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Safety and Preliminary of Immunogenicity Following

Recombinant Hepatitis B (Bio Farma) Vaccine in Adults &
Children

Phase I

Protocol Number: HepB 0119

STUDY PROTOCOL

Sponsor PT BIO FARMA (PERSERO)

Jl.Pasteur no.28 Bandung – 40161 INDONESIA

Investigational Product Recombinant Hepatitis B (Bio Farma)

Manufacturing Sites PT Bio Farma, Jl.Pasteur no. 28 Bandung – 40161

Indonesia.

Principal Investigator Prof. Dr. Kusnandi Rusmil, dr.,Sp.A(K).,MM.

Medical Advisor Prof. Cissy B. Kartasasmita, dr.,Sp.A(K).,MSc.,PhD.

Subinvestigators Dr. Eddy Fadlyana, dr.,Sp.A(K).,MKes.

Dr. Meita Dhamayanti, dr.,Sp.A(K).,MKes.
Rodman Tarigan, dr.,Sp.A(K).,Mkes.

Biometry Dr. Drs. Hadyana Sukandar, MSc.

Monitor Dr. Novilia Sjafri Bachtiar, dr., M.Kes.

Rini Mulia Sari, dr.
Asep Irham F.Q, dr.

Date March 2019

Version 1.0

The clinical study will be performed in compliance with Good Clinical Practice (GCP)
guidelines, including archiving of essential documents. The information contained in this
document is the property of Bio Farma and is confidential. It may be submitted to a
Regulatory Authority, an Institutional Review Board/Ethics Committee, or an Investigator or
a Pharmacist for the purpose of assessment in relation to registration of the product or
initiation of a clinical trial. Reproduction or disclosure of the information in whole or in part
is forbidden without the written consent of Bio Farma. This document must be returned to
Bio Farma upon request

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TABLE OF CONTENTS

SYNOPSIS 4
FLOW CHART 8
Schedule 9
Abbreviations and Symbols Used 10
Glossary 11
1. Background and rationale 12
1.1. Introduction 12
1.2 Epidemiology 13
1.3. Prevention and Control of Hepatitis among Humans 14
1.4. Rationale 14
1.5. Previous Study of recombinant Hepatitis B Vaccine 15
2. Objectives 17
2.1 Primary Objectives: 17
2.2 Secondary Objectives: 17
3. Trial Design and Methodology 18
3.1. Trial Design 18
3.1.1 Recruitment 19
3.1.2 Treatment Allocation Procedures 19
3.2. Trial Population 19
3.2.1. Study Population: 19
3.2.2. Inclusion Criteria 19
3.2.3. Exclusion Criteria 20
3.2.4. Allocation of Participant Numbers 21
3.2.5. Prior and Concomitant Therapy 21
3.3. Trial Plan 21
3.3.1. Conditions for conducting the trial 21
3.3.2. Study Calendar/Timelines 23
3.3.3.Trial Center 23
3.3.4. Dosing and Serology Schedule 24
3.3.5. Procedure for Obtaining, Handling and Shipment of Serum Specimen 24
3.4. Case Report Form and Data Collection 25
3.5. Subject Diaries and Interim Histories 26
3.6. Clinical Supplies 26
4. Products 27
4.1. Investigational Product Characteristics: New Recombinant Hepatitis B (Bio Farma)
Vaccine 27
4.1.1. Product Description 27
4.1.2. Composition 27
4.1.3. Preparation 27
4.1.4. Precautions for use 27
4.2. Control Product Characteristics: Recombinant Hepatitis B (Bio Farma) Vaccine 27
4.2.1. Product Description 27
4.2.2. Composition 28
4.2.3. Preparation 28
4.2.4. Precautions for use 28
4.3. Administration 28
4.4. Labeling and Packaging 28
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4.5 Storage and Shipment Conditions 29

4.5.1. Shipment Conditions 29
4.5.2. Storage Conditions 29
4.6. Accountability 29
4.7. Return of Unused Products 29
5. Trial Administration 30
5.1. Personnel involved in the trial 30
5.2. Visit Procedures 30
5.3. Conditions for Withdrawal from the Trial 33
5.4. Lost to Follow-up Procedures 33
5.5. Termination Classification 33
5.6. Monitoring, Auditing and Archiving 33
5.6.1. Routine Monitoring 33
5.6.2. Audits and Inspections 34
5.6.3. Archiving 35
6. Adverse Event Reporting 36
6.1. Definitions 36
6.2. Expected Reactions 36
6.3. Safety Data Collection and Management Procedures 36
6.4. Reporting of Serious Adverse Events 38
6.5 Causality Assessment 38
7. Evaluation Criteria 41
7.1. Primary Evaluation Criteria 41
7.1.1. Definition of the Criteria 41
7.1.2. Parameters to be measured 41
7.1.3. Method and Timing of Measurement 41
7.2. Secondary Evaluation Criteria 41
7.2.1. Definition of the Criteria 41
7.2.2. Parameters to be measured 41
7.2.3. Method and Timing of Measurement 42
8. Biometry 44
8.1. Determination of sample size 44
8.1.1. Data sets to be analyzed 44
8.1.2. Statistical Methodology 45
8.2. Data Management 46
9. Adverse Events Compensation and Confidentiality 47
9.1. Confidentiality 47
9.1.1. Confidentiality of Data 47
9.1.2. Confidentiality of Patient Records 47
9.2. Adverse Events Compensation and Insurance 47
10. Publication Policy 48
11. Bibliographical References 49
12. Appendices 51
Appendix 1: Personnel involved in the Trial 52
Appendix 2: SAE Reporting Forms 53
Appendix 3: Plastic Bangle Model 54
Appendix 4. Signatures/Investigator’s Agreement to the Protocol 56

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SYNOPSIS

Sponsor: Finished Product: Composition (1 ml):

Bio Farma Recombinant rHbsAg adsorbed 20 mcg
Hepatitis B (Bio Aluminum hydroxi 0.5 mg
Farma) Vaccine Thimerosal 0.01w/v%
Title of study
Safety and Preliminary of Immunogenicity Following Recombinant Hepatitis B
(Bio Farma) Vaccine in Adults & Children
Principal Investigator Prof. Dr. Kusnandi Rusmil, dr.,Sp.A(K).,MM.

Medical Advisor Prof. Cissy B. Kartasasmita, dr.,Sp.A(K).,MSc.,PhD.

Subinvestigators Dr. Eddy Fadlyana, dr.,Sp.A(K).,MKes.

Dr. Meita Dhamayanti, dr.,Sp.A(K).,MKes.
Rodman Tarigan, dr.,Sp.A(K).,Mkes.

Monitor Dr. Novilia Sjafri Bachtiar, dr., M.Kes.

Rini Mulia Sari, dr.
Asep Irham F.Q, dr.
Study center : Hasan Sadikin General Hospital/Medicine Faculty-Padjadjaran
University, Bandung
Planned Study period: July – October 2019
Phase of development: Phase I
Primary Objectives: To assess immediate reaction within the first 30 minutes after
one dose of Hepatitis B vaccination.

Secondary Objectives:
 To describe the safety following one dose of Hepatitis B vaccination
 To assess preliminary information of immunogenicity following one dose of
Hepatitis B vaccination
 To compare the safety and preliminary information on immunogenicity of the
trial vaccine with the control registered vaccine.

For subjects with anti-HBs not protective (<10mIU/mL) before immunization,

additional 2 doses will be required with the schedule:
 To describe the safety following three doses of Hepatitis B vaccination
 To assess immunogenicity following three doses of Hepatitis B vaccination

Methodology:
Experimental, randomized, double blinded, prospective intervention study
Study Population:
 Adults : 18 – 40 years old
 Children : 10-17 years old
Planned Sample size:
100 healthy subjects
 50 Adults for two arms : 18 – 40 years old
 50 Children for two arms: 10-17 years old

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Inclusion criteria
Adult:
1. Healthy individu as determined by clinical judgment, including a medical history,
physical exam, rontgen thorax and laboratory results, which confirms the absence
of a current or past disease state considered significant by the investigator.
2. Subjects have been informed properly regarding the study and signed the
informed consent form
3. Subjects will commit to comply with the instructions of the investigator and the
schedule of the trial.

Children:
1. Healthy individu as determined by clinical judgment, including a medical history,
physical exam and rontgen thorax which confirms the absence of a current or past
disease state considered significant by the investigator.
2. Subjects/parents/guardian(s) have been informed properly regarding the study
and signed the informed consent form and
3. Subject/parents/guardian(s) will commit to comply with the instructions of the
investigator and the schedule of the trial.

Exclusion criteria:
1. Subject concomitantly enrolled or scheduled to be enrolled in another trial
2. Any direct relatives relationship with the study team.
3. Evolving mild, moderate or severe illness, especially infectious diseases or
fever (axillary temperature ³ 37.5°C) within the 48 hours preceding
enrollment.
4. Known history of allergy to any component of the vaccines (based on
anamnesis)
5. Known history of immunodeficiency disorder (HIV infection, leukemia,
lymphoma, or malignancy)
6. History of uncontrolled coagulopathy or blood disorders contraindicating for
phlebotomy.
7. Subject who has received in the previous 4 weeks a treatment likely to alter the
immune response (intravenous immunoglobulins, blood-derived products, or
corticosteroid therapy and other immunosuppresant).
8. Any abnormality or chronic disease which according to the investigator might
interfere with the assessment of the trial objectives.
9. Pregnancy or planning a pregnancy within the next 3 months & lactation. (for
Adults)
10. Subject already immunized with any vaccine within 4 weeks prior and expects
to receive other vaccines within 4 weeks following immunization.
11. HbsAg positive
12. Subjects with known history of Hepatitis B infection.
13. Subjects who have received Hepatitis B vaccination which proven by
vaccination records.
14. Subject planning to move from the study area before the end of study period.

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Test product:
Investigational Product Recombinant Hepatitis B (Bio Farma) Vaccine
Form Liquid (in uniject)
Dose 1 mL
Route Intramuscular injection (deltoid)
Batch Number 3660318UK
Active Comparator Recombinant Hepatitis B (Bio Farma) Vaccine
Form Liquid (in uniject)
Dose 1 mL
Route Intramuscular injection (deltoid)
Batch Number 3660718
Immunization Schedule
V1 (1st Dose) : Day 0

For subjects with anti-HBs not protective(<10mIU/mL) before immunization,

additional 2 doses will be required with the schedule:
V2 (2nd Dose) : V1 + 28 (-4/+7) days
V3 (3rd Dose) : V2 + 28 (-4/+7) days

Serology schedule
V0 : within 3 days before V1
V1a : 10 ml blood sample for adults only
V2 : V1 + 28 (-4/+7) days

For subjects with anti-HBs not protective (<10mIU/mL) before immunization,

additional 2 doses will be required and additional blood sample will be taken at V4
(V3 + 28 (-4/+7) days
Evaluation Criteria
Primary Evaluation Criteria
The main evaluation criteria are number and percentage of subjects with at least one
immediate reaction (local reaction or systemic event) within 30 minutes after one dose
of Hepatitis B vaccination.

Secondary Evaluation Criteria

Safety
 Number and percentage of subjects with at least one of these adverse events,
solicited or not, within 24 h, 48h, 72h and 28 days after one dose of trial vaccine.
 Number and percentage of subjects with serious adverse event from inclusion until
28 day after one dose vaccination.
 Any deviation from routine laboratory evaluation that probably related to the
vaccination (adults subject)
 Description of safety data between groups

Immunogenicity: Preliminary assessment of immunogenicity of anti-HBs following 1

dose of vaccination
 Number and percentage of subjects with anti HbsAg ≥10mIU/ml, 28 days
after 1 doses of vaccination.
 Number and percentage of subjects with ³ 4 times increasing antibody

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 Geometric Mean Titers (GMT) following immunization

 Anti-HBs description between groups

For subjects with anti-HBs not protective (<10mIU/mL) before immunization,

additional 2 doses will be required with the schedule:
Safety
 Number and percentage of subjects with at least one of these adverse events,
solicited or not, within 24 h, 48h, 72h and 28 days after each dose of trial vaccine.
 Number and percentage of subjects with serious adverse event from inclusion until
28 day after each dose vaccination.

Immunogenicity: Preliminary assessment of immunogenicity of anti-HBs following 3

dose of vaccination:
 Number and percentage of subjects with anti HbsAg ≥ 10mIU/ml, 28 days
after 3 doses of vaccination.
 Number and percentage of subjects with ³ 4 times increasing antibody
 Geometric Mean Titers (GMT) following immunization

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FLOW CHART

Visit for subjects with antbody level > 10 mIU/ml

V0 V1 V1 +3 V1a V2 V2 + 3 V3 V3 + 3 V4

IP
Adults
only

Active
Comparator

For subjects with anti-HBs < 10mIU/mL before immunization, vaccination will be continued
to 3 doses with 1 month interval.

= serology = 3 ml for children and adults at V4 and 10 ml for adults at V0 and V1a

= Hepatitis B immunization

= immunization reaction recording

= follow up by phone

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Schedule
Visit Number V0 V1 V1 + 3 V1a V2 V2 + 3 V3 V3 + 3 V4
Within 3 Visit 1+ 28 Visit 2+ 28 Visit 3+28 days
Visit 1 + 3 V1 + 10 days
Visit Interval (Days) days before Day 0 days days (-4/+7 days)
days (adults only)
V1 (-4/+7 days) (-4/+7 days)
Informed consent signed X
Inclusion & Exclusion
X X
Criteria
Past Medical History X
Physical Examination X X X X X X
Blood Sampling (3 cc) X X X X
Blood Sampling (10 cc) X X
HbsAg test & X
Vaccination Dose VAC VAC VAC
Immediate surveillance
X X X
(30 min)
Assessment of Local
Reactions & Systemic X X X X X X X
Events
DC1 DC2 DC3
Diary Cards Provided
Diary Cards Collected DC1 DC2 DC3
Prior & Concomitant
X X X X
Therapies
Termination
X X
Record/Final
Serious Adverse Events
For subjects with anti-HBs not protective (<10mIU/mL) before immunization, additional 2 doses will be required and additional blood sample
will be taken at V4 (V3 + 28 (-4/+7) days

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Abbreviations and Symbols Used

Anti-HBs Anti-Hepatitis B Surface

AE Adverse Event
cGMP Current Good Manufacture Pratice
CRF Case Report Form
D Day (D1=Day1)
DC Diary Card
GCP Good Clinical Practice
GLP Good Laboratory Practice
GMT Geometric Mean Titers
HbsAg Hepatitis B Surface Antigen
Hbs Hepatitis B Surface
IEC Institutional Ethics Committee
ITT Intention To Treat
IP Investigational Product
IRB Institutional Review Board
NIHRD National Institute of Health Research and Development
NIP National Immunization Programme
NIS National Immunization Schedule
PHC Primary Health Centre
PI Principal Investigator
rHbsAg Recombinant Hepatitis B Surface Antigen
SAE Serious Adverse Event
SOP Standard Operating Procedure
V Visit (V1 = Visit 1)
WHO World Health Organization

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Glossary

1. Blinding; a procedure in which one or more parties to the trial are kept unaware of
the treatment assignment(s). In case of measurement blinding, the technician being
unaware of the measure sample(s) before or after immunization.
2. Case report form (CRF); a printed, optical, or electronic document designed to
record all of the protocol required information to be reported to the sponsor on each
trial subject.
3. Clinical Trial/Study; any investigation in human subjects intended to discover or
verify the clinical, pharmacological and/or other pharmacodynamic effects of an
investigational product(s), and/or identify any adverse reactions to an investigational
product(s), and/or to study absorption, distribution, metabolism, and excretion of an
investigational product(s) with the objects of ascertaining its safety and/or efficacy.
The terms clinical trial and clinical study synonymous.
4. Impartial witness; a person, who is independent of the trial, who cannot be unfairly
influenced by people involved with the trial, who attends the informed consent
process if the subject or the subject’s legally acceptable representative cannot read,
and who reads the informed consent form and any other written information supplied
to the subject.
5. Immunogenicity; capabality of inducing an immune reponse.
6. Informed consent; a process by which a subject voluntarily confirms his or her
willingness to participate in a particular trial, after having been informed of all aspects
of the trial that are relevant to the subject’s decision to participate. Informed consent
is documented by means of a written, signed and dated informed consent form.
7. Investigator; a person responsiblefor the conduct of the clinical trial at a trial site. If a
trial is conducted by a team of individuals at a trial site, the investigator is the
responsible leader of the team and may be called the principal investigator. See also
subinvestigator.
8. Monitoring; the act of overseeing the progress of a clinical trial, and of ensuring that
it is conducted, recorded, and reported in accordance with the protocol, SOPs
(Standard Operating Procedures), GCP (Good Clinical Practice) and the applicable
regulatory requirement(s).
9. Solicited; specific local and general symptoms, actively elicited from parent
(s)/guardian (s) through prompting in a diary card
10. Sponsor; an individual, company, institution, or organization which takes
responsibility for the initiation, management, and/or financing of a clinical trial.
11. Subinvestigator; any individual member of the clinical trial team designated and
supervised by the investigator at a trial site to perform critical trial-related procedures
and/or to make important trial-related decisions (e.g., associates, residents, research
fellows). See also investigator.
12. Unsolicited; any other adverse event not including solicited adverse events

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1. Background and rationale

1.1. Introduction
Viral hepatitis is an international public health challenge, comparable to other major
communicable diseases, including HIV, tuberculosis and malaria. 1 Although many different
viruses can cause hepatitis, hepatitis as the main manifestation of viral infection in humans is
caused by only 5 virus species: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C
virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). All of the hepatitis
viruses cause acute hepatitis; HBV, HCV and HDV also frequently cause chronic hepatitis.
Chronic hepatitis can lead to cirrhosis which may progress to hepatocellular carcinoma
(HCC), the most common type of primary liver cancer. 2
In 2016, WHO issued the first global health sector strategy on viral hepatitis. The strategy
addresses all five hepatitis viruses (hepatitis A, B, C, D and E), with a particular focus on
hepatitis B and C, owing to the relative public health burden they represent. Ending hepatitis
epidemics as a major public health threat is feasible with the tools and approaches currently
available and in the pipeline. Five core intervention areas are vaccine; prevention of mother-
to-child transmission of hepatitis B virus; injection, blood and surgical safety; harm reduction
for people who inject drug; and treatment. Effective vaccines exist for preventing viral
hepatitis A, B and E infections.1
Hepatitis B virus immunization is a critical intervention for the elimination of hepatitis B
virus epidemics. Wider provision of the existing, safe and effective hepatitis B virus vaccine,
including through universal childhood vaccination and by delivery of birth-dose, will
drastically reduce new hepatitis B infections, reducing rates of chronic illness and death. 1 The
strategy calls for an increase in routine childhood hepatitis B virus vaccination coverage from
82% in 2015 to 90% by 2020, which will require strengthening of overall childhood
immunization programmes along with specific efforts to target hepatitis B virus vaccination
for those people at increased risk.1
For countries, to implement a comprehensive hepatitis B virus immunization programme,
based on WHO guidance: inclusion of hepatitis B virus vaccine in national childhood
immunization schedules; strengthening hepatitis B virus birth-dose programmes;
consideration of catch-up hepatitis B virus vaccination for children or adolescents with low

1
WHO. Global Health Sector Strategy on Viral Hepatitis 2016-2021 towards Ending Viral Hepatitis. 2016.
2
WHO, Weekly epidemiological record, Hepatitis B vaccines: WHO position paper – July 2017, Geneva 2017,
27(92); 369-392.

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coverage; and offering hepatitis B virus vaccination to people who are at increased risk of
acquiring and transmitting the virus.1

1.2 Epidemiology
Disease caused by HBV has a worldwide distribution. The endemicity of active HBV
infection is reflected in the serologic prevalence of the hepatitis B surface antigen (HBsAg) in
the general population of a defined geographical area. HBsAg prevalence of ≥8% defines
highly endemic areas, prevalence of 5%–7% defines high intermediate, 2%–4% low
intermediate, and <2% defines low endemic areas.2
High(est) endemicity of hepatitis B (currently defined as ≥8% of the population HBsAg-
positive) is found in areas of sub-Saharan Africa, South-East Asia, the Eastern Mediterranean
countries, South and Western Pacific islands, the interior of the Amazon Basin and in certain
parts of the Caribbean; in these areas up to 20% of the population may be chronically
infected. Intermediate endemicity (2%–8% of the population HBsAg-positive) are located in
South-Central and South-West Asia, Eastern and Southern Europe, the Russian Federation
and most of Central and South America. In Australia, New Zealand, Northern and Western
Europe and North America, the prevalence of chronic HBV infection is low (<2% of the
population HBsAg-positive).3
Indonesia is a country with high endemicity of hepatitis B, the second largest in
Southeast Asia country after Myanmar. Based on the results of Riskesdas, study and blood
screening of PMI donors, it is estimated that among 100 Indonesians, 10 of them have been
infected with hepatitis B and C. So now there are estimated 28 million Indonesians infected
with hepatitis B.4
Although other primates have been infected in laboratory conditions, HBV infection
affects only humans. No animal or insect hosts or vectors are known to exist.5 Humans are the
only reservoir of HBV. The virus is highly contagious and is transmitted by percutaneous and
permucosal exposure to blood, and in other body fluids, including saliva, semen and vaginal
secretions. Four different modes of HBV transmission exist: from mother to child (perinatal),
from child to child (horizontal), through unsafe injections and blood transfusions (parenteral),
and through sexual contact (sexual).3

3
WHO. The Immunological Basis for Immunization Series: Module 22: Hepatitis B, Geneva. 2011)
4
Ministry of Health. Infodatin: Situasi dan Analisis Hepatitis. 2014.
5
Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases.
Atkinson W, Wolfe S, Hamborsky J, eds. 12th ed., second printing. Washington DC: Public Health Foundation,
2012.

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1.3. Prevention and Control of Hepatitis among Humans

Safe and effective vaccines against hepatitis B have been available since 1982. As of
2015, 185 (95%) countries worldwide had introduced hepatitis B vaccination in their infant
schedules with 97 (49%) countries providing the recommended birth dose. WHO has
estimated that 84% of all infants worldwide received at least 3 doses of hepatitis B containing
vaccine in 2015 and 39% of newborns received the birth dose. Vaccinating against hepatitis B
has been associated with substantial reductions in the incidence of acute and chronic hepatitis
B infections and mortality from hepatocellular carcinoma.6
SAGE recommends that all infants receive the birth dose during the first contact with
health facilities at any time up to the time of the first primary dose. The birth dose given after
24 hours should be reported as a late birth dose vaccination. 5 The birth dose should be
followed by 2 or 3 doses to complete the primary series.7
A large variety of hepatitis B vaccination schedules have been shown to induce
seroprotective anti-HBs levels2 in over 95% of healthy infants and children. In general, the
minimum recommended interval between the doses is four weeks. Longer dose intervals may
increase the final anti-HBs titres but not the seroconversion rates. In any age group, an HBV
vaccination schedule that is interrupted should be continued as soon as possible, while
respecting the minimum interval between the remaining doses.3

1.4. Rationale
WHO recognizes the importance of hepatocellular carcinoma and other HBV-related
diseases as global public health problems and reiterates its recommendation that hepatitis B
vaccines should be included in national immunization programmes. Hepatitis B vaccination is
recommended for all children worldwide. Reaching all children with at least 3 doses of
hepatitis B vaccine should be the standard for all national immunization programmes.
Importantly, all national programmes should include a monovalent hepatitis B vaccine birth
dose. WHO recommends hepatitis B vaccination of persons at high risk of HBV infection in
older age groups and catch-up vaccination of unvaccinated cohorts if the necessary resources
are available.2
Bio Farma as the only government-owned vaccine manufacture in Indonesia has now
developed a new recombinant Hepatitis B vaccine. Therefore it is necessary to conduct phase
6
WHO, Weekly epidemiological record, Meeting of the Strategic Advisory Group of Experts on Immunization,
October 2016 – conclusions and reccomendation, Geneva 2016, 48(91); 561-584.
7
WHO. Hepatitis B; 2015 July [cited 2018 May 25]. Available from:
http://www.who.int/mediacentre/factsheets/fs204_Jul2014/en/

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1 clinical trials. Bio Farma will produce this new recombinant Hepatitis B vaccine to supply
national immunization programme as well as for global supply.

1.5. Previous Study of recombinant Hepatitis B Vaccine (bulk imported)

Bio Farma Vaccine Institute had started producing the Hepatitis B recombinat vaccine
since the year of 2000. At first Bio Farma had produced the plasma derived vaccine. After the
issues of the human blood, Bio Farma changes their product to the recombinant vaccine.
The first study for hepatitis B vaccine recombinant in Indonesia was conducted by Center
for Disease Control, NIH R & D, Ministry of Health. This study was conducted in Bogor
regency to evaluate the immunogenicity and safety of Hepatitis B vaccine recombinant. Two
hundreds and twenty infants were involved in this study divided into two groups; the first
group with schedule 0,2,3 months and the second group with schedule 2,3,4 months of age.
Immunogenicity and GMT of antibody titre in both groups were 97.47 %; 95.70 % and
190.22 mIU/ml; 219.33 mIU/ml respectively. Systemic reaction was observed in 0.64%
(fever) and 0.48% (vomiting) whilst local reaction 0.97% (redness). Recommendation from
this study is to administer hepatitis B vaccine in newborn infants.8
Another study was conducted in 2001 in infants with different immunization schedule by
Diet Rustama et al, from Hasan Sadikin General Hospital in Bandung, West Java. In total 290
infants were involved in this study; divided into 2 schedules, 0,1,2 and 0,1,6 months of age.
The result of this study was 95.4% infants were protected in 0,1,2 schedule and 98.9% were
protected in 0,1,6 schedule. Vaccination schedule 0,1,6 months of age induced higher
antibody (Geometric Mean Titer) 703.1 mIU/ml compare to schedule 0,1,2 months of age:
496.1 mIU/ml.9
A bridging study was conducted in 2005 to evaluate two different accelerated schedules
0,7,21 days (group I) & 0,1,2 months (group II), of hepatitis B vaccination in adults. Booster
dose on day 365 was administered for each group. At day 28, significant difference in
seroprotection rate was observed in 81.5% in group I and 40.9% in group II. One month after
the third dose, seroprotection rate was 72.2% in group I and 98.2% in group II. There were no
significant difference between those two groups in term of seroprotection (95.0% vs 95.3%)

8
Muljati Prijanto, Sarwo Handayani, Julitasari, Sumarno, Siti Mariani S. Immunogenicity & Reactogenicity of
Recombinant DNA Hepatitis B (Uniject) Bio Farma Vaccine Study In Bogor. CDC, NIH R & D, Ministry of
Health, 2002;JKPKBPPK/2002-12-31.
9
Diet Rustama et al. Respon antibody dan kejadian ikutan pasca imunisasi pada bayi baru lahir yang diimunisasi
Hepatitis B rekombinan uniject; SMF/Bagian Ilmu Kesehatan Anak RS Hasan Sadikin Bandung, 2002.

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at day 365 (before booster vaccination). One month after 1 dose of booster the seroprotection
rate was 99% in group I and 100% in group II.10
A Post Marketing Surveillance study (Protectivity and Safety Following Recombinant
Hepatitis B (Bio Farma) Vaccine Immunization in Late Adolescents) was conducted in
healthy late adolescents (15-18 years old) not previously received Hepatitis B vaccine to
assess protectivity and safety against Hepatitis B vaccine recombinant after 3 doses. Subjects
were administered three doses (1.0 ml) intramuscular injection of hepatitis B vaccine
recombinant (20 µg of HBsAg) into the upper arm with interval 1 month. Anti HBs
antibodies were detected in 95.5% of 113 subjects with anti HBs < 10 mIU/mL, GMT was
682.65 (495.11 – 941.24) mIU/mL. The most frequent local and systemic reaction was pain
8.5% and fever 5.7%. No serious adverse events occurred and all vaccinations were well
tolerated.11

10
Eddy Fadlyana, Rachmat Gunadi, Sadeli Masria, Ina Madiadipura, Dedi Subardja, Lina H Soemara, H Kartini
S, Novilia Sjafri Bachtiar. The Immunogenicity and Safety of recombinant Hepatitis B vaccine (Bio Farma)
with two different accelerated schedules in Adults., Research Center of Health, Food and Community Nutrition,
Padjadjaran University, 2006.
11
Eddy Fadlyana, Nur Suryawan, Rodman Tarigan, Kusnandi Rusmil, Novilia S Bachtiar. Protectivity and
Safety Following Recombinant Hepatitis B (Bio Farma) Vaccine Immunization in Late Adolescents; Hasan
Sadikin Hospital/School of Medicine, Padjadjaran University, Bandung, 2011.

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2. Objectives

2.1 Primary Objectives:

 To assess immediate reaction within the first 30 minutes after one dose of Hepatitis B
vaccination.

2.2 Secondary Objectives:

 To describe the safety following one dose of Hepatitis B vaccination

 To assess preliminary information of immunogenicity following one dose of Hepatitis
B vaccination
 To compare the safety and preliminary information on immunogencity of the trial
vaccine with the control registered vaccine.

For subjects with anti-HBs not protective (<10mIU/mL) before immunization, additional 2
doses will be required with the schedule:
 To describe the safety following three doses of Hepatitis B vaccination
 To assess immunogenicity following three doses of Hepatitis B vaccination

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3. Trial Design and Methodology

3.1. Trial Design

This trial is an experimental, randomized, double blind, prospective intervention study

Approximately 100 subjects will be enrolled in this trial, divided into 2 arms, as follow:
For adult (18-40 years old)
Vaccine dose
Group Number of dose i. Total Subject
m
A 1 dose of recombinant
Hepatitis B trial 1 ml 25
vaccine
B 1 dose of registered Hepatitis
1 ml 25
B vaccine

For children (10-17 years old):

Vaccine dose
Group Number of dose i. Total Subject
m
A 1 dose of recombinant
Hepatitis B trial 1 ml 25
vaccine
B 1 dose of registered Hepatitis
1 ml 25
B vaccine
For subjects with anti-HBs not protective (< 10mIU/mL) before immunization, additional 2
doses will be required with 1 month interval.

This Study is sequential age de-escalation. To be conducted in heathy adults (18-40 years old)
and followed by children (10-17 years old) )

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3.1.1 Recruitment
The candidate subjects will be identified by participating sites. Expecting subjects or
parent(s) will be approached by a member of the study team who will describe the study to
them, provide some written information and, if they are interested, arrange to discuss the
study in more detail at a later time. Expecting subject or parent(s) will be encouraged to
discuss the study with their usual doctor, midwife, and family members.

3.1.2 Treatment Allocation Procedures

After being informed about the study, collecting a signed informed consent/and assent from
the subjects/parents/guardians, all subjects will be evaluated through a medical history,
phisical exam and chest radiology and some serology tests and ECG (for adults)
The investigator will check inclusion and exclusion criteria. For each subject recruited,
inclusion number will be allocated in the chronological order of the subject which include in
the trial from 001 to 050 (for adult group) and 051 to 100 (for children group). The subject
will be randomized per treatment group.
The doctor will strictly follow the list of randomization provided by Bio Farma. Treatment
will be allocated in accordance with a randomization list, so that to each randomization
number, corresponds only one strictly randomly assigned treatment group (A/B)

3.2. Trial Population

3.2.1. Study Population:
• Adults: 18 – 40 years old
• Children: 10-17 years old

3.2.2. Inclusion Criteria

Adult:

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1. Healthy individu as determined by clinical judgment, including a medical history,

physical exam, rontgen thorax and laboratory results, which confirms the absence of a
current or past disease state considered significant by the investigator.
2. Subjects have been informed properly regarding the study and signed the informed
consent form
3. Subjects will commit to comply with the instructions of the investigator and the
schedule of the trial.

Children:
1. Healthy individu as determined by clinical judgment, including a medical history,
physical exam and rontgen thorax which confirms the absence of a current or past
disease state considered significant by the investigator.
2. Subjects/parents/guardian(s) have been informed properly regarding the study and
signed the informed consent form and
3. Subject/parents/guardian(s) will commit to comply with the instructions of the
investigator and the schedule of the trial.

3.2.3. Exclusion Criteria

1. Subject concomitantly enrolled or scheduled to be enrolled in another trial
2. Any direct relatives relationship with the study team.
3. Evolving mild, moderate or severe illness, especially infectious diseases or fever
(axillary temperature ³ 37.5°C) within the 48 hours preceding enrollment.
4. Known history of allergy to any component of the vaccines (based on anamnesis)
5. Known history of immunodeficiency disorder (HIV infection, leukemia, lymphoma,
or malignancy)
6. History of uncontrolled coagulopathy or blood disorders contraindicating for
phlebotomy.
7. Subject who has received in the previous 4 weeks a treatment likely to alter the
immune response (intravenous immunoglobulins, blood-derived products, or
corticosteroid therapy and other immunosuppresant).

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8. Any abnormality or chronic disease which according to the investigator might

interfere with the assessment of the trial objectives.
9. Pregnancy or planning a pregnancy within the next 3 months & lactation. (for Adults)
10. Subject already immunized with any vaccine within 4 weeks prior and expects to
receive other vaccines within 4 weeks following immunization.
11. HbsAg positive
12. Subjects with known history of Hepatitis B infection.
13. Subjects who have received Hepatitis B vaccination which proven by vaccination
records.
14. Subject planning to move from the study area before the end of study period.

3.2.4. Allocation of Participant Numbers

Inclusion number will be allocated in the chronological order of the subject inclusion in the
trial. The subject will be randomized per treatment group. The doctor will strictly follow the
list of randomization provided by Bio Farma. Treatment will be allocated in accordance with
a randomization list, so that to each randomization number, corresponds only one strictly
randomly assigned treatment group (A/B)

3.2.5. Prior and Concomitant Therapy

Treatments that are forbidden during the trial: Any treatment such as, but not limited to,
intravenous immunoglobulins, systemic corticoids or blood products, susceptible to alter the
immune response. In this case, 4 weeks are required between previous treatment stop date
and administration of investigational vaccine(s).
Forbidden concomitant dosing’s: other Hepatitis B vaccine.

For all treatments mentioned above and other therapies taken during the trial, the following
items should be reported on the CRF:
 Trade name
 Total daily dose
 Route of administration
 Start and stop dates of administration
 Indication. The investigator should use acceptable medical terminology to detail the
reason for prescription.

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3.3. Trial Plan

3.3.1. Conditions for conducting the trial
3.3.1.1. Ethical Considerations/Protocol Review
Protocol review
Before the inclusion of the first subject in the center, the protocol should be signed by the
investigators and sponsor’s representatives and approved by the Quality Assurance Division
of Bio Farma, by the Institutional Ethics Committee and Indonesian Regulatory Authorities.

Ethical Considerations
This trial will be conducted in accordance with the latest Edinburg, Scotland revision of the
Declaration of Helsinki, ICH Good Clinical Practice guidelines and local regulatory
requirements.
The investigator shall be responsible for obtaining approval of the protocol from the
Institutional Ethics Committee before starting the trial, as well as approval of all amendments
in compliance with local law. Copies of these approvals must be forwarded by the
investigator to Bio Farma with the composition (names and qualification of the members) of
the Institutional Ethics Committee.

Clinical Trial Registration

Before conducting the trial, the study should be registered in the international clinical trial
registry platform (ex.https://clinicaltrials.gov/).

3.3.1.2. Informed Consent

The investigator or delegate must obtain the written informed consent/ and assent from the
subject or parent/guardian(s) before any study-related procedures are performed and after the
subjects or parent/guardian(s) have been informed of the nature of the trials, the potential
risks and his/her obligations.
Written informed consent should be given by the subject 18-40 years of age, or by the
parent/guardian(s) for children 10 - 11 years of age. While the subject 12-17 years of age
should give his/her written assent before their parent/guardian(s) give written informed
consent.
Informed consent should be signed by an impartial witness (hierarchically independent of the
investigator and not specified on the list of trial contributors) if the subject’s legally
authorized representative is not able to read and sign the form.

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By signing the consent form, the witness will attest that the information in the consent form
and any other written information were accurately explained to the parents, or to his/her
legally acceptable representative, and apparently understood.

3.3.1.3. Subject Benefits/Potential Risks

The subjects enrolled in this trial would potentially gain benefit from dosing with
recombinant Hepatitis B vaccine. As to the risks, refer to the Investigational Brochure or
Package Insert/IB of the products.

3.3.1.4. Modification of the protocol

No amendments to this protocol will be made without consultation with and agreement of the
sponsor. Any amendment to the trial that seems indicated as the trial progresses must be
discussed by the investigator and sponsor concurrently. If agreement is reached concerning
the need for an amendment, such amendment will be produced in writing by the sponsor
and/or the investigator and be made a formal part of the protocol.
An amendment requires Institutional Ethics Committee approval. It should also be
transmitted to Indonesian Regulatory Authorities, if applicable.
An administrative change to the protocol is one that modifies administrative and logistic
aspect of a protocol and that does not affect the subject safety, the objectives of the trial and
its progress. An administrative change only requires Institutional Ethics Committee
notification.
The investigator is responsible for insuring that changes in approved trial, during the period
for which Institutional Ethics Committee approval has already been given, may not be
initiated without Institutional Ethics Committee review and approval except where necessary
to eliminate apparent immediate hazards to the human subjects.

3.3.1.5. Interruption of the Trial

The trial may be discontinued for administrative reasons, if new data about the investigational
product(s) resulting from this trial become available, and/or on advice of the sponsor, the
investigators and/or the Institutional Ethics Committee.
If a trial is prematurely terminated or suspended, the sponsor shall promptly inform the
investigators, the Indonesian Regulatory Authorities and the Institutional Ethics Committee
of the reason for termination or suspension.
3.3.2. Study Calendar/Timelines
Enrollment : July 2019

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End of Follow up for 28 days after 1 dosing : August 2019

Data Safety Management : June- August 2019
Statistical analysis for safety : September 2019
Serology testing : September 2019
Clinical Report : October 2019
*This timeline may change at any time according to condition during the trial

3.3.3.Trial Center
This trial will be implemented in one center, Department Of Child Health Hasan Sadikin
General Hospital/Medicine Faculty Padjadjaran University Bandung, West Java.
The subjects will be recruited in Puskesmas Garuda (Primary Health Center)

3.3.4. Dosing and Serology Schedule

Immunization Schedule
V1 (1st Dose) : Day 0

Serology schedule
V0 : within 3 days before V1
V1a : 10 ml blood sample for adults only
V2 : V1 + 28 (-4/+7) days

For subjects with anti-HBs not protective (<10mIU/mL) before immunization, additional 2
doses will be required and additional blood sample will be taken at V4 (V3 + 28 (-4/+7) days

3.3.5. Procedure for Obtaining, Handling and Shipment of Serum Specimen

3.3.5.1. Obtaining Serum Samples

The blood sample will be collected in vacutainer tubes. The person in charge of blood
drawing should verify the subject’s identity and should check that the initials on the
laboratory request are those of the subject just before taking the blood sample.
Then, he/she should write the subject’s initials on all labels of the corresponding band. He/she
should affix one label onto the vacutainer tube immediately prior to blood sample drawing. It
is absolutely necessary to obtain a sterile blood sample.
For Adults, ten mL of blood sample will be collected at visit V0 and V1a while three ml of
blood sample will be collected at visit V2 or /and V4.
The V0 blood sample will be divided into 2 aliquot. The first aliquot will be used for HbsAg
test and serology screening before recruitment while the second aliquot will be used for

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evaluation of pre-immunization antibody titer (Anti-HBs test). The V1a blood sample will be
used for safety evaluation. The V2 or /and V4 blood sample will be used for evaluation of
post-immunization antibody titer (Anti-HBs test), and the remain sample should be stored
until dispatched to Bio Farma.
For Children, three mL of blood sample will be collected at visit V0, V2 or /and V4.
The V0 blood sample will be divided into 2 aliquot. The first aliquot will be used for HbsAg
test while the second aliquot will be used for evaluation of pre-immunization antibody titer
(Anti-HBs test). The V2 or /and V4 blood sample will be used for evaluation of post-
immunization antibody titer (Anti-HBs test), and the remain sample should be stored until
dispatched to Bio Farma.

Sample Processing
For the samples that will be used for antibody assessment, after clotting at room temperature
from 30 minutes to 2 hours, blood samples will be centrifuged at 3000 rpm for 15 minutes.
Before centrifuge the blood sample, it can be stored at 2-8°C for 24 hours. Sera will be
rapidly stored in a freezer at –20°C/-80°C pending collection.

Each blood sample will be labeled with sticker, which indicates the blood sampling stage
(V0, V1a, V2 or /and V4), the trial code, the inclusion number and the subject’s initials.

3.3.5.2. Handling Serum Samples

3.3.5.2.1. Storage Conditions
Each sample properly labeled should be frozen at –20°C to –80°C. Temperature should be
monitored and documented on the appropriate form during the entire trial.

3.3.5.2.2. Method and Timing of Measurement

Antibody titers are measured at visit V0 (within 3 days before V1) and at visit V2 or/and V4.
Anti-Hepatitis B will be measured by Chemiluminescent Microparticle Immunoassay
(CMIA) Architect ausab reagent kit on architect i 1000sr. The measurement will be held at
Prodia using Abbott Kit.

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Any additional serological analysis on antigen(s) included in the vaccine tested in this trial
may be performed if Bio Farma considers it necessary to further document the
immunogenicity results of this trial or other trials.

3.3.5.3. Blinding Procedure

The blinding code and list will be prepared by the statistician. The blinding procedure should
be witnessed by the investigator and team. The samples will be stored in the cryo box
according to the new code. The key of the blinding code will be kept by the statistician and
the investigator.The blinding code will be opened after the result of serology testing has been
received by the investigators.

3.4. Case Report Form and Data Collection

All information will be recorded by the investigator or a designated person in the Case Report
Forms provided by Bio Farma. They will be filled out with a black ball-point pen, in capital
letters and signed by the investigator.
Explanations must be given for all missing information. All incorrect data must be crossed
out with a single line, then signed and dated by the investigator or a designated person
“White-out” correction fluid should not be used.

3.5. Subject Diaries and Interim Histories

Subjects will keep an observation card (diary) to assess and record information for solicited
& unsolicited systemic reactions and serious adverse event (SAE) for 28 days following
immunization, with special attention within the first three days after dosing. Safety data in
day 1, 2 and 3 after 1st immunization will be follow up by phone. The subjects will be
observed for 30 minutes after dosing by designated person.
The local reaction assessment will involve assessment of the vaccination site. The systemic
event assessment will involve daily axillary temperature readings (subjects will be supplied
with a thermometer and instruction how to use it) and recording any systemic complaints on a
diary card. Any medical office visit, emergency room visit or hospitalization for any reason
will be recorded throughout the trial period. Moreover, any serious adverse event occurring
throughout the trial period should be reported immediately and will also be recorded in the
CRF.

3.6. Clinical Supplies

Protocols, CRFs, and diaries will be provided by Bio Farma.

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4. Products

4.1. Investigational Product Characteristics: Recombinant Hepatitis B (Bio Farma)

Vaccine

4.1.1. Product Description

Recombinant Hepatitis B vaccine is an inactivated HbsAg produced in yeast cells (Hansenula
polymorpha) using recombinant DNA technology. It is a whitish liquid produced by culture
genetically engineered yeast cell which carry the relevant gene of the HbsAg and purified and
inactivated by several physicochemical steps such as ultracentrifugation, column
chromatography and formaldehyde treatment.

4.1.2. Composition
Each dose of vaccine contains (one dose corresponse to 1 mL):
HbsAg 20 mcg
Aluminum hydroxide 0.5 mg
Thimerosal 0.01w/v%
Batch number : 3660318UK

4.1.3. Preparation
Each injection device was packed in one foil pouch. Open the foil pouch and remove the
device. Hold the device by the port with forefinger and thumb, with a firm rapid motion; push
the needle sheet into the port. As the device activated, it will “clicked”. Continue to push
firmly until the gap between the needled sheet and the port are closed. Remove the needle
shield. Continue to hold the device by the port and insert the needle into the left deltoid
region of the patient.

Squeeze the reservoir firmly to inject. After the resevoir is completely emptied, remove the
device and discard into the sharps collection boxes.

4.1.4. Precautions for use

The vaccine must be stored at +2°C to +8°C and should not be frozen.
The skin at the sites of injection will be cleaned and disinfected prior to injection. The
vaccines will be injected intramuscularly into the left deltoid region, by inserting the needle
with a brisk dart-like action at a right angle to the skin surface. The full length of the needle
will be inserted (intramuscularly).

4.2. Control Product Characteristics: Recombinant Hepatitis B (Bio Farma) Vaccine

4.2.1. Product Description

Recombinant Hepatitis B vaccine is an inactivated HbsAg produced in yeast cells (Hansenula
polymorpha) using recombinant DNA technology. It is a whitish liquid produced by culture

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genetically engineered yeast cell which carry the relevant gene of the HbsAg and purified and
inactivated by several physicochemical steps such as ultracentrifugation, column
chromatography and formaldehyde treatment.

4.2.2. Composition
Each dose of vaccine contains (one dose corresponse to 1 mL):
HbsAg 20 mcg
Aluminum hydroxide 0.5 mg
Thimerosal 0.01w/v%
Batch number : 3660718
Expired date : 31 August 2020

4.2.3. Preparation
Each injection device was packed in one foil pouch. Open the foil pouch and remove the
device. Hold the device by the port with forefinger and thumb, with a firm rapid motion; push
the needle sheet into the port. As the device activated, it will “clicked”. Continue to push
firmly until the gap between the needled sheet and the port are closed. Remove the needle
shield. Continue to hold the device by the port and insert the needle into the left deltoid
region of the patient.
Squeeze the reservoir firmly to inject. After the resevoir is completely emptied, remove the
device and discard into the sharps collection boxes.

4.2.4. Precautions for use

The vaccine must be stored at +2°C to +8°C and should not be frozen.
The skin at the sites of injection will be cleaned and disinfected prior to injection. The
vaccines will be injected intramuscularly into the left deltoid region, by inserting the needle
with a brisk dart-like action at a right angle to the skin surface. The full length of the needle
will be inserted (intramuscularly).

4.3. Administration
The vaccines will be injected intramuscularly into the left deltoid region

4.4. Labeling and Packaging

Vaccines will be supplied in a single dose uniject devices. Special blinding label will be used
for each investigational product and control. The information on the label will be coded,
except expired date, instruction of storage and route of administration. Additional label
“hanya untuk uji klinis” (for clinical study only) will be added to each label. The vaccine

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code will be determined by the Pharmaceutical Production Division of Bio Farma and is
confidential.

4.5 Storage and Shipment Conditions

4.5.1. Shipment Conditions
All vaccines will be provided by Bio Farma.
Products will then be shipped to the center according to this pre-determined schedule.
For each vaccine transfer, the person in charge of product receipt will check the record of
temperature recording device. Thermometer will be packed together with the vaccines. Cold
chain has to be maintained during the transfer. In case of problem, he/she should alert the
Monitor immediately.

4.5.2. Storage Conditions

Vaccines shall be stored at a temperature ranging from +2°C to +8°C (in a refrigerator).
Temperature should be monitored and documented on the appropriate form (see Operating
guidelines) during the entire trial.
In case of deep freezing or accidental disruption of the cold chain, vaccines should never be
administered and the investigator or the responsible person should contact the Monitor to
receive further instructions.

4.6. Accountability
Products should be kept in a secure place.
The investigator or the person in charge of product management should maintain records of
the product’s delivery to the trial site, the inventory at the site, the dose(s) given to each
subject (1 vial for each subject) and the return of unused doses to the sponsor.
Should the investigator run out of product doses during the trial, he/she should alert the
Monitor who will undertake the necessary steps to provide extra doses.

4.7. Return of Unused Products

Unused and/or open products will be returned to Bio Farma at the end of the vaccination
period together with the form “Return of unused and/or open products” in accordance with
the Monitor’s instructions.

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5. Trial Administration

5.1. Personnel involved in the trial

Principal Investigator Prof. Dr. Kusnandi Rusmil, dr.,Sp.A(K).,MM.

Sub-Investigators Dr. Eddy Fadlyana, dr.,Sp.A(K).,MKes.

Dr. Meita Dhamayanti, dr.,Sp.A(K).,MKes.
Rodman Tarigan, dr.,Sp.A(K).,Mkes.

Medical Advisor Prof. Cissy B. Kartasasmita, dr.,Sp.A(K).,MSc.,PhD.

Biometry Dr. Drs. Hadyana Sukandar, MSc.

Bio Farma
Monitor Dr. Novilia Sjafri Bachtiar, dr, Mkes
Rini Mulia Sari, dr
Asep Irham F.Q, dr.

5.2. Visit Procedures

 Visit 0. (Within 3 days before V1; pre-inclusion pre-immunization blood sample)
a. Provide subjects with relevant information concerning the trial.
b. Obtain informed consent, dated and signed by the subject/subject’s parents/subject’s
guardian and investigator.
c. Check eligibility criteria.
d. Perform a physical examination.
e. Perform rontgen thorax (for all subject) and ECG (for adults)
f. Take a pre-immunization blood sample (V0, 10 mL for adults and 3 mL for children)
g. Check the HbsAg, Anti HBs (for all subject) and laboratory screening (for adults)
h. Instruct the subjects to come for the visit 1.

 Visit 1. (Day 0; inclusion and immunization)

a. Provide subject with relevant information concerning the trial.
b. Check eligibility criteria.
c. Perform a physical examination.
d. Allocate an inclusion number, chronologically to the enrolment of the subject.
e. Investigator administers 1 dose of Hepatitis B vaccine intramuscularly.
f. Put the initial name and the inclusion number of the subject on the used vaccine.
g. Record the code of vaccine in the CRF and the list of participant.

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h. Keep the subjects under observation for 30 minutes and evaluate the immediate local and
systemic event.
i. Complete the CRF
j. Provide the subjects or parents/guardian(s) with a thermometer, plastic bangle and the
diary card (DC1) along with instructions for use.
k. Inform the subjects or parents guardian(s) that he/she should contact the investigator or
the study nurse in case of Serious Adverse Event.
l. Instruct the subjects to return for visit 1a
Safety data in day 1, 2 and 3 after immunization will be follow up by phone.

Visit 1a. (V1 + 7 days); (safety evaluation for all subjects) and take blood sample in
adult subjects
a. Perform a physical examination.
b. Check the possible Serious Adverse Event.
c. Record the safety data from DC to CRF.
d. Check the concomitant therapies and report the new ones in the CRF.
e. Take a second blood sample (10 ml for adults)
f. Instruct the subjects to return for visit 2

Visit 2. (V1 + 28 (-4/+7) days; immunization)

a. Perform a physical examination.
b. Check the possible Serious Adverse Event.
c. Report the safety data from DC to CRF.
d. Check the concomitant therapies and report the new ones in the CRF.
e. Collect the post-immunization blood sample (3 cc).
f. Complete the CRF and the termination form..

Additional Visit:
For subjects with anti-HBs not protective (<10mIU/mL) before immunization, additional 2
doses with 1 month interval will be required and additional blood sample will be taken at V4
(V3 + 28 (-4/+7) days
a. Investigator administers the second dose of Hepatitis B vaccine intramuscularly.
b. Put the initial name and the inclusion number of the subject on the used vaccine.
c. Record the code of vaccine in the CRF and the list of participant.

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d. Keep the subjects under observation for 30 minutes and evaluate the immediate local and
systemic event.
e. Complete the CRF
f. Provide the subjects or parents/guardian(s) with a diary card (DC2) along with
instructions for use.
g. Inform the subjects or parents guardian(s) that he/she should contact the investigator or
the study nurse in case of Serious Adverse Event.
h. Instruct the subjects to return for visit 3
Safety data in day 1, 2 and 3 after immunization will be follow up by phone

Visit 3. (V2+ 28 (-4/+7) days; immunization)

a. Perform a physical examination.
b. Investigator administers the third dose of Hepatitis B vaccine intramuscularly.
c. Put the initial name and the inclusion number of the subject on the used vaccine.
d. Record the code of vaccine in the CRF and the list of participant.
e. Keep the subjects under observation for 30 minutes and evaluate the immediate local and
systemic event.
f. Complete the CRF
g. Provide the subjects or parents/guardian(s) with a diary card (DC3) along with
instructions for use.
h. Inform the subjects or parents guardian(s) that he/she should contact the investigator or
the study nurse in case of Serious Adverse Event.
i. Instruct the subjects to return for visit 4
Safety data in day 1, 2 and 3 after immunization will be follow up by phone

Visit 4. (V3+ 28 (-4/+7) days; post-immunization blood sample)

a. Perform a physical examination.
b. Check the possible Serious Adverse Event.
c. Report the safety data from DC to CRF.
d. Check the concomitant therapies and report the new ones in the CRF.
e. Collect the post-immunization blood sample (3 cc).
f. Complete the CRF and the termination form.

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5.3. Conditions for Withdrawal from the Trial

The investigator may decide to discontinue the treatment (i.e. immunization), should an event
which is considered as a definite contra-indication, occur throughout the trial.

5.4. Lost to Follow-up Procedures

In the case of subjects who fail to appear for a follow-up examination, extensive effort should
be undertaken to locate or recall them or at least to determine their health status. These efforts
should be documented in the subject’s CRF and source documents.

5.5. Termination Classification

Definitions:
 Discontinuation by the investigator: an observation is considered a discontinuation by the
investigator when the latter decides to terminate the subject’s participation for medical
reasons (for subject’s safety), for personal reason (it is his opinion that the subject can not
continue to participate), etc.
 Drop-out: a subject included in the trial is said to have dropped out after deciding, on his
own volition, to terminate his participation in the trial. Subjects may decide to withdraw
their consent from the trial at any time. The investigator should makesure, however, that
withdrawal was not due to an adverse event. The reason for withdrawal should be noted
in the space provided for this purpose in the CRF.
 Protocol non-compliance
 Lost to follow-up: the subject could not be found in spite of the investigator’s researches.
 Death.

If a participant is discontinued from the study, they should continue to be followed up

according to the protocol schedule, unless consent is withdrawn or the subjects is lost to
follow up. Withdrawn subjects will not be replaced.

5.6. Monitoring, Auditing and Archiving

5.6.1. Routine Monitoring
5.6.1.1. Initial Visit
A set-up visit will be performed before the inclusion of the first volunteer in the center. The
monitor will verify and document that the material to be used during the trial has been
received and that the investigational team has been properly informed about the trial,
regulatory requirements and the SOPs established by Bio Farma. If the medical file is in

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electronic form, the Monitor will request that the investigator provide a hard copy that he/she
will date and sign for each follow-up visit.

5.6.1.2. Follow-up Visit

The Monitor will carry out regular follow-up visits.
The investigator commits himself to be available for these visits and to allow the monitoring
staff direct access to medical file, CRFs and other source documents. The Monitors are
committed to professional secrecy.
During the visits, the Monitor:
- will carry out a quality control assessment of the trial progress: with respect to protocol
and operating guidelines, data collection, signature of consent forms, sample and product
management, cold chain monitoring, completion of document and appearance of SAE,
- will collect the CRFs and correspondent correction sheets,
- will assess the inclusions in order to evaluate the number of complete or ongoing
observations.
The Monitor will discuss any problem with the investigator and define, after conservation,
the actions to be taken.
Once the CRFs corresponding to the last visit have been returned duly completed and signed,
the investigator must be available to continue the filling out of the correction sheets
transmitted by the Monitor, if necessary, until the database is locked.

5.6.1.3. Close-out visit

A close-out visit will be performed at the end of the trial. Its goals are to make sure that:
- the center has all the documents necessary for archiving,
- all unused material has been recovered,
- all products have been returned to the sponsor.

5.6.2. Audits and Inspections

If necessary, a quality assurance audit could be carried out by Bio Farma Quality Assurance
Department or by independent auditors to make sure that the trial has been conducted
according to the protocol and the applicable regulations.
An inspection may be conducted by Indonesian Regulatory Authorities.
The investigator shall allow direct access to trial documents.

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5.6.3. Archiving
The investigator must keep all trial documents provided by Bio Farma for at least 5 years
after the completion or discontinuation last participant, whatever the center (private, hospital,
institution).
The investigator will inform Bio Farma of any address change.

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6. Adverse Event Reporting

6.1. Definitions
 Adverse event (AE):
Any untoward medical occurrence which follows immunization and which does not
necessarily have a casual relationship with the usage of the vaccine. The adverse event may
be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease.

 Solicited AE; specific local and general symptoms, actively elicited from subjects or
parent (s)/guardian (s) through prompting in a diary card.

 Unsolicited AE; any other adverse event not including solicited adverse events

 Serious adverse event (SAE):

A serious adverse event (experience) is any untoward medical occurrence that at any dose:
- results in death,
- is life-threatening.
- requires inpatient hospitalization or prolongation of existing hospitalization,
- results in persistent or significant disability/incapacity, or
- is a congenital anomaly/birth defect.

6.2. Expected Reactions

Anticipated reactions to the trial vaccines are those expected for Hepatitis B vaccine and
should be mild and transient. Reactions that have been reported may be found in the
Investigational Brochure or Package Insert of Hepatitis B vaccine.

6.3. Safety Data Collection and Management Procedures

The safety data will be collected up to one month after the last immunization. During this
period, each subject will be provided with a diary card to record the appearance, the duration
and the intensity (coded 1, 2 or 3) of any local and systemic event expected or not. The
intensity of local reactions will be assessed using a plastic bangle presented in Appendix 3.

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For any subjects, a local reaction is defined as the occurrence of one or several reaction(s)
(solicited or unsolicited) at the injection site within 28 days following vaccination. Local
reactions are:

 Local pain
 Redness
 Induration
 Swelling
 Other local reaction

For any subjects, a systemic event is defined as the occurrence of one or several symptom(s)
(solicited and unsolicited) within 28 days following vaccination. Systemic events are:

 Fever (axillary temperature ³ 38.0°C)

 Other systemic event

The intensity will be coded in the Diary as follows and CRF as follows

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1=Mild 2=Moderate 3=Severe

Local pain Mild pain to touch Pain with Significant pain at
move rest
ment
s
Redness/induration/ Reaction Largest diameter of Reaction beyond the
swelli com the large
ng/uns plet reacti st
olicite ely on circle
d local incl inclu
reactio ude ded
n d in betw
the een
sma the
ller two
circ circle
le s
Fever (axillary 38.0 – 38.4°C 38.5 – 38.9°C ≥ 39.0°C
tempe
rature
)
Other systemic No interference Some interference Prevents daily
events wit with activi
* h activi ty,
(Adult acti ty not requi
s) vity requi res
ring medi
medi cal
cal interv
inter entio
venti n
on
Other systemic Easily tolerated Sufficiently Prevents daily
events disco activi
* mfort ty,
(Child ing to requi
ren) interf res
ere medi
with cal
daily interv
activi entio
ty, n
not
requi

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ring
medi
cal
inter
venti
on
* Other systemic events should refer to published case definition for example Brighton
Collaboration Definition.

Collection and follow-up of adverse events

Adverse events will be collected as indicated in the DCs.
Adverse events likely to be related to the product, whether serious or not, which persist at the
end of the trial will be followed up by the investigator until their complete disappearance.
The investigator will inform the Medical Responsible or the Monitor of the date of final
disappearance of the adverse event and will document it on a correction sheet.
Moreover, any serious adverse event likely to be related to the product and occurring after
trial termination should be reported by the investigator to Bio Farma according to the
procedure described below.

6.4. Reporting of Serious Adverse Events

Every serious adverse event occurring throughout the trial should be notified to the Sponsor,
and Ethics Committee, by the investigator as soon as he/she is alerted of it i.e. within 24
hours, even if the investigator considers that the adverse event is not related to the treatment.
- Notification should be made by phone message/email: then the investigator should
immediately send the completed alert form to Ethics Committee. The copy of alert
form should be sent to Bio Farma

The investigator should then fill in the SAE reporting form as soon as possible, i.e. within
five working days or seven calendar days. This form should be signed by the investigator and
sent by email to the sponsor and Ethics Committee.
Bio Farma as a sponsor should send the reporting form for SAEs-related product (Adverse
Drug Reaction) to the NRA within 7 days for life threatening and death cases and 15
calendar days for other cases, since the cases was found.

6.5 Causality Assessment

Causality is the relationship between two events (the cause and the effect), where the second
event is a consequence of the first. A direct cause is a factor in absence of which the effect

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would not occur (necessary cause). Sometimes there are multiple factors that may precipitate
the effect (event) or may function as co-factors so that the effect (event) occurs).

Causality assessment is the systematic review of data about AEFI case; it aims to determine
the likelihood of a casual association between the event and the vaccines(s) received. For
individual cases, one tries to apply the evidence available on the basis of the history and time
frame of the event to arrive at a causal likelihood.
Case selection of cases for causality assessment should focus on:
- Serious AEFI
- The occurrence of events above the expected rate or of unusual severity;
- Signals generated as a result of individual or clustered cases as these could signify a
potential for large public health impact.

The causal relationship between the investigational product and each AE above will be
categorised by the investigator, sponsor and DSMB with the following classification:

WHO Classification12, 13:

I. Case with adequate information for causality conclusion
A. Consistent casual association to immunization: A case with adequate information for
causality conclusion
A1. Vaccine product-related: An AEFI that is caused or precipitated by a vaccine
due to one or more of the inherent properties of the vaccine product
A2. Vaccine quality defect-related reactions: An AEFI that is caused or
precipitated by a vaccine due to one or more quality defects of the vaccine
product, including the administration device, as provided by the manufacturer.
A3. Immunization error-related reaction: An AEFI that is caused by inappropriate
vaccine handling, prescribing or administration and that thus, by its nature is
preventable.
A4. Immunization anxiety-related reaction: An AEFI arising from anxiety about
the immunization.
B. Indeterminate
B1. Temporal relationship is consistent but there is insufficient definitive evidence
that vaccine caused the event (it may be a new vaccine-linked event). This a
potential signal and needs to be considered for further investigation.
B2. Reviewing factors result in conflicting trends of consistency and inconsistency
12
WHO. Causality Assessment of an Adverse Event Following Immunization. Geneva: WHO; 2013.
13
WHO. Global Manual on Surveillance of AEFI. Geneve: WHO; 2014.

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with casual association to immunization (i.e. it may be vaccine-associated as

well as coincidental and it is not possible clearly to favour one or the other.
C. Inconsistent causal association to immunization (coincidental): This could be due to
underlying or emerging condition(s) or conditions caused by exposure to something
other than vaccine.
Case without adequate information for causality conclusion
This case is categorized as “unclassifiable” and requires additional information for further
review of causality. The available information on unclassifiable cases should be placed in a
repository or an electronic database which should be periodically reviewed to see if
additional information is availavle for classification and to perform analyses for identifying
signals.
The decision to modify or discontinue the trial, or to break individual or all study codes may
be made after mutual agreement between the sponsor and the investigator(s).

Regulatory requirements
In order to comply with current regulations on serious adverse event reporting to Health
Authorities and to allow Bio Farma to carry out a precise analysis of the safety of the
developed products, the investigator pledges to document accurately the event, to respect
notification deadlines, to provide Bio Farma with all necessary information and if requested
by the sponsor, to give access to source documents.
Bio Farma pledges to inform Health Authorities as soon as it is informed of any serious
adverse event likely to be related to the product. The sponsor also pledges to inform the
Authorities of any trial discontinuation and specify the reason for discontinuation.

Blood sampling
A blood sample to be taken as soon as possible might be requested in case of serious adverse
event if it can help in analyzing the SAE.

Determination of SAE
Determination of SAE and its causal relationship with the product (vaccine) will be held by
special committee authorized by Director General of Ministry of Health as well as Regional
Vaccine Safety Advisory Committee.

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7. Evaluation Criteria

7.1. Primary Evaluation Criteria

7.1.1. Definition of the Criteria
The main evaluation criteria are number and percentage of subjects with at least one
immediate reaction (local reaction or systemic event) within 30 minutes after one dose of
Hepatits B vaccination.

7.1.2. Parameters to be measured

Immediate reaction rates occurring within 30 minutes will be assessed with 95% confidence
interval.

7.1.3. Method and Timing of Measurement

Safety assessment: the investigator will assess the intensity (code 1, 2 or 3), duration and
relation of each adverse event to the trial vaccine. Immediate safety will be evaluated within
the first 30 minutes after one dose immunizatin.

7.2. Secondary Evaluation Criteria

7.2.1. Definition of the Criteria
Safety
 Number and percentage of subjects with at least one of these adverse events, solicited or
not, within 24 h, 48h, 72h and 28 days after one dose of trial vaccine.
 Number and percentage of subjects with serious adverse event from inclusion until 28 day
after one dose vaccination.
 Any deviation from routine laboratory evaluation that probably related to the vaccination
(adults subject).
 Description of safety data between groups

Immunogenicity: Preliminary assessment of immunogenicity of anti-HBs following 1 dose of

vaccination depends on the antibody before immunization:
 Number and percentage of subjects with anti HbsAg ³ 10mIU/ml, 28 days after 1
doses of vaccine.
 Number and percentage of subjects with ³ 4 times increasing antibody
 Geometric Mean Titers (GMT) following immunization
 Anti-HBs description between groups

7.2.2. Parameters to be measured

 Local reactions and systemic events occurring within 24h, 48h, 72h and 28 days after
injection and unsolicited event rates, which occurred after 24h, 48h, 72h and 28 days will
be assessed with 95% CI.
 Any Serious Adverse Events occurring over the study period will be described.
 The result of safety will be analyzed between groups.

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Routine biochemical, hematological for vaccine safety evaluation in Adult Group.

Biochemical Hematological
SGOT Hb
SGPT Ht
Ureum Dif. Leucocyte Count
Creatinine Total Leucocyte
Total Erythrocyte
Total Thrombocyte

Immunogenicity:
Seroprotection and seroconversion will be described.

7.2.3. Method and Timing of Measurement

Safety assessment:
The investigator will assess the intensity (code 1, 2 or 3), duration and relation of each
adverse event to the trial vaccines.
Local and systemic reactions, expected or not, occurring after 24h, 48h, 72h and 28 days after
injection will be evaluated by interviewing the subjects during the post surveillance visits: V1
and V2. Particularly, the axillary temperature will be measured for three days after
vaccination, in the evening and/or at time of febrile peak, and the highest temperature will be
recorded in the diary card, expressed as Celsius degrees, using a thermometer. The trial team
will record the information in the CRF.
Any unexpected local/systemic event occurring from 72 hours to 28 days after each injection.

Immunogenicity measurements:
The anti-HBS wil be performed using Chemiluminescent Microparticle Immunoassay
(CMIA) Architect ausab reagent kit on architect i 1000sr. The architect ausab assay is a
chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of
antibody to hepatitis b surface antigen (anti-hbs) in human adult and pediatric serum and
plasma (Dipotassium edta, lithium heparin, and sodium heparin) and neonatal serum. It is
intended for quantitative measurement of antibody response following hepatitis b virus (hbv)
vaccination, determination of hbv immune status, and for the laboratory diagnosis of hbv

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disease associated with hbv infection when used in conjunction with other laboratory results
and clinical information.

The architect ausab calibrators are used to calibrate the architect i system when the system is
used for the quantitative determination of antibody to hepatitis b surface antigen (anti-hbs)
using the architect ausab reagent kit. The performance of the architect ausab calibrators has
not been established with any other anti-hbs assay.
The architect ausab controls are used for monitoring the performance of the architect i system
when used for the quantitative determination of antibody to hepatitis b surface antigen (anti-
hbs) using the architect ausab reagent kit.

7.2.4 Safety and Immunogenicity Evaluation for subjects with anti-HBs not protective
(< 10mIU/mL) before immunization

For subjects with anti-HBs not protective (< 10mIU/mL) before immunization, additional 2
doses with 1 month interval will be required and blood sample will be taken at V4 (V3 + 28
(-4/+7) days. Local reactions and systemic events occurring within 24h, 48h, 72h and 28 days
after each injection and unsolicited event rates will be recorded and evaluated. Anti-HBs will
be evaluated 28 days after third dose of vaccination.

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8. Biometry

8.1. Determination of sample size

Generally phase I studies are small-scale studies and the primary focus is determination of
clinical tolerance and safety. In phase I clinical studies, initial testing of a vaccine is carried
out in small numbers (e.g. 20) of healthy adults.14

In this phase I study, 100 subjects will be involved, which divided into two group of age
@ 50 adults and @ 50 children.

8.1.1. Data sets to be analyzed

8.1.1.1. Definition of the population
“Full Analysis Set” (Intention To Treat, ITT): Every subject included in the study will be
analyzed in this population, except if he/she did not receive any product of one of the study
vaccines.

“Per Protocol Subjects” (PP): Following non-compliant subjects will be excluded from this
population:
- Subjects included without meeting at least one inclusion criterion
- Subjects included despite meeting at least one non-inclusion criterion
- Subjects found non-compliant with the immunization or blood sampling schedule.
- Subjects vaccinated at least once with the wrong vaccine (non compliance with the
randomization schedule).
- Subjects excluded from the ITT analysis.

8.1.1.2. Populations used in the analysis

Safety Analysis:
All included and vaccinated subjects will be analyzed.

Immunogenicity Analysis:
The immunogenicity analysis will be conducted on the Per Protocol population, each subject
being analyzed according to the group.

14
WHO: WHO Guideline on Clinical Evaluation of Vaccines: Regulation Expect: Technical Report Series 924.
2004.

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8.1.2. Statistical Methodology

8.1.2.1. Primary Criteria
Safety analysis: number and percentage of subjects with at least one immediate reaction with
the frequencies of each type of immediate reaction.

8.1.2.2. Secondary Criteria

Safety analysis
At each follow-up visit, the following parameters will be computed:
 Number and percentage of subjects with at least one local reaction after 24h, 48h, 72h,
and 28 days after1st immunization, with the frequencies of each type of local reaction.
 Number and percentage of subjects with at least one systemic event after 24h, 48h, 72h,
and 28 days after 1st immunization, with the frequencies of each type of event.
 Number and percentage of subjects with at least one Serious Adverse Event, with the
frequencies of each type of event within 28 days after 1st immunization.
 Any deviation from routine laboratory evluation that probably related to the vaccination.

Immunogenicity Analysis
 Seroprotection and/or seroconversion rates after one dose immunization (V2): the
following parameters will be presented: crude rates with their 95% confidence intervals
(computed using the exact binomial probability)
 Geometric means of titers (GMTs) with their 95% CI will be presented at V0 and V2.

Safety and Immunogenicity Analysis for subjects with anti-Hbs not protective (<10
mIU/mL) before immunization

At each follow-up visit, the following parameters will be computed:

 Number and percentage of subjects with at least one local reaction after 24h, 48h, 72h,
and 28 days after 1st, 2nd and 3rd immunization, with the frequencies of each type of local
reaction.
 Number and percentage of subjects with at least one systemic event after 24h, 48h, 72h,
and 28 days after 1st, 2nd and 3rd immunization, with the frequencies of each type of event.
 Number and percentage of subjects with at least one Serious Adverse Event, with the
frequencies of each type of event within 28 days after 1st, 2nd and 3rd immunization.

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Immunogenicity Analysis
 Seroprotection and/or seroconversion rates after one and third dose immunization (V2
and V4): the following parameters will be presented: crude rates with their 95%
confidence intervals (computed using the exact binomial probability)
 Geometric means of titers (GMTs) with their 95% CI will be presented at V0, V2 and V4

8.2. Data Management

Throughout regular data collection and monitoring, clinical data reported on CRFs and/or
relevant serological/biological samples analysis results scheduled in the protocol will be
integrated into a clinical data management system.
For each batch of data, single entry, quality control and triggers to computerized logic and/or
consistency checks will be systematically applied in order to detect errors or omissions. After
integration of all corrections in the complete set of data, the data based will be locked and
saved before being released for statistical analysis.
Each step of this process will be monitored through the implementation of individual
passwords and/or regular backups in order to maintain appropriate database access and to
guarantee database integrit

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9. Adverse Events Compensation and Confidentiality

9.1. Confidentiality

9.1.1. Confidentiality of Data

Prior to initiation of the trial, the investigator will sign a fully executed confidentiality
agreement with Bio Farma.

9.1.2. Confidentiality of Patient Records

Confidentiality of patient records will be ensured by identifying documents using subject
inclusion number and initials (first three letters of the name).

9.2. Adverse Events Compensation and Insurance

Bio Farma shall insure all clinical trial subjects as consequence of their participation on this
clinical study and Bio Farma’s consequences as a sponsor. Bio Farma shall not be liable for
all claims from third parties caused by or resulting from malpractice and/or negligence or
willful misconduct of investigators and its staff.

If there is any doubt raised by cause and effect relation between adverse reactions and their
participation on this clinical study, judgment of Indonesian Vaccine Safety Advisory
Committee or NRA shall be needed.

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10. Publication Policy

The final report will be prepared by a publication committee which includes the investigators
and representatives of Bio Farma. It will be signed by the coordinating (or principal)
investigator.

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11. Bibliographical References

1. WHO. Global Health Sector Strategy on Viral Hepatitis 2016-2021 towards Ending Viral
Hepatitis. 2016.
2. WHO, Weekly epidemiological record, Hepatitis B vaccines: WHO position paper – July
2017, Geneva 2017, 27(92); 369-392.
3. WHO. The Immunological Basis for Immunization Series: Module 22: Hepatitis B,
Geneva. 2011)
4. Ministry of Health. Infodatin: Situasi dan Analisis Hepatitis. 2014.
5. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-
Preventable Diseases. Atkinson W, Wolfe S, Hamborsky J, eds. 12th ed., second printing.
Washington DC: Public Health Foundation, 2012.
6. WHO, Weekly epidemiological record, Meeting of the Strategic Advisory Group of
Experts on Immunization, October 2016 – conclusions and reccomendation, Geneva
2016, 48(91); 561-584.
7. WHO. Hepatitis B; 2015 July [cited 2018 May 25]. Available from:
http://www.who.int/mediacentre/factsheets/fs204_Jul2014/en/
8. Muljati Prijanto, Sarwo Handayani, Julitasari, Sumarno, Siti Mariani S. Immunogenicity
& Reactogenicity of Recombinant DNA Hepatitis B (Uniject) Bio Farma Vaccine Study
In Bogor. CDC, NIH R & D, Ministry of Health, 2002;JKPKBPPK/2002-12-31.
9. Diet Rustama et al. Respon antibody dan kejadian ikutan pasca imunisasi pada bayi baru
lahir yang diimunisasi Hepatitis B rekombinan uniject; SMF/Bagian Ilmu Kesehatan
Anak RS Hasan Sadikin Bandung, 2002.
10. Eddy Fadlyana, Rachmat Gunadi, Sadeli Masria, Ina Madiadipura, Dedi Subardja, Lina H
Soemara, H Kartini S, Novilia Sjafri Bachtiar. The Immunogenicity and Safety of
recombinant Hepatitis B vaccine (Bio Farma) with two different accelerated schedules in
Adults., Research Center of Health, Food and Community Nutrition, Padjadjaran
University, 2006.
11. Eddy Fadlyana, Nur Suryawan, Rodman Tarigan, Kusnandi Rusmil, Novilia S Bachtiar.
Protectivity and Safety Following Recombinant Hepatitis B (Bio Farma) Vaccine
Immunization in Late Adolescents; Hasan Sadikin Hospital/School of Medicine,
Padjadjaran University, Bandung, 2011.
12. WHO. Causality Assessment of an Adverse Event Following Immunization. Geneva:
WHO; 2013.
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13. WHO. Global Manual on Surveillance of AEFI. Geneve: WHO; 2014.

14. WHO: WHO Guideline on Clinical Evaluation of Vaccines: Regulation Expect: Technical
Report Series 924. 2004.

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12. Appendices

The following is a non-comprehensive list of possible appendices

Appendix 1: Personnel involved in the Trial
Appendix 2: Sample SAE reporting form.
Appendix 3: Plastic Bangle
Appendix 4: Signatures/Investigator’s Agreement to the Protocol

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Appendix 1: Personnel involved in the Trial

Principal Investigator Prof. Dr. Kusnandi Rusmil, dr.,Sp.A(K).,MM.

Sub-Investigators Dr. Eddy Fadlyana, dr.,Sp.A(K).,MKes.

Dr. Meita Dhamayanti, dr.,Sp.A(K).,MKes.
Rodman Tarigan, dr.,Sp.A(K).,Mkes.

Medical Advisor Prof. Cissy B. Kartasasmita, dr.,Sp.A(K).,MSc.,PhD.

Biometry Dr. Drs. Hadyana Sukandar, MSc.

Bio Farma
Monitor Dr. Novilia Sjafri Bachtiar, dr, Mkes
Rini Mulia Sari, dr
Asep Irham F.Q, dr.

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Appendix 2: SAE Reporting Forms

FORMULIR PELAPORAN KEJADIAN IKUTAN PASCA IMUNISASI Kode sumber data : ……………..
(KIPI) SERIUS Tgl.terima : ……………………..
PASIEN
Nama : …………………………… Tanggal lahir: ……./……../……… Penanggung jawab (dokter)
Nama Orangtua : …………………… Jenis kelamin: …………………………………..
Alamat : …………………………… Laki-laki ………...  Alamat (RS, Puskesmas, Klinik):
……………………………. Perempuan ………  …………………………………..
Kota : …………………………… Bagi Wanita Usia Subur (WUS): RT/RW : ……..Kel………………
Prop. : …………………………… Hamil ……………  Kota : ………..Kode Pos…….
Telp. : …………………………… Tidak hamil ……..  Prop. : ………………………..
Tidak tahu ………  Telp. : ………………………..
Pemberi imunisasi:
Dokter/bidan/perawat/jurim
Daftar vaksin yang pernah diberikan dalam 4 minggu terakhir, termasuk imunisasi terakhir
Pemberian
Tempat pemberian
Jenis vaksin Pabrik No.Lot/Batch Cara tetes Jumlah dosis Tanggal imunisasi
imunisasi (*)
oral/i.m/s.c/i.c
1
2
3
4
(*) Tempat pemberian imunisasi di:
1. Dokter Praktek/RS 2. Puskesmas 3. Posyandu 4. Balai Pengobatan/Bidan 5. Balai Imunisasi 6. Sekolah 7. Dll (sebutkan)
Manifestasi kejadian ikutan (keluhan, gejala klinis)
Waktu Lamanya
Keterangan lanjutan hasil akhir:
Mulai Mm Jam Hr
Kesadaran menurun Pasien meninggal tgl.: …../…./…..
Kejang-kejang Sakit
Demam tinggi lebih sehari Perlu tindakan darurat/dokter
Adanya kelumpuhan atau kelemahan otot Perlu perawatan RS (…..hari)
Infeksi berat ditempat injeksi Sembuh
Infeksi berat diluar tempat injeksi Belum sembuh
Reaksi alergi: Tidak diketahui
- pembengkakan bibir & tenggorokan Lain-lain …………………………
- sesak nafas …………………………
- erythema
- papula
- tekanan darah menurun (*) Ditentukan berdasarkan
Diare diagnosa dokter
Muntah
Encephalopathy (*)
Meningitis dan atau encephalitis (*)
Kelumpuhan (*)
Trombositopenia (*)
Lain-lain: ………………………………..

Pengobatan yang diberikan:

 …………………………………………...  …….……………………………………  …………………………………………
Riwayat efek samping obat/vaksin yang pernah dialami:

Obat-obatan yang diberikan bersamaan: Data laboratorium (bila ada)

………………….. …………………  ……………………
Penyakit yang diduga diderita pada saat vaksinasi (spesifik) Diagnosa dokter tentang:
Alergi, kelainan sejak lahir, pengobatan khusus (spesifik):
ada/tidak
Bila ada sebutkan: ……………………………………………
Waktu penerimaan laporan Kejadian Ikutan …………………………., tgl. ………/………./…………
Tanggal: ………./………../………… Tanda Tangan Pelapor

( )

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Appendix 3: Plastic Bangle Model

Plastic Bangle Subjects (12-40 years old)

This bangle will be printed on a transparent plastic square and will be used to assess the
intensity of local reactions, which may occur after the injection of vaccine. The bangle is
composed of one 10 cm diameter circle and one 5 cm diameter circle. These two circles
are concentric and the cross corresponds to the center of the circles.

This plastic bangle will be given to the health worker with instruction for use, as follows :
1. Place the cross at the center of the reaction (middle of the largest diameter, see
diagram)
2. Do not press on the plastic square so as not to increase the diameter of the reaction.
3. Note the intensity (1, 2 or 3).

Intensity 1 and 2 are represented by the circle that completely encircles the largest
diameter of the reaction. If the largest diameter of the reaction goes outside the biggest
circle, the intensity is 3.

For example, in this figure, the intensity is coded 2.

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Plastic Bangle (for subjects: 10-11 years old)

This bangle will be printed on a transparent plastic square and will be used to assess the
intensity of local reactions, which may occur after the injection of vaccine. The bangle is
composed of one 5 cm diameter circle and one 2.5 cm diameter circle. These two circles are
concentric and the cross corresponds to the center of the circles.

This plastic bangle will be given to the health worker with instruction for use, as follows:
1. Place the cross at the center of the reaction (middle of the largest diameter, see diagram)
2. Do not press on the plastic square so as not to increase the diameter of the reaction.
3. Note the intensity (1, 2 or 3).

Intensity 1 and 2 are represented by the circle that completely encircles the largest diameter
of the reaction. If the largest diameter of the reaction goes outside the biggest circle, the
intensity is 3.

For example, in this figure, the intensity is coded 2.

+1
2

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Appendix 4. Signatures/Investigator’s Agreement to the Protocol

Signatures Investigator’s Agreement to the protocol of

Protectivity and Safety Following Recombinant Hepatitis B (Bio Farma) Vaccine in

Adults, Adolescent & Children

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Signatures Agreement to the protocol of

Protectivity and Safety Following Recombinant Hepatitis B (Bio Farma) Vaccine in

Adults, Adolescent & Children

I have read and agree to conduct this trial according to the procedures outlined in this
protocol and in accordance with local regulations and Good Clinical Practices.

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