 
▪ Any relevant reports (laboratory, discharge, etc.) 
Accompanying documentation, such as copies of hospital case reports, autopsy report, and other 
documents when applicable, should be sent as soon as they are available.   
Subsequent additional information (follow-up) about any SAE unavailable at the initial reporting 
should be forwarded by the site to the Sponsor representative and study monitor within 24 hours of 
the information becoming available.  
SAEs should also be reported to the IRB/IEC according to local regulations. 
Subjects who have had an SAE during the treatment period must be followed clinically until all 
parameters (including laboratory) have either returned to normal or have stabilized or are otherwise 
explained.  
Any newly emergent SAE after treatment is discontinued or the subject has completed the study 
and is considered to be related to the study drug or study participation should be recorded and 
reported immediately. The post-study period for the purpose of SAE reporting is up to 30 days 
following last visit of the study. 
Follow-up Reports for non-serious AEs 
All AEs, that do not meet any of the criteria for serious, should be regarded as non-SAEs. All AEs 
must be followed until resolution or stabilization and will be recorded on the Adverse Event Record 
in the CRF and if relevant, the Concomitant Medications Record in the CRF. Severity and 
relationship to study drug will be assigned by the Investigator as described in the section above.   

 
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9.5 
ANTICIPATED ADVERSE EVENTS 
Previous human experience and known adverse effects of the test product are detailed in the 
Product Information leaflet.  
 
10 
STATISTICAL METHODOLOGY 
A total of 84 subjects, are expected to be recruited into study. The trial will follow-up eligible 
subject for a total duration of 12 months. One interim analysis is planned to be conducted at the 
time when approximately 50% of the subjects will reach Month 7 or early terminated the study. 
10.1 
INTERIM AND FINAL ANALYSES 
One interim analysis is planned for possible early termination of the study.. The interim  analysis 
will be performed at the time when approximately 50% of the subjects will reach Month 7 (1 month 
after the 3rd vaccine) or early terminated the study.. 
10.2 
SIGNIFICANCE LEVEL 
The overall significance level for this study will be 5% using two-tailed tests. 
10.3 
SAMPLE SIZE RATIONALE  
Sample size determination was performed under the following assumptions: 
• 
The primary endpoint for the study is the Seroprotection Rate (SPR), defined as the proportion 
of subjects with anti-HBs antibody titer at least equal to 10mIU/ml, at Month 7 (i.e. one month 
after the third immunization with Sci-B-Vac™). Subjects early terminated from the study for 
any reason at any time while having an anti-HBs antibody concentrations ≥ 10mIU/ml will be 
considered among those who met endpoint. 
• 
It is expected that the true rate of SPR following treatment with Sci–B-Vac™ is 95% or more. 
• 
The principal analysis of the primary endpoint will be a non-inferiority analysis testing the 
below hypothesis: 
✓ H0: P-p0 <= -Margin  
✓ H1: P-p0 >   -Margin  
• 
Where p0, the assumed true SPR is 95% and the non-inferiority margin is 9.0%, employing that 
study will be considered successful if the lower bound of the 95.0% exact CI  will be 86.0% or 
more (lower non-inferiority limit). 
• 
The rational for sample size calculation is based on demonstrating an expected SPR rate of 
95%. The lower bound of a calculated 95% confidence interval (CI) using Exact binomial 
method ensures that the actual SPR rate will not exceed the calculated lower limit (will not be 
lower than the lower bound). 
• 
The sample size is adjusted to a total of 84 subjects to account for an anticipated withdrawal 
rate of approximately 20%.  
 

 
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Sample Size Justification: 
When the sample size is 70, a one-sided 95.0% confidence interval (CI) for a single proportion 
using Exact binomial method will demonstrate a lower bound of 86.0% or more for an expected 
proportion of 0.95. 
10.4 
ANALYSES SETS 
10.4.1 Modified Intent-to-Treat (mITT) Analysis Set  
The Modified Intent-to-Treat (mITT) analysis set is a subset of the ITT set. This set will consist of 
all enrolled subjects who were vaccinated at least once with Sci-B-Vac™ and had at least one post 
study IP administration follow-up visit. This analysis set will serve as the primary analysis set for 
efficacy and safety inference. 
10.4.2 
Full Treatment (FT) Analysis Set 
The Full Treatment (FT) analysis set is a subset of the mITT analysis set and will consist of all 
subjects who were vaccinated 3 times with Sci-B-Vac™ and had at least one visit following the 3rd 
vaccination.  
10.5 
SUBJECT DISPOSITION 
Data from subjects who are screened but not treated, subjects in the mITT, FT analysis sets, as well 
as study withdrawal data will be summarized using descriptive statistics. This summary will include 
all subjects screened into the study. The denominator for calculating the percentages will be the set 
of the mITT. 
10.6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic and baseline data as well as disease prognostic factors, medical history and prior 
medications will be summarized for the mITT analysis set using descriptive statistics. For 
continuous variables, descriptive statistics (number [n], mean, standard deviation (SD), standard 
error, median, minimum, and maximum) will be provided. For categorical variables, subject counts 
and percentages will be provided. Categories for missing data will be presented if necessary. 
Missing categories will be presented if necessary. 
10.7 
EFFICACY ENDPOINTS AND ANALYSES  
Analyses of primary and secondary efficacy endpoints will use the mITT Analysis Set including all 
enrolled subjects who were vaccinated at least once with Sci-B-Vac™ and had at least one post first 
Sci-B-Vac™ administration follow-up visit.  
10.7.1 Primary Endpoint Definition and Analysis  
The primary endpoint of the study is the Seroprotection rate (SPR), defined as the proportion of 
subjects with anti-HBs antibody titer at least equal to 10mIU/ml, at Month 7 (i.e. one month after 
the third immunization with Sci-B-Vac™). Subjects early terminated from the study for any reason 
at any time while having an anti-HBs antibody concentrations ≥ 10mIU/ml will be considered 
among those who met endpoint. 

 
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The principal analysis of the primary endpoint will employ a non-inferiority analysis [SAS PROC 
FREQ with binomial (noninf margin=0.09 p=(1-α) exact)] statement will be used for testing the 
below hypothesis: 
H0: P-p0 <= -Margin  
H1: P-p0 >   -Margin  
Where p0, the assumed true SPR is 95% and the non-inferiority margin is 9.0%, employing that 
study will be considered successful if the lower bound of the (1-α) exact CI will be 86.0% or more. 
10.7.2 Secondary Endpoints and Analyses  
The secondary endpoints for the study are: 
•  
SPR atone  month after the first injection and at  every month until Month 6 inclusive 
and at months 9 and 12. 
• Percentage of subjects with anti-HBs antibodies titer ≥ 100mIU/ml at Month 0, and then at 
every month until Month 7 inclusive and at months 9 and 12.  
•  
• The geometric mean concentration (GMC) as determined by anti-HBsAg antibody titers at 
Month 0, then at every month until Month 7 inclusive and at months 9 and 12.  
SPR at all time points as above defined will be analyzed using the principal analysis method as 
above defined. The geometric mean concentration (GMC) as determined by anti-HBsAg 
antibody titers at Month 0, then at every month until Month 7 inclusive and at months 9 and 12 
will be displayed across time in order to establish the kinetic of the immunological response 
during the study. 
10.7.3 Exploratory Endpoints and analyses  
The exploratory endpoints for the study are: 
• The anti-preS1 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12. 
• The anti-preS2 antibody titers measured at Month 0, then at every month until Month 7 
inclusive and at months 9 and 12. 
The geometric mean concentration (GMC) at Month 0, then at every month until Month 7 inclusive 
and at months 9 and 12 will be displayed across time in order to establish the kinetic of the 
immunological response during the study. 
10.8 
DESCRIPTIVE STATISTICS  
All measured variables and derived parameters will be listed individually and tabulated and 
descriptive statistics will be provided. For categorical variables summary tables will be provided 
displaying sample size, absolute and relative frequency and percentages. For continuous variables 
summary tables providing sample size, mean value or geometric means where appropriate, median, 
standard deviation (SD), standard error, minimum and maximum values. Summary statistics of 
Anti-HBs antibody concentrations and Anti-PreS1 and Anti-PreS2 antibodies concentrations will 
use geometric means due to the expected dispersion and skewness of the data. 
Descriptive statistics for each of the study endpoints will be provided for the mITT Analysis Set and 
for both mITT and FT analyses set for the primary endpoint only. 

 
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10.9 
SAFETY ASSESSMENTS  
10.9.1  Treatment Emergent Adverse Events  
Adverse events will be recorded from the time when a subject has signed the Informed Consent 
Form and throughout the study, including the follow-up period. The MedDRA dictionary will be 
used to standardize the terms used by the investigator to describe the Adverse Events. The 
following were incorporated into the analyses which will include only Treatment Emergent Adverse 
Events (TEAEs), namely, events that were started on the day of first study dose or afterwards. 
• 
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down by SOC 
and by SOC and Preferred Term according to MedDRA dictionary. 
• 
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down by events 
attributes.  
• 
The derived dictionary used in the analyses. 
• 
Listing of SAEs (regardless if started before or after first study dose) of randomized and dosed 
subjects captured in the clinical database until database drop date.  
• 
Listing of Non-Treatment Emergent AEs. 
10.9.2  Vital Signs  
Vital signs will be measured at each treatment visit including at unscheduled or early termination 
visits. Analyses of vital signs were performed in the following manner: 
• 
Box-Plots of vital signs before first study dose and afterwards by scheduled visit will be 
generated.  
• 
Descriptive statistics of vital signs before first study dose and afterwards as well as the changes 
from baseline by scheduled visit will be generated.  
• 
The incidence (no. of subjects) of potentially clinically significant (PCS) abnormal values will 
be summarized in a frequency table and will be listed. 
10.9.3 Laboratory Evaluations  
Analyses of safety laboratory data will be performed in the following manner: 
• 
Box-Plots of laboratory measurements first study dose and afterwards by scheduled visit will 
be provided.  
• 
Descriptive statistics of quantitative tests results and changes from baseline by scheduled visit. 
• 
Quantitative laboratory measurements will be categorized with reference to the normal ranges 
as Low, Normal or High. Shift analysis of the categorical change form baseline to each 
scheduled visit and to the last observed assessment will also be presented. 
• 
Incidence tables of PCS lab values as well as the individual subject listing will also be 
provided. 
 
 
 

 
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10.9.4 Other Safety Outcome Measures  
Summary statistics of other safety evaluations including assessment of local safety evaluations and 
pain evaluations will be tabulated and listed. Kaplan-Meier curves will be used to describe time to 
study withdrawal. 
10.10 
REPORTING DEVIATIONS FROM THE STATISTICAL PLAN  
Deviations from the statistical plan, along with the reasons for the deviations, will be described in 
protocol amendments, the clinical study report, or any combination of these, as appropriate. 
10.11 
STATISTICAL SOFTWARE   
Study accumulated data will be analyzed and summarized using the SAS® version 9.3(SAS 
Institute, Cary North Carolina) or higher. 
 
11 
ETHICS 
11.1 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE 
Prior to initiation of the study, the Investigator will submit the study protocol and amendments, 
sample ICF, and any other documents that may be requested to the IRB/IEC for review and 
approval.  The Investigator will request that the IRB/IEC provide written approval of the study and 
will keep on file records of approval of all documents pertaining to this study. The Investigator will 
not begin the study until the protocol and ICF have been approved by the IRB/IEC. The Investigator 
must agree to make any required progress reports to the IRB/IEC, as well as reports of SAEs, life-
threatening conditions, or death. 
11.2 
ETHICAL CONDUCT OF THE STUDY 
All clinical work conducted under this protocol is subject to GCP guidelines. This includes an 
inspection by Sponsor or its designee, health authority or IRB/IEC representatives at any time.  The 
Investigator must agree to the inspection of study-related records by health authority representatives 
and/or Sponsor or its designee.  
The study will be conducted in accordance with Sponsor’s standards operating procedures and the 
following guidelines: 
• GCP: Consolidated Guideline (International Conference on Harmonisation of Technical 
Requirements for the Registration of Pharmaceuticals for Human Use, May 1996). 
• Declaration of Helsinki: Seoul, 2008 
• Israeli Guidelines, Laws and Regulations for the conduct of clinical trials (2006) 
11.3 
SUBJECT INFORMATION AND CONSENT 
Prior to screening for the study each subject will be informed in detail about the study drugs to be 
administered, and the nature of the clinical investigation with its risks and discomforts to be 
expected. The basic elements of informed consent as specified by the FDA (21 CFR 50.25) and 
ICH-GCP will be followed.  The subjects will also be instructed that they are free to withdraw their 

 
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consent and discontinue their participation in the study at any time without prejudice. Written 
consent will be obtained from each subject to be involved in the clinical trial by using the IRB/IEC-
approved ICF prior to the conduct of any study-related activity.  A copy of the ICF will be 
submitted together with this protocol and must be approved by the IRB/IEC prior to study 
commencement. Each subject will be given a copy of the written ICF, and each subject’s chart will 
include the signed ICF for study participation. The original subject signed and dated ICFs will be 
maintained by the site for 15 years.  Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the study.   
11.4 
SUBJECT INSURANCE 
A product liability to cover against injury and damages arising from the use of products in this 
project is provided by SciVac for the total duration of the study covering the subjects and 
Investigators in respect of the risks involved in conducting this study according to this protocol.  
The insurance policy will be filed in the Investigator’s site file or can be made available to the 
Investigator and to the IRB/IEC upon request. 
Where applicable, subjects will be insured through contract between an insurance company and the 
Sponsor. 
11.5 
PERSONAL DATA PROTECTION 
SciVac complies with the principle of subject’s right to protection against invasion of privacy. 
Throughout this trial, all subject data will be identified only by a subject identification number and 
subject initials and date of birth. The data will be blinded in all data analyses. The subject must be 
informed and consent as required that authorized personnel on behalf of SciVac such as study 
monitor, auditor etc. and relevant health regulatory agency will have direct access to personal 
medical data to assure a high quality standard of the study.  
At the subject's request, medical information may be given to his or her personal physician or other 
appropriate medical personnel responsible for his or her welfare.   
11.6 
INFORMING THE GENERAL PRACTITIONER 
The Investigator will inform the subject's primary care physician of the subject’s participation in the 
study, by sending a letter to the physician as required by the Israeli Guidelines for the Conduct of 
Clinical Trials. 
11.7 
PROTOCOL EXCEPTIONS AND DEVIATIONS 
It is expected that subjects will meet all eligibility criteria as specified in the protocol.  Deviations 
from the protocol should be avoided, unless required for the safety of the subject.  Protocol 
deviations, and if possible the reason for occurrence, will be documented by the study monitor and 
will be included in the final clinical study report.  The Investigator must report any protocol 
deviation to the Sponsor and if required, to the IRB/IEC in accordance with local regulations, 
within reasonable time. 
11.8 
PROTOCOL AMENDMENTS 
All protocol modifications must be submitted to the site IRB/IEC in accordance with local 
requirements and, if required, to the Regulatory Authority, either as an amendment or a notification.