Conditions: End Stage Renal Disease on Hemodialysis (Diagnosis)
Keywords: ESRD Hemodialysis End Stage Renal Disease Hepatitis B HEPLISAV-B Prevention and Control HBV Vaccine Hepatitis B Vaccine HEPLISAV
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 119
Healthy volunteers: no

Brief summary:
This is an open-label, single arm study design to evaluate HEPLISAV-B® in adults with ESRD who are initiating or undergoing hemodialysis.

Detailed description:
Eligible participants will receive single doses of HEPLISAV-B® at Weeks 0, 4, 8, and 16 and will be followed through Week 68 or end of study (EOS). The study is designed to evaluate the immunogenicity over a 20-week period and safety over a 68-week period.

Arms:
arm 1: A single dose of 0.5 mL HEPLISAV-B® administered intramuscularly in the deltoid muscle at Week 0 (Visit 1), Week 4 (Visit 2), Week 8 (Visit 3), and Week 16 (Visit 4).

Interventions: intervention 1: HEPLISAV-B®
Intervention descriptions: intervention 1: HEPLISAV-B®, a licensed, commercially-available hepatitis B vaccine for adults 18 years of age and older, consisting of the adjuvant cytidine phosphoguanosine (CpG) 1018 combined with the antigen recombinant hepatitis B surface antigen (rHBsAg).

Protocol document:
Prot_000.pdf: 
 
DV2-HBV-24 
STUDY PROTOCOL 
An Open-label, Single Arm Study, Evaluating the 
Immunogenicity and Safety of HEPLISAV-B® in Adults 
With End-Stage Renal Disease Undergoing Hemodialysis 
NCT03934736 
Amendment 4: 17 April 2020 
Amendment 3: 22 July 2019 
Amendment 2: 13 February 2019 
Amendment 1: 18 December 2018 
Original: 20 August 2018 
 


Dynavax Technologies Corporation 
HEPLISAV-B® 
Protocol DV2-HBV-24 
Amendment 4 
CONFIDENTIAL 
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Protocol Title: An Open-label, Single Arm Study, Evaluating the Immunogenicity 
and Safety of HEPLISAV-B® in Adults With End-Stage Renal 
Disease Undergoing Hemodialysis 
 
Protocol No.: 
DV2-HBV-24 
 
Investigational Product: HEPLISAV-B® 
 
US IND Number: IND 12692 
 
Indication: Prevention of Hepatitis B Virus Infection 
 
Study Phase: 1 
 
Sponsor: Dynavax Technologies Corporation 
2100 Powell Street, Suite 900 
Emeryville, CA 94608 
U.S.A 
 
 
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Amendment 4: 17 April 2020 
Amendment 3: 22 July 2019 
Amendment 2: 13 February 2019 
Amendment 1: 
Original: 
18 December 2018 
20 August 2018 
 
This study will be conducted in accordance with the International Council for Harmonisation (ICH) E6(R2) Good 
Clinical Practice (GCP) guidelines and applicable local legal and regulatory requirements. 


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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: An Open-label, Single Arm Study, Evaluating the Immunogenicity and 
Safety of HEPLISAV-B® in Adults With End-Stage Renal Disease 
Undergoing Hemodialysis 
 
Protocol No.: 
DV2-HBV-24 
 
Amendment 4: 
Amendment 3: 
Amendment 2: 
Amendment 1: 
Original: 
17 April 2020 
22 July 2019 
13 February 2019 
18 December 2018 
20 August 2018 
 
Sponsor: 
Dynavax Technologies Corporation 
2100 Powell Street, Suite 900 
Emeryville, CA 94608 
U.S.A 
 
 
DECLARATION OF INVESTIGATOR 
 
I confirm that I have read and understood this protocol and agree to conduct the study as outlined 
in the protocol and other information supplied to me. I agree to conduct the study in accordance 
with ICH E6(R2) GCP guidelines and applicable local legal and regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
Investigator Signature 
Date 
 
 
 
 
 
Investigator Name (Print) 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................... 4 
LIST OF TABLES ......................................................................................................................... 7 
LIST OF FIGURES ....................................................................................................................... 7 
LIST OF APPENDICES ................................................................................................................. 7 
PROTOCOL SYNOPSIS .............................................................................................................. 8 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................... 14 
2.0 
INTRODUCTION AND RATIONALE ......................................................................... 16 
2.1 
Hepatitis B Infection in Patients With Chronic Kidney Disease ............................ 16 
2.2 
Clinical Experience With HEPLISAV-B ............................................................... 16 
2.3 
Overview of Immunogenicity in CKD Subjects .................................................... 17 
2.4 
Study Rationale ...................................................................................................... 18 
3.0 
STUDY OBJECTIVES .................................................................................................... 20 
3.1 
Primary Objective ................................................................................................... 20 
3.2 
Secondary Objectives ............................................................................................. 20 
4.0 
INVESTIGATIONAL PLAN .......................................................................................... 20 
4.1 
Study Design .......................................................................................................... 20 
4.2 
Study Endpoints ..................................................................................................... 21 
4.2.1 
Primary Endpoint ................................................................................... 21 
4.2.2 
Secondary Endpoints ............................................................................. 21 
4.3 
Duration of Study ................................................................................................... 21 
4.4 
Randomization ........................................................................................................ 21 
4.5 
Blinding .................................................................................................................. 22 
4.6 
Appropriateness of Measurements ......................................................................... 22 
5.0 
SELECTION OF PATIENTS ......................................................................................... 22 
5.1 
Inclusion Criteria .................................................................................................... 22 
5.2 
Exclusion Criteria ................................................................................................... 23 
6.0 
STUDY TREATMENT AND SUPPLIES ...................................................................... 24 
6.1 
Study Treatments .................................................................................................... 25 
6.2 
Instructions for Administration .............................................................................. 25 
6.3 
Labeling .................................................................................................................. 25 
6.4 
Storage and Handling Instructions ......................................................................... 25 
6.5 
Control and Accountability of Investigational Medicinal Product......................... 26 


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6.6 
Treatment Compliance .......................................................................................... 26 
7.0 
TREATMENT OF SUBJECTS ..................................................................................... 26 
7.1 
Treatments Administered and Treatment Period................................................... 26 
7.2 
Prohibited Treatments or Therapies ...................................................................... 27 
7.3 
Permitted Therapy ................................................................................................. 27 
8.0 
MANAGEMENT OF STUDY TREATMENT TOXICITIES .................................... 28 
8.1 
Reasons for Stopping a Subject From Receiving Additional Injections ............... 28 
8.2 
Potential Reasons for Termination of Study ......................................................... 29 
8.3 
Management of Subject Safety ............................................................................. 29 
9.0 
STUDY PROCEDURES ................................................................................................. 30 
9.1 
Informed Consent, Screening, and Eligibility ....................................................... 30 
9.1.1 
Informed Consent and Screening ......................................................... 30 
9.1.2 
Eligibility .............................................................................................. 31 
9.1.3 
Demographics and Medical and Medication History ........................... 31 
9.2 
Study Visits ........................................................................................................... 31 
9.3 
Immunogenicity Assessments ............................................................................... 31 
9.4 
Safety Assessments ............................................................................................... 31 
9.4.1 
Medical and Medication History .......................................................... 32 
9.4.2 
Physical Examinations .......................................................................... 32 
9.4.3 
Safety Laboratory Assessments ............................................................ 32 
9.4.4 
Pregnancy Testing ................................................................................ 32 
9.4.5 
Confirmation of Subject Eligibility ...................................................... 32 
9.4.6 
Post-injection Reaction Assessments ................................................... 33 
9.4.7 
Medically-Attended Adverse Events .................................................... 33 
9.4.8 
Serious Adverse Events ........................................................................ 34 
9.4.9 
Concomitant Medications ..................................................................... 34 
9.5 
End of Study .......................................................................................................... 35 
9.6 
Unscheduled Visit for Safety ................................................................................ 35 
9.7 
Duration of Follow-up ........................................................................................... 35 
10.0 
REPORTING AND DOCUMENTATION OF MEDICALLY-ATTENDED 
ADVERSE EVENTS ....................................................................................................... 35 
10.1 
Post-Injection Reactions ........................................................................................ 35 
10.2 
Adverse Events ...................................................................................................... 36 


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10.2.1 
Overdoses ............................................................................................. 37 
10.2.2 
Definition of Adverse Reaction ............................................................ 37 
10.2.3 
Definition of Suspected Adverse Reaction ........................................... 37 
10.2.4 
Definition of Unexpected Medically-Attended Adverse Event or 
Unexpected Suspected Adverse Reactions ........................................... 37 
10.3 
Serious Adverse Events ......................................................................................... 38 
10.3.1 
Definition of Serious Adverse Events .................................................. 38 
10.3.2 
Serious Adverse Event Reporting Requirements ................................. 39 
10.4 
Medically-Attended Adverse Event Severity and Relationship to Study 
Treatment .............................................................................................................. 40 
10.4.1 
Severity Grading of Medically-Attended Adverse Events and 
Abnormal Laboratory Test Results ...................................................... 40 
10.4.2 
Relationship of Medically-Attended Adverse Events to Study 
Treatment .............................................................................................. 40 
10.5 
Reporting and Documentation of Pregnancy ........................................................ 41 
11.0 
STATISTICAL METHODS........................................................................................... 42 
11.1 
Sample Size Considerations .................................................................................. 42 
11.2 
Study Analysis Populations ................................................................................... 43 
11.3 
Demographic and Baseline Characteristics ........................................................... 43 
11.4 
Immunogenicity Analyses ..................................................................................... 43 
11.5 
Safety Analyses ..................................................................................................... 43 
11.6 
Interim Analysis .................................................................................................... 44 
12.0 
DATA QUALITY ASSURANCE .................................................................................. 44 
13.0 
ETHICS ............................................................................................................................ 44 
13.1 
Institutional Review Board/Independent Ethics Committee ................................. 44 
13.2 
Ethical Conduct of the Study ................................................................................ 44 
13.3 
Informed Consent .................................................................................................. 44 
13.4 
Subject Confidentiality .......................................................................................... 45 
14.0 
DATA HANDLING AND RECORD KEEPING ......................................................... 45 
14.1 
Source Documents ................................................................................................. 45 
14.2 
Direct Access to Source Data/Documents ............................................................. 46 
14.3 
Case Report Forms ................................................................................................ 46 
14.4 
Data Handling ....................................................................................................... 47 
14.5 
Coding of Medically-Attended Adverse Events, Drugs, and Diseases ................. 47 


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14.6 
Record Retention ................................................................................................... 47 
15.0 
USE OF INFORMATION AND PUBLICATION ........................................................ 48 
16.0 
REFERENCES ................................................................................................................ 50 
 
 
LIST OF TABLES 
Table 2-1: 
Comparison of Anti-HBs Seroprotection Rates Between 
HEPLISAV-B and Engerix-B by Baseline GFR Strata and by Visit 
(mITT Population) ..................................................................................... 18 
Table 2-2: 
Comparison of Seroprotection Rates Between HEPLISAV-B and 
Engerix-B by Visit in Hemodialysis Subjects (HBV-17 mITT 
Population) ................................................................................................ 19 
Table 10-1: 
Grading Scale for Medically-Attended Adverse Events Not Included in 
the CBER Guidance on Toxicity Grading for Healthy Volunteers in 
Vaccine Clinical Trials .............................................................................. 40 
Table 10-2 
Definitions for Relationship of Medically-Attended Adverse Events to 
Trial Treatment .......................................................................................... 41 
Table 11-1: 
Sample Size Estimates .............................................................................. 42 
 
LIST OF FIGURES 
Figure 4-1: 
Study Flow Diagram ................................................................................. 21 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Assessments ........................................................................... 52 
Appendix 2: 
HEPLISAV-B® United States Package Insert ........................................... 55 
Appendix 3: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials ......................................... 67 
Appendix 4: 
List of Adverse Events of Special Interest ................................................ 68 


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PROTOCOL SYNOPSIS 
 
Protocol Title: 
An Open-label, Single Arm Study, Evaluating the Immunogenicity and 
Safety of HEPLISAV-B® in Adults With End-Stage Renal Disease 
Undergoing Hemodialysis 
 
Protocol No.: 
DV2-HBV-24 
 
Investigational 
Medicinal Product: 
HEPLISAV-B® 
 
Study Phase: 
1 
 
No. of Centers: 
25 
 
Sample Size: 
N = Approximately 115 subjects 
 
Study Objectives: 
Primary 
• 
To evaluate the safety of HEPLISAV-B with respect to clinically 
significant adverse events 
• 
To evaluate the immunogenicity induced by HEPLISAV-B at 
Week 20 as measured by seroprotection rate (SPR) 
Secondary 
• 
To evaluate the immunogenicity of HEPLISAV-B as measured by the 
percentage of subjects with anti-HBs (antibodies against hepatitis B 
surface antigen) concentration ≥100 mIU/mL 
• 
To evaluate the immunogenicity of HEPLISAV-B as measured by the 
anti-HBs geometric mean concentration (GMC) 
• 
To evaluate the immunogenicity of HEPLISAV-B at each study visit 
through 20 weeks after the first dose of study vaccine as measured by 
the SPR 
Study Design: 
This is an open-label, single arm study design to evaluate HEPLISAV-B in 
adults with end-stage renal disease (ESRD) who are initiating or 
undergoing hemodialysis. Eligible subjects will receive HEPLISAV-B at 
Weeks 0, 4, 8 and 16 and will be followed through Week 68. The study is 
designed to evaluate the immunogenicity over the 20-week period and 
safety over the 68-week period. 
Subjects will be evaluated for participation in a screening period of up to 
4 weeks prior to first dose. Subjects will return to the clinic for periodic 


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Day: 
-28 
1 29  57 113 141 197 295 477 
Week: 
-4 
0  4 
8 
16 
20 
28 
42 
68 
X X 
X 
X 
N = approx 115 
 
 
visits as per the schedule of assessments for study specific evaluations 
including evaluation of immunogenicity and safety. 
For subjects who are not seroprotected at the end of Week 20, the 
investigator will discuss options for obtaining seroprotection. 
 
Study Flow Diagram 
 
Screening 
HEPLISAV-B 
Treatment 
Follow-Up 
 
 
 
 
 
 
 
 
X = study injection 
 
 
Study Duration: 
The total duration of study participation is up to 72 weeks, which includes 
a 4-week screening period, a 16-week injection period, and a 52-week 
follow-up period. 
 
Study Assessments: 
The schedule of visits and study assessments is presented in detail in 
Appendix 1. 
Immunogenicity: Anti-HBs will be measured at baseline and then at 
Weeks 4, 8, 16, and 20. 
Safety: Subjects will be monitored for safety until Week 68. Safety 
evaluations include assessment of: 
• 
The subject’s continued eligibility (per eligibility criteria, as relevant) 
to receive an injection prior to the administration of each study 
injection 
• 
Medically-attended adverse events (MAEs) occurring from 
immediately post the first study injection through End-of-Study (EOS) 
Visit. 
• 
Serious adverse events (SAEs) and deaths occurring from the time the 
subject signs informed consent through EOS Visit. 
• 
Acute Myocardial Infarctions (AMIs; including ST-segment elevation 
and non-ST-segment elevation) and adverse events of special interest 
(AESIs; defined in Appendix 4) occurring from immediately post the 


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Study 
Treatment: 
first study injection through EOS Visit. AMIs and AESIs will be 
reviewed periodically by a Safety Monitoring Committee (SMC). 
• 
Post-injection local and systemic reactions for 7 days after each study 
injection 
HEPLISAV-B, a licensed, commercially-available hepatitis B vaccine 
consisting of 20 mcg of HBsAg and 3000 mcg of cytidine 
phosphoguanosine (CpG) 1018 adjuvant 
Dosage and Administration: 
• 
A single dose of 0.5 mL HEPLISAV-B administered intramuscularly 
in the deltoid muscle at Week 0 (Visit 1), Week 4 (Visit 2), Week 8 
(Visit 3), and Week 16 (Visit 4) 
Study Population: 
Adults with ESRD initiating or undergoing hemodialysis who have not 
previously received a hepatitis B vaccine 
 
Eligibility Criteria: 
Inclusion Criteria: 
A subject must meet all of the following criteria to be eligible for the 
study: 
1) Male and female subjects at least 18 years of age 
2) Laboratory confirmed negative serology result to hepatitis B virus 
(HBV) surface antigen (HBsAg), antibody to hepatitis B surface 
antigen (anti-HBs), and antibody to hepatitis B core antigen 
(anti-HBc) prior to first study injection 
3) Must be clinically stable and in the opinion of the investigator able to 
comply with all study procedures 
4) Must be able and willing to provide informed consent 
5) Receiving hemodialysis or will initiate hemodialysis within 4 weeks of 
first study injection 
6) Women of childbearing potential (WOCBP) must consistently use an 
acceptable method of contraception or confirm in writing she will 
abstain from sexual activity from the Screening visit through 4 weeks 
after the last dose of study injection. Acceptable birth control methods 
include but are not limited to oral contraceptive medication, an 
intrauterine device (IUD), an injectable contraceptive (such as 
medroxyprogesterone acetate or Depo-Provera®), a birth control 


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patch, or a barrier method (such as condom or diaphragm with 
spermicide). 
 
 
Exclusion Criteria: 
A subject with any one of the following criteria is not eligible for the 
study: 
1) Previous receipt of any hepatitis B vaccine 
2) History of human immunodeficiency virus (HIV) or hepatitis C virus 
(HCV) infection or antibody to HIV or HCV 
3) History of sensitivity to any component of HEPLISAV-B vaccine 
4) Substance or alcohol abuse that in the opinion of the investigator 
would interfere with compliance or with interpretation of the study 
results 
5) Recent or ongoing history of febrile illness (within 7 days of the first 
study injection) 
6) Has received any of the following prior to the first study injection: 
a) Within 14 days: 
i) Any inactivated vaccine 
b) Within 28 days: 
i) Systemic corticosteroids (more than 3 consecutive days) or 
other immunomodulatory or immune suppressive medication 
with the exception of inhaled steroids 
ii) Any live virus vaccine 
iii) Granulocyte colony-stimulating factor (G-CSF) or 
granulocyte-macrophage colony-stimulating factor (GM-CSF) 
iv) Any other investigational medicinal agent 
c) Within 90 days: 
i) Blood products or immunoglobulin 
7) If female and pregnant, nursing, or planning to become pregnant 
during the study 


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8) Undergoing chemotherapy or expected to receive chemotherapy 
during the study period. 
9) Has a medical condition considered by the investigator likely to 
interfere with the subject’s compliance or the interpretation of study 
assessments, including the following laboratory abnormalities which 
the investigator may consider if severe: 
a) Anemia 
b) Thrombocytopenia 
c) Leukocytosis 
d) Neutropenia 
e) Metabolic acidosis 
f) Increased alanine aminotransferase or aspartate aminotransferase 
g) Hyperkalemia 
h) Hypokalemia 
10) Is scheduled to undergo a kidney transplant within 6 months of the 
first study injection 


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Statistical Methods 
The Safety Population will comprise all subjects who received at least 1 
study injection, excluding subjects who have no on-study safety data. 
The Per-protocol (PP) Population for the immunogenicity analysis will 
comprise all subjects who receive all study injections, have no major 
protocol violations (to be specified in the Statistical Analysis Plan), and 
have anti-HBs levels obtained within study visit windows at Week 20. 
The modified intent-to-treat (mITT) population for the immunogenicity 
analysis will comprise all subjects who receive at least 1 study injection 
and have at least 1 post-injection immunogenicity evaluation. 
For immunogenicity analysis, the SPR at specified timepoints will be 
estimated. The associated 2-sided 95% confidence interval will be 
calculated using the Clopper-Pearson method. 
For safety analysis, the incidence and proportion of post-injection 
reactions and MAEs will be summarized. MAEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) System of Organ 
Class (SOC) and Preferred Term (PT). 
The sample size calculation is based on approximately 100 subjects in the 
per-protocol population. With an expected 15% loss to follow up prior to 
week 20, approximately 115 subjects will be enrolled. This sample size 
would allow estimating immunogenicity response at the following 
accuracy levels depending on the observed immunogenicity responses: 
 
N 
If Observed 
Immunogenicity 
Response is 
Width of the 
Resulting 95% 
Confidence Interval 
Lower Limit of the 
Resulting 95% 
Confidence 
Intervala 
100 
80.0% 
0.165 
70.8% 
100 
86.0% 
0.145 
77.6% 
100 
90.0% 
0.127 
82.4% 
100 
95.0% 
0.096 
88.7% 
N = number of subjects 
a Calculation based on exact method (Clopper-Pearson) 
Note: Approximately 115 subjects will be enrolled to meet the N of 100 evaluable subjects 
in the per-protocol population. 
A preliminary analysis may be performed to assess the primary 
immunogenicity objective of the SPR at Week 20 after approximately 50 
subjects have completed their Week 20 visit. 


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1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AMI 
acute myocardial infarction 
anti-HBc 
antibodies against hepatitis B core antigen 
anti-HBs 
antibodies against hepatitis B surface antigen 
AR 
adverse reaction 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CpG 
cytidine phosphoguanosine 
CRF 
case report form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End-of-Study (visit) 
ESRD 
end-stage renal disease 
FDA 
United States Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GMC 
geometric mean concentration 
HBcAg 
hepatitis B core antigen 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IUD 
intrauterine device 


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Abbreviation or Term 
Definition 
MAE 
medically-attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat (population) 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SMC 
Safety Monitoring Committee 
SPR 
seroprotection rate 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
UNS 
unscheduled visit/safety follow-up visit 
WOCBP 
women of child-bearing potential 


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2.0 
INTRODUCTION AND RATIONALE 
2.1 
Hepatitis B Infection in Patients With Chronic Kidney Disease 
 
Chronic Kidney Disease (CKD) patients are at increased risk of exposure to hepatitis B virus 
(HBV) in the hemodialysis setting where prolonged vascular access is required. In an 
environment where multiple patients receive dialysis concurrently, repeated opportunities exist 
for person-to-person transmission of infectious agents, directly or indirectly via contaminated 
devices, equipment and supplies, environmental surfaces, or hands of healthcare personnel. 
 
The Advisory Committee on Immunization Practices recommends that hemodialysis patients 
receive hepatitis B vaccination (Schillie, Vellozzi et al. 2018). Unlike healthy individuals, in 
patients with CKD, long-term protection against HBV infection depends on maintenance of 
anti-HBs (antibodies against HBsAg) because of impaired anamnestic responses (Girndt and 
Litjens 2010). Long-term maintenance of an anti-HBs level ≥ 10 mIU/mL is desirable since 
breakthrough infections have occurred in patients with CKD with levels < 10 mIU/mL (Buti, 
Viladomiu et al. 1992, Miller, Alter et al. 1999), and the duration of protection against HBV 
depends on the peak post-vaccination antibody level (Jilg, Lorbeer et al. 1984, Floreani, Baldo et 
al. 2004). Some authors have proposed that an anti-HBs level ≥ 100 mIU/mL is desirable in 
CKD patients because it correlates better with longer duration of protection than lower levels 
(Navarro, Teruel et al. 1996, Sezer, Ozdemir et al. 2000, Chaves, Daniels et al. 2011). 
At the end of 2015, an estimated 444,337 patients were on chronic hemodialysis in the US with 
more than 108,826 patients initiating hemodialysis that year, many of whom likely needed 
hepatitis B vaccination (National Institutes of Health 2017).While the number of HBV infections 
reported in hemodialysis patients in the US is low, the risk of transmission remains high and 
dialyzing patients with HBV infection requires special precautions including using dedicated 
rooms, machines, instruments, medications, supplies, and staff to reduce the risk of infecting 
other patients (Centers for Disease Control and Prevention 2001, Schillie, Vellozzi et al. 2018). 
2.2 
Clinical Experience With HEPLISAV-B 
 
A summary of the clinical studies conducted with HEPLISAV-B® in healthy adults is provided in 
the United States Package Insert (USPI) (Appendix 2) and the Investigator’s Brochure. 


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In the CKD clinical development program, Dynavax completed the following 3 studies to 
evaluate the use of HEPLISAV-B in patients with CKD, which included patients on 
hemodialysis: 
• 
DV2-HBV-17, Safety and immunogenicity: An Observer-Blinded, Randomized Study 
Comparing the Safety and Immunogenicity of HEPLISAV™ to Licensed Vaccine 
(Engerix-B®) among Adults (18 to 75 Years of Age) with Chronic Kidney Disease (CKD) 
• 
DV2-HBV-18, Booster: An Open-Label, Randomized, Multi-Center Study Comparing the 
Safety and Immunogenicity of HEPLISAV™ to Engerix-B® and Fendrix® in Adults on 
Hemodialysis Who Have Previously Received Hepatitis B Vaccination and Are Not 
Seroprotected 
• 
DV2-HBV-19, Long-term follow up: An Observational Study Evaluating the Long-Term 
Safety and Immunogenicity of HEPLISAV™ Compared with Engerix-B® in Adults With 
Chronic Kidney Disease Who Have Previously Received at Least One Hepatitis B Vaccine 
Series 
 
Dynavax vaccinated 620 adults with CKD in trials HBV-17 and HBV-18, including 308 subjects 
who received HEPLISAV-B and 312 subjects who received Engerix-B (HBV-19 was a 
long-term observational study of subjects who were enrolled in HBV-17). 
 
For additional information on experience with CKD, please refer to the Investigator's Brochure. 
 
2.3 
Overview of Immunogenicity in CKD Subjects 
 
The HBV-17 study enrolled 521 subjects (HEPLISAV-B: n = 258; Engerix-B: n = 263). Of 
these, a subset of patients (N = 68, or 13.1%) in study HBV-17 were on hemodialysis either at 
the start of the study or initiated hemodialysis during the study. 
 
The HBV-17 trial compared the immune response following a 3-injection regimen with 
HEPLISAV-B administered over a 6-month period (Weeks 0, 4, and 24) versus the standard 
8-injection (4 double doses) regimen of Engerix-B, also administered over a 6-month period 
(Weeks 0, 4, 8, and 24). The primary objective of HBV-17 was to demonstrate the noninferiority 
of the seroprotection rate (SPR) at 4 weeks after the last active dose of HEPLISAV-B (Week 28) 
to the SPR at 4 weeks after the last active dose of Engerix-B (Week 28). The noninferiority 
margin was -10% in the difference in SPRs (HEPLISAV-B minus Engerix-B). Both the primary 
endpoint of noninferiority and the secondary endpoint of significantly higher immune response, 
measured by SPR, were demonstrated. 
 
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2.4 
Study Rationale 
 
In this study, the safety and immunogenicity in patients on hemodialysis will be evaluated 
further to investigate an optimal dosing regimen for this patient population. An optimal dosing 
regimen for HEPLISAV-B that induces higher rates of protection, earlier onset of protective 
immunity, and longer duration of protection in hemodialysis patients would be an important 
advance in vaccine development given the ongoing risk of HBV infection in the hemodialysis 
setting and consequences of HBV infection in this highly compromised patient population. 
 
This study will consist of a 4-injection (0.5 mL per injection) regimen of HEPLISAV-B at 
Weeks 0, 4, 8, and 16. It is anticipated that a fourth dose of HEPLISAV-B will provide improved 
seroprotection than what was seen in study HBV-17 for hemodialysis patients. 


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For the primary immunogenicity endpoint, SPR will be evaluated at Week 20, 4 weeks after the 
last injection, because the peak SPR for hemodialysis subjects in study HBV-17 was observed 
4 weeks after the last injection (Week 28). 
 
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Data Source: HBV-17 post-hoc analysis Table 8.1. 
CI = confidence interval; mITT = modified intent-to-treat; SPR = seroprotection rate. 
a 
Study injections were given at Weeks 0, 4, 8 (placebo), and 24. 
b 
Study injections were given at Weeks 0, 4, 8, and 24. 
c 
Calculated using the Clopper Pearson method. 
d 
Two-sided 95% CIs of the difference in seroprotection rates between HEPLISAV-B and Engerix-B at each visit week were 
computed using the Newcombe score method with continuity correction. 


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
• To evaluate the safety of HEPLISAV-B with respect to clinically significant 
adverse events 
• To evaluate the immunogenicity induced by HEPLISAV-B at Week 20 as 
measured by the seroprotection rate (SPR) 
3.2 
Secondary Objectives 
• To evaluate the immunogenicity of HEPLISAV-B as measured by the percentage 
of subjects with anti-HBs concentration ≥100 mIU/mL 
• To evaluate the immunogenicity of HEPLISAV-B as measured by the anti-HBs 
geometric mean concentration (GMC) 
• To evaluate the immunogenicity of HEPLISAV-B at each study visit through 20 
weeks after the first dose of study vaccine as measured by the SPR 
4.0 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
 
This is an open-label, single arm study design to evaluate HEPLISAV-B in adults with end-stage 
renal disease (ESRD) who are initiating or undergoing hemodialysis. Eligible subjects will 
receive HEPLISAV-B at Weeks 0, 4, 8 and 16 and will be followed through Week 68 (Figure 4- 
1). The study is designed to evaluate the immunogenicity and safety over the 68-week period. 
Study assessments are outlined in Appendix 1. 
 
Subjects will be evaluated for participation in a screening period of up to 4 weeks prior to first 
dose. Subjects will return to the clinic for periodic visits as per the schedule of assessments for 
study specific evaluations including evaluation of immunogenicity and safety (Appendix 1). 
 
For subjects who are not seroprotected at the end of Week 20, the investigator will discuss 
options for obtaining seroprotection. 


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Day: 
-28 
1 29  57 113 141 197 295 477 
Week: 
-4 
0  4 
8 
16 
20 
28 
42 
68 
X X 
X 
X 
N = approx 115 
 
 
Figure 4-1: 
Study Flow Diagram 
 
 
Screening 
HEPLISAV-B 
Treatment 
Follow-Up 
 
 
 
 
 
 
 
 
 
X = study injection 
 
4.2 
Study Endpoints 
4.2.1 
Primary Endpoint 
• Proportion of subjects with treatment-emergent MAEs 
• Proportion of subjects with treatment-emergent SAEs, acute myocardial 
infarctions (AMIs), or deaths 
• Proportion of subjects with treatment-emergent immune-mediated adverse events 
of special interest (AESIs) 
• SPR at Week 20 
4.2.2 
Secondary Endpoints 
• Proportion of subjects with anti-HBs concentration ≥100 mIU/mL 
• Anti-HBs geometric mean concentration (GMC) 
• SPR at each study visit after the first dose of study vaccine 
 
4.3 
Duration of Study 
 
The total duration of study participation is up to 72 weeks, which includes a 4-week screening 
period, a 16-week injection period, and a 52-week follow-up period. 
4.4 
Randomization 
 
None of the patients in this study will be randomized. 


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4.5 
Blinding 
 
Blinding will not be performed as this is an open-label study. 
 
4.6 
Appropriateness of Measurements 
 
The measures of both immunogenicity and safety in the study are routine clinical and laboratory 
procedures. The definition of seroprotection used in this study (anti-HBs ≥ 10 mIU/mL) is the 
same as that upon which the approval of licensed HBV vaccines has been based (Centers for 
Disease Control and Prevention 1985, Keating and Noble 2003) and is considered the standard in 
the medical-scientific community. 
5.0 
SELECTION OF PATIENTS 
 
The study population will include adults with ESRD initiating or undergoing hemodialysis who 
have not previously received a hepatitis B vaccine and who meet the inclusion and exclusion 
criteria as described in detail in Sections 5.1 and 5.2. 
5.1 
Inclusion Criteria 
 
A patient must meet all of the following criteria to be eligible for enrollment (defined as 
receiving the first study treatment [ie, HEPLISAV-B injection]) in the study: 
 
1) Male and female subjects at least 18 years of age 
2) Laboratory confirmed negative serology result to hepatitis B virus (HBV) surface antigen 
(HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core 
antigen (anti-HBc) prior to first study injection 
3) Must be clinically stable and in the opinion of the investigator able to comply with all study 
procedures 
4) Must be able and willing to provide informed consent 
5) Receiving hemodialysis or will initiate hemodialysis within 4 weeks of first study injection 
 
6) Women of childbearing potential (WOCBP) must consistently use an acceptable method of 
contraception or confirm in writing she will abstain from sexual activity from the Screening 
visit through 4 weeks after the last dose of study injection. Acceptable birth control methods 
include but are not limited to oral contraceptive medication, an intrauterine device (IUD), an 
injectable contraceptive (such as medroxyprogesterone acetate or Depo-Provera®), a birth 
control patch, or a barrier method (such as condom or diaphragm with spermicide). 


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5.2 
Exclusion Criteria 
A subject with any one of the following criteria is not eligible for the study: 
1) Previous receipt of any hepatitis B vaccine 
2) History of human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection or 
antibody to HIV or HCV 
3) History of sensitivity to any component of HEPLISAV-B vaccine 
4) Substance or alcohol abuse that in the opinion of the investigator would interfere with 
compliance or with interpretation of the study results 
5) Recent or ongoing history of febrile illness (within 7 days of the first study injection) 
6) Has received any of the following prior to the first study injection: 
a) Within 14 days: 
i) Any inactivated vaccine 
b) Within 28 days: 
i) Systemic corticosteroids (more than 3 consecutive days) or other immunomodulatory 
or immune suppressive medication with the exception of inhaled steroids 
ii) Any live virus vaccine 
iii) Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage 
colony-stimulating factor (GM-CSF) 
iv) Any other investigational medicinal agent 
c) Within 90 days: 
i) Blood products or immunoglobulin 
7) If female and pregnant, nursing, or planning to become pregnant during the study 
8) Undergoing chemotherapy or expected to receive chemotherapy during the study period 


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9) Has a medical condition considered by the investigator likely to interfere with the subject’s 
compliance or the interpretation of study assessments, including the following laboratory 
abnormalities which the investigator may consider if severe: 
a) Anemia 
b) Thrombocytopenia 
c) Leukocytosis 
d) Neutropenia 
e) Metabolic acidosis 
f) Increased alanine aminotransferase or aspartate aminotransferase 
g) Hyperkalemia 
h) Hypokalemia 
10) Is scheduled to undergo a kidney transplant within 6 months of the first study injection 
 
5.2.1 
Contraception 
 
WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal. All female patients are considered to be WOCBP 
except if they have been postmenopausal (amenorrhea for at least 12 consecutive months or on 
hormone replacement therapy) for at least 1 year or surgically sterile for at least 1 year. 
 
NOTE: 
 
• Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, 
skin patches, or implanted or injectable products), or mechanical products such as an 
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent 
pregnancy, or where their partner is sterile (eg, vasectomy) should be considered to be of 
childbearing potential. 
• Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
patient. Abstinence as a contraceptive method must be documented in writing by the subject. 
6.0 
STUDY TREATMENT AND SUPPLIES 
 
The identity and instructions for administration, storage, and handling of HEPLISAV-B are 
described below. 


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6.1 
Study Treatments 
 
The investigational vaccine to be tested is HEPLISAV-B, a licensed, commercially-available 
hepatitis B vaccine consisting of 20 mcg of HBsAg and 3000 mcg of cytidine 
phosphoguanosine (CpG) 1018 adjuvant. 
 
HEPLISAV-B [Hepatitis B Vaccine (Recombinant), Adjuvanted] is a sterile solution for 
intramuscular injection. Each 0.5 mL dose contains HEPLISAV-B in a solution for injection 
supplied as a single-dose. Additional information for HEPLISAV-B is provided in the USPI 
(Appendix 2). 
6.2 
Instructions for Administration 
Administer HEPLISAV-B by intramuscular injection in the deltoid muscle region using the 
pre-filled syringe. HEPLISAV-B administration must be performed prior to the start of dialysis 
on study visit days. 
6.3 
Labeling 
 
During the course of the study, HEPLISAV-B labeled for clinical study use will be provided. 
 
At a minimum, HEPLISAV-B will be labeled with the following information: product name, 
product lot number, contents, volume, concentration, sponsor name, and a statement indicating 
that the drug is for investigational use only. 
6.4 
Storage and Handling Instructions 
 
HEPLISAV-B must be stored in a refrigerator at 2°C to 8°C (35°F to 46°F). Do not freeze. If 
frozen, continue to store the vaccine in the refrigerator but isolate it from other study vaccine and 
follow the temperature excursion procedures outlined in the Pharmacy Manual. Do not use the 
vaccine after the expiration date shown on the product label. 
 
The clinical supplies storage area at the site must be monitored closely by the designated site 
staff for temperature consistency and documentation of temperature monitoring must be 
maintained. Temperature excursions outside of the recommended storage range may impact 
product quality and must be reported to Dynavax or its designee per the detailed instructions in 
the Pharmacy Manual. 


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6.5 
Control and Accountability of Investigational Medicinal Product 
 
All investigational medicinal product must be received by a trained designated person at the 
study site, handled and stored safely and properly, and kept in a secured location with limited 
access. 
 
The investigator (or responsible designee) must maintain current and accurate records of the 
receipt (documentation from shipments of study treatments received), administration 
(patient-by-patient and overall accounting) and return of study treatments to a Dynavax-specified 
facility for destruction. All study treatments must be stored in a location with access restricted to 
authorized personnel only. 
 
A study monitor will be responsible for monitoring the drug accountability at the site. The 
monitor should be contacted with any questions concerning administration of study treatments. 
 
Records of study treatments accountability, storage, and handling must be made available to the 
study monitor for the purposes of study treatments accountability. Any discrepancy and/or 
deficiency must be recorded with an explanation. 
 
The investigator must retain all used product and expired, damaged, and unused study treatments 
until accountability has been confirmed by the study monitor. Any exceptions to this policy must 
be specifically permitted by Dynavax. 
 
At the end of the study, or upon request by Dynavax, all unused study treatments must be 
returned to a Dynavax-specified facility for adequate disposition. 
 
Refer to the Pharmacy Manual for detailed instructions on study treatments. 
 
Study treatments may not be used for any purpose other than that described in the protocol. 
 
6.6 
Treatment Compliance 
 
All study injections will be administered by designated personnel only. 
 
7.0 
TREATMENT OF SUBJECTS 
7.1 
Treatments Administered and Treatment Period 
 
Subjects will receive HEPLISAV-B administered intramuscularly in the deltoid muscle at 
Week 0 (Visit 1), Week 4 (Visit 2), Week 8 (Visit 3), and Week 16 (Visit 4) as outlined in the 
Schedule of Assessments (Appendix 1). HEPLISAV-B must be administered prior to the start of 
dialysis on each vaccine administration day. 


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7.2 
Prohibited Treatments or Therapies 
 
The following non-study medications are prohibited: 
 
14 days prior to Injection 1 and through 28 days following each injection: 
• any inactivated virus vaccine 
28 days prior to Injection 1 and through Week 28: 
• Systemic corticosteroids (more than 3 consecutive days) or other immunomodulators or 
immune suppressive medication, with the exception of inhaled steroids 
• Any live virus vaccine 
• Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage 
colony-stimulating factor (GM-CSF) 
28 days prior to Injection 1 and through Week 68 (unless approved by sponsor): 
• Any other investigational medicinal agent (may be allowed after Week 28 [Day 197] 
upon sponsor approval) 
90 days prior to Injection 1 and through Week 28: 
• Blood products or immunoglobulin 
 
If a subject requires treatment that is prohibited, the investigator should contact the Dynavax 
medical monitor or designee to determine whether the subject should receive further study 
injections. If the subject is not eligible for subsequent study injections, the subject will not be 
withdrawn from the study, but will be followed for safety through End-of-Study (EOS) Visit. 
7.3 
Permitted Therapy 
 
Use of any permitted medication, including over-the-counter medications or vaccine during the 
28 days prior to first injection through Week 28 or Early Discontinuation Visit should be 
solicited from each subject and recorded in source documents. Use of vitamins and dietary 
supplements will not be collected unless they are indicated as a concomitant therapy for 
conditions directly related to undergoing hemodialysis. Medications started prior to first dose, 
and any medication used in the 28 days prior to first dose but not continued at the time of first 
dose, will be recorded. 
 
All collected concomitant medications will be recorded in the electronic Case Report Form 
(eCRF) through Week 28. After Week 28, only prescription medication or over-the-counter drug 
taken by the subject for the treatment of MAEs, SAEs, AMIs, or AESIs will be recorded on the 


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eCRF through EOS Visit (further details regarding safety monitoring of AMIs and AESIs are 
provided in Section 9.4.7.2). 
8.0 
MANAGEMENT OF STUDY TREATMENT TOXICITIES 
8.1 
Reasons for Stopping a Subject From Receiving Additional Injections 
 
The investigator will discontinue study treatment and notify the sponsor if any of the following 
MAEs occur: 
• Grade 4 post-injection reaction within 7 days after any study injection 
• Clinically significant Grade 3 or higher systemic reaction (eg, angioedema, generalized 
urticaria) within 7 days after any study injection 
• Grade 3 or 4 hypotension within 24 hours of any study injection 
• Grade 3 or 4 respiratory reaction or symptoms occurring within 24 hours of any study 
injection 
• Any life-threatening event, regardless of relationship to study drug 
• Any AMI (further details regarding safety monitoring of AMIs are provided in 
Section 9.4.7.2) 
• Any confirmed AESI (further details regarding safety monitoring of AESIs are provided in 
Section 9.4.7.2) 
 
Subjects must also be discontinued from study treatment for any of the following reasons: 
 
• Violation of protocol eligibility criteria 
• Prohibited medications 
• SAE assessed as a suspected adverse reaction (SAR) or adverse reaction (AR) 
• Pregnancy or breastfeeding 
 
Subjects may be discontinued from the study for any of the following reasons: 
 
• Violation of protocol eligibility criteria (only if the subject has not received any study 
treatment) 
• Prohibited medications (only if the subject has not received any study treatment) 
• Noncompliance with study procedures as determined by the investigator or sponsor 
• The discretion of the investigator 


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• The sponsor’s administrative decision to terminate the study 
 
The investigator or designee must notify Dynavax within 24 hours when a subject has been 
discontinued from treatment due to an MAE. The subject should not be withdrawn from the 
study and should continue to be followed for safety (as defined in Section 9.7) through EOS 
Visit. 
8.2 
Potential Reasons for Termination of Study 
 
The study will terminate on the date of the last visit of the last participant. However, the sponsor 
reserves the right to terminate the study at any time. Reasons for termination include but are not 
limited to: 
• Inability to enroll sufficient subjects into the study 
• Federal regulations/Good Clinical Practice (GCP) compliance issues that compromise the 
validity of the study and/or subject safety 
• AMIs occurring in ≥ 10% of subjects AND occurring in ≥ 4 subjects (further details 
regarding safety monitoring of AMIs are provided in Section 9.4.7.2) 
• AESIs occurring in ≥ 5% subjects AND occurring in ≥ 3 subjects (further details regarding 
safety monitoring of AESIs are provided in Section 9.4.7.2) 
8.3 
Management of Subject Safety 
 
Subjects will be evaluated prior to each study injection to confirm the subject is eligible (per 
eligibility criteria [Section 5.0], as relevant) to receive an injection. 
 
Injection-site reactions are expected to spontaneously subside. Local pruritus and pain can be 
treated with oral medications. If significant symptoms of pain and induration persist for more 
than 12 hours, an ice pack may be applied locally for 30 minutes every 2 hours, as needed. Use 
of an ice pack prior to 12 hours after the onset of symptoms is discouraged, as it may interfere 
with the action of the study vaccine. Do not inject into a site if local pain, tenderness, swelling, 
or pruritus persists from a previous injection or other cause. 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
investigator. The investigator should ensure that adequate medical care is provided to a subject 
for any MAE, including clinically significant laboratory values, related to the study. For each 
disorder, attempts should be made to rule out other causes, which might require additional 
supportive care. The investigator should inform the study medical monitor when medical care is 
needed for intercurrent illness(es) of which the investigator becomes aware. 


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An unscheduled visit (UNS) should be performed if there are suspected subject safety concerns. 
All supportive therapies will be recorded in the subject’s eCRF. 
 
Subjects who are discontinued from the study will be scheduled for an Early Discontinuation 
Visit 28 days following their last vaccine administration. 
9.0 
STUDY PROCEDURES 
 
All tests and evaluations required at specified time points are listed in the Schedule of 
Assessments (Appendix 1). The results of these tests and evaluations must be entered in the 
subject’s source document and also recorded on the subject's eCRF. Additional evaluations may 
be done at the discretion of the investigator and with sponsor approval. 
9.1 
Informed Consent, Screening, and Eligibility 
9.1.1 
Informed Consent and Screening 
 
The investigator or designee must review the informed consent form (ICF) with each prospective 
subject to be certain that the prospective subject understands the procedures and risks of the 
study. Prospective subjects who wish to participate in the study must provide written informed 
consent by signing the ICF before undergoing any screening procedures. Subjects may undergo 
study screening tests prior to giving written informed consent provided that these tests are 
considered part of standard care. 
 
The information from the consent form should be translated and communicated to the subject in 
language understandable to the subject. 
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the study. The initial ICF and any subsequent revised written ICF, and written information 
must receive the Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available that 
may be relevant to the subject’s willingness to continue participation in the study. The 
communication of this information should be documented. 
 
The investigator or designee will maintain a log of all subjects who sign the ICF. At a minimum, 
the log will include a subject identifier, the dates of informed consent and screening procedures, 
the outcome of the screening, and the reason the subject did not enroll in the study, if applicable. 
 
For screen failures, at a minimum age, sex, ethnicity, race, height, and weight, the reason for 
screen failure, and any SAEs that occur during the screening period will be collected. 


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Additional requirements for informed consent are presented in Section 13.3. 
 
9.1.2 
Eligibility 
 
After written consent is obtained, screening procedures must be carried out per the Schedule of 
Assessments (Appendix 1). A subject must meet all of the inclusion criteria and none of the 
exclusion criteria to be eligible to participate in the study. Documentation of ESRD must be 
obtained prior to enrollment. Assignment of subject number is described in the Study Reference 
Manual. 
9.1.3 
Demographics and Medical and Medication History 
 
Demographic and baseline characteristics of sex, race, ethnicity, age, weight, and height of the 
subject will be collected. Medical history, defined in Section 9.4.1, will also be recorded. 
9.2 
Study Visits 
 
Procedures should be performed as close to the scheduled time as possible. The window for 
study visits is ± 7 days. A detailed outline of all scheduled study procedures is provided in the 
Schedule of Assessments (Appendix 1). Procedures should be performed at the study center 
where the subject is being treated, except for Weeks 28 and 42 which will be conducted via 
telephone call. Subjects who fail screening may be rescreened per approval by the sponsor. 
 
The exact time at which a procedure is performed must be recorded in the subject’s study records 
or appropriate worksheet (if applicable). Any nonscheduled procedures required for urgent 
evaluation of safety concerns take precedence over all routine scheduled procedures. 
 
Blood collections for safety evaluation assume priority over other procedures. Laboratory 
samples must be collected prior to HEPLISAV-B administration on study injection visit days. 
Blood collection and HEPLISAV-B administration must be performed prior to the start of 
dialysis on study visit days. 
9.3 
Immunogenicity Assessments 
 
Serum sample will be obtained for anti-HBs measurements at baseline and then at Weeks 4, 8, 
16, and 20. 
9.4 
Safety Assessments 
 
The safety assessments are listed below. The Schedule of Assessments is provided in 
Appendix 1. 


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9.4.1 
Medical and Medication History 
 
Medical history includes clinically significant diseases, surgeries, kidney disease history, 
autoimmune diseases, and all medications (eg, prescription drugs, over-the-counter drugs) used 
by the subject within 28 days prior to the Screening Visit. 
9.4.2 
Physical Examinations 
 
The investigator or qualified designee will conduct physical examinations. A full physical 
examination (excluding pelvic/genital, rectal, and breast examination) will be conducted at 
Screening, and a targeted physical examination based on subject-reported symptoms (excluding 
pelvic/genital, rectal, and breast examination) will be conducted at each study injection visit and 
End-of-Study (EOS) Visit or Early Discontinuation Visit. 
9.4.3 
Safety Laboratory Assessments 
 
Laboratory assessments are listed below and will be performed according to the Schedule of 
Study Assessments (Appendix 1). Sample collections will be prior to injection on vaccination 
days. Laboratories obtained within 7 days of Day 1 visit do not need to be repeated on Day 1. 
• Serum chemistry and hematology will be performed at Screening by a central laboratory. 
• Hepatitis and HIV testing at Screening Visit by a central laboratory: serum hepatitis B, 
hepatitis C, and HIV testing by laboratory tests for HBsAg, anti-HBc, anti-HBs, anti-HCV, 
and anti-HIV-1/2, respectively 
• Reserve serum and plasma aliquot specimens will be collected and stored frozen for possible 
future testing. 
• Additional details for specific tests are provided in the Laboratory Manual. 
9.4.4 
Pregnancy Testing 
 
All WOCBP (as defined in Section 5.2.1) who are being considered for participation in the study 
will be tested for pregnancy with a serum test at Screening Visit and a serum or urine β-human 
chorionic gonadotropin (β-hCG) test within 72 hours prior to taking each dose of study 
treatment. If the urine test is positive or cannot be confirmed as negative, then a serum test is 
required which must be negative for the subject to enroll. 
9.4.5 
Confirmation of Subject Eligibility 
 
Subjects will be evaluated prior to each study injection to confirm the subject is eligible (per 
eligibility criteria [Section 5.0], as relevant) to receive an injection. 


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9.4.6 
Post-injection Reaction Assessments 
 
Assessments of post-injection reactions will be collected for a minimum of 30 minutes following 
each of the HEPLISAV-B injections at the clinical site and as reported by the subject in a diary 
for 7 days. Information about the presence and severity of post-injection local (injection site) 
reactions (redness, swelling, and pain at or near the injection site) and systemic reactions 
(malaise, headache, myalgia, and fatigue) that are listed in the subject diary are considered 
solicited post-injection reactions. Oral temperature is also collected. Solicited post-injection 
reactions are related to treatment and recorded for 7 days following each study injection, 
including the day of injection. Post-injection reactions documented by the subject will be 
collected, reviewed by the study nurse/coordinator with the subject, and recorded on the 
appropriate eCRF. The grading criteria for post-injection reactions are in Appendix 3. Further 
information is provided in the Study Reference Manual. 
9.4.7 
Medically-Attended Adverse Events 
 
All MAEs, as defined in Section 10.2, will be evaluated from immediately after the first study 
treatment on Day 1 through EOS Visit. (Additionally, if the subject is discontinued early from 
study treatment, the subject should not be withdrawn from the study and should continue to be 
followed for safety, as described in Section 9.7, through EOS Visit.) 
9.4.7.1 
Adverse Events of Special Interest 
 
Subjects who experience signs or symptoms that the investigator or designee considers to be 
associated with potential AESIs (defined according to a pre-specified list of event terms 
including autoimmune, autoinflammatory, and hypersensitivity disorders; Appendix 4 provides 
the full list), as well as any other potentially immune-mediated medical conditions that do not 
appear in Appendix 4, will be referred for consultation with appropriate experts (eg, 
rheumatology, immunology) for confirmation. 
9.4.7.1.1 
Adverse Events of Special Interest Reporting Requirements 
 
All potential AESIs, regardless of seriousness, severity, or relationship to the injection, will be 
reported to Dynavax or the Dynavax designee. In addition to describing the event on the 
appropriate eCRFs and in the source documents, Dynavax should be informed within 72 hours 
by contacting the Dynavax Medical Monitor or designee by submitting a completed Potential 
Autoimmune Event Report Form (events assessed as serious must be reported to Dynavax or its 
designee within 24 hours of investigator awareness of the event, as described in Section 10.3.2). 
Follow-up information should be actively sought and submitted as it becomes available. 


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Any AESI regardless of relationship to study treatment will be followed as clinically indicated 
until its resolution or, if non-resolving, until it is considered chronic or stable by the investigator. 
 
Once the site principal investigator refers a subject to an expert evaluation for possible AESI, 
injections should be discontinued until further notice. If the expert evaluation reveals that the 
subject did NOT have an AESI, injections can be resumed. If the expert evaluation confirms an 
AESI, then injections will be permanently discontinued for the subject. In either event, the 
subject will be followed for safety (as defined in Section 9.7) through EOS Visit. 
9.4.7.2 
Safety Monitoring Committee 
 
The sponsor will establish a Safety Monitoring Committee (SMC) to evaluate AMI (including 
ST-segment elevation and non-ST-segment elevation) and AESIs (defined according to a 
pre-specified list of event terms including autoimmune, autoinflammatory, and hypersensitivity 
disorders provided in Appendix 4; other potentially immune-mediated medical conditions that do 
not appear in Appendix 4 are also considered AESIs). 
 
All AMIs and AESIs occurring from immediately after the first study treatment on Day 1 
through EOS Visit will be collected and evaluated. 
 
Refer to SMC charter for details on the conduct, membership, and meeting frequency of the 
SMC. 
9.4.8 
Serious Adverse Events 
 
All serious adverse events (SAEs), as defined in Section 10.3.1, will be evaluated from the time 
the consent is signed through EOS Visit. Any SAE must be reported to Dynavax or its designee 
within 24 hours of the knowledge of the event. 
 
If the SAE is assessed as possibly or probably related to study treatment, it must be followed 
until it is considered stable or resolved, including beyond EOS Visit. 
 
Any SAE assessed as not related to study treatment will be followed as clinically indicated until 
its resolution or, if nonresolving, until it is considered chronic or stable, or until study 
completion. 
9.4.9 
Concomitant Medications 
 
Any prescription medication or over-the-counter drug taken by the subject from first study 
injection through Week 28 must be recorded in the eCRF. Use of vitamins and dietary 
supplements will not be collected unless they are indicated as a concomitant therapy for 
conditions directly related to undergoing hemodialysis. After Week 28, only prescription 


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medication or over-the-counter drug taken by the subject for the treatment of MAEs, SAEs, 
AMIs, or AESIs will be recorded on the eCRF through EOS Visit (further details regarding 
safety monitoring of AMIs and AESIs are provided in Section 9.4.7.2). 
9.5 
End of Study 
 
An EOS Visit is required at Week 68 unless the subject is discontinued early from the entire 
study, in which case an Early Discontinuation Visit is required 28 days after the last dose. 
9.6 
Unscheduled Visit for Safety 
 
A UNS should be performed if there are suspected subject safety concerns. Procedures for the 
visit will depend on the reason for visit as determined by the treating principal investigator or 
sub-investigator. If a UNS is performed because of a safety concern related to study treatments, 
at a minimum, the following should be performed: a targeted physical examination based on 
subject-reported symptoms, serum chemistry, and hematology. 
 
If the subject has permanent discontinuation of HEPLISAV-B (ie, discontinues treatment), the 
subject should continue to be followed for safety (as defined in Section 9.7) through EOS Visit. 
If the subject permanently discontinues the study, an EOS Visit (Section 9.5) should be 
scheduled 28 days after the date of last HEPLISAV-B administration. 
9.7 
Duration of Follow-up 
 
All subjects must be followed through EOS Visit (Section 10.0). If the subject is discontinued 
early from study treatment, the subject should not be withdrawn from the study and should 
continue to be followed for safety through EOS Visit. If the subject is discontinued early from 
the study, an Early Discontinuation Visit is required 28 days after the last dose. 
10.0 
REPORTING AND DOCUMENTATION OF MEDICALLY-ATTENDED 
ADVERSE EVENTS 
10.1 
Post-Injection Reactions 
 
Local and systemic post-injection reactions are to be recorded on the subject diary. If they persist 
longer than 7 days (ie, 8 days or longer) and are medically attended (ie, subject seeks medical 
attention), they should also be recorded and reported as MAEs, per protocol Section 10.2. The 
severity of the post-injection reactions will be graded using the Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
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Certain local and systemic events are routinely monitored in vaccine clinical trials as indicators 
of vaccine reactogenicity. It is recognized that each of these events, and particularly those of 
systemic nature, may under certain circumstances, in an individual subject, have a cause that is 
unrelated to study vaccine. However, as a matter of convenience and in accordance with 
common clinical practice, such events occurring within a specified period of time after 
immunization are herein termed ‘post-injection reactions’ and will be recorded as related to 
treatment. 
 
Post-injection reactions documented by the subject via a diary will be collected, reviewed by the 
study nurse/coordinator with the subject, and recorded on the appropriate eCRF (Section 9.4.6). 
 
Further information is provided in the Study Reference Manual. 
 
10.2 
Adverse Events 
 
An AE is any untoward medical occurrence associated with the use of a drug, whether or not 
considered drug-related. An AE can therefore be any unfavorable and unintended sign (including 
a clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the study 
treatment. In this trial, only MAEs, AEs for which a subject seeks medical attention at a doctor’s 
office, clinic, study site, emergency room, or is hospitalized, will be collected. 
 
Medical conditions present at Screening (ie, before informed consent is obtained) or present 
before the first study treatment (Day 1) are not MAEs and are not recorded on the MAE eCRF. 
These medical conditions should be adequately documented on the Medical History eCRFs. Any 
increase in severity or frequency of a medical condition documented as medical history after the 
first study treatment will be recorded as an MAE and will be captured on the MAE eCRF. 
 
An uncomplicated pregnancy is not an MAE or SAE and should not be reported as an 
MAE/SAE. Subjects should be followed as described in Section 10.5. 
 
The reporting period for all non-serious MAEs begins at the time of the first study treatment 
(Day 1) through EOS Visit. All MAEs will be captured on the MAE eCRF. 
 
MAEs should be documented in terms of a single medical diagnosis. When this is not possible, 
the MAE should be documented in terms of signs and/or symptoms observed by the investigator 
or reported by the subject at each study visit. 


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10.2.1 
Overdoses 
 
If an MAE is associated with or resulted from an overdose of HEPLISAV-B (for the purpose of 
this study defined as more than twice the protocol-specified dose), it will be documented on the 
MAE eCRF. If it is an SAE, it will also be reported to Dynavax or the Dynavax designee 
following the SAE reporting process (see Section 10.3.2). 
10.2.2 
Definition of Adverse Reaction 
 
An AR is defined as any MAE caused by the use of a pharmaceutical product. ARs are a subset 
of all suspected MAEs for which there is reason to conclude that the pharmaceutical product 
caused the event. 
10.2.3 
Definition of Suspected Adverse Reaction 
 
Suspected adverse reaction (SAR) means any MAE for which there is a reasonable possibility 
that the study treatment caused the MAE. Reasonable possibility means there is evidence to 
suggest a causal relationship between the study treatment and MAE. An SAR implies a lesser 
degree of certainty about causality than AR, which means an MAE caused by a study treatment. 
10.2.4 
Definition of Unexpected Medically-Attended Adverse Event or Unexpected 
Suspected Adverse Reactions 
 
An MAE or SAR is considered unexpected if it is not listed in the Investigator’s Brochure or 
USPI or is not listed at the specificity or severity that has been previously observed. 


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10.3 
Serious Adverse Events 
10.3.1 
Definition of Serious Adverse Events 
 
An MAE is considered an SAE if it meets any of the following criteria: 
 
• Results in death; 
• Is life-threatening; 
Note: An MAE or SAR is considered life-threatening if, in the view of either the investigator 
or sponsor, its occurrence places the subject at immediate risk of death. It does not include an 
MAE or SAR that, had it occurred in a more severe form, might have caused death; 
• Requires in-patient hospitalization or prolongs existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
That is, the event severely or permanently disrupts the subject's ability to perform normal life 
functions or daily activities. 
• Results in a congenital anomaly or birth defect; 
• Is medically significant (Important Medical Event); 
Medical and scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject. Examples 
of such events are allergic bronchospasm requiring treatment in an emergency room, serious 
blood dyscrasias, or seizures/convulsions that do not result in hospitalization. The 
development of drug dependence or drug abuse would also be examples of important medical 
events. 


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10.3.2 
Serious Adverse Event Reporting Requirements 
Any SAE that occurs from the time the consent is signed through EOS Visit, whether or not the 
SAE is related to the study treatment, must be reported to Dynavax or its designee within 
24 hours of investigator awareness of the event. The contact information for reporting SAEs is 
provided in the Study Reference Manual. General SAE reporting instructions are as follows: 
• Submit SAE documents according to instructions in the Study Reference Manual. 
• Record all SAEs on the MAE eCRF. 
• For SAEs, record the primary event on the MAE eCRF; describe events occurring secondary 
to that primary event on the SAE form in the narrative description of the case. 
• Death is an outcome, not an event. Record the event that resulted in the death as the fatal 
event on the MAE eCRF. 
• For hospitalizations for surgical or diagnostic procedures, record the illness leading to the 
surgical or diagnostic procedure as the SAE, not the procedure itself. Capture the procedure 
in the narrative as part of the action taken in response to the illness. 
• Elective hospitalizations will not be considered SAEs and do not need to be reported. 
Complications that prolong elective hospitalizations should be recorded as SAEs. Emergency 
room visits of less than 24 hours do not meet the criterion of hospitalization for SAE 
reporting purposes. 
 
The SAE report should contain, at a minimum, the following information: 
 
• Subject identifiers (ie, subject number) 
• Suspected medicinal product 
• MAE term (must be listed as serious) 
• Contact information for person reporting event 
 
The relationship of the SAE to study treatment will be assessed by the investigator 
(Section 10.4.2). Follow-up information should be actively sought and submitted as it becomes 
available. 
 
The investigator will assess relationship to study treatment. In addition, the sponsor will assess 
relationship to study treatment and determine expectedness to HEPLISAV-B based on the 
current HEPLISAV-B Investigator's Brochure and USPI. The sponsor will report all 
HEPLISAV-B suspected unexpected serious adverse reactions (SUSARs) to regulatory 
authorities as expedited reports in accordance with applicable regulatory requirements 


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(eg, 21 CFR 312.32[c] and 314.80[e] in the US). All other SAEs will be reported as part of 
regulatory safety updates, as required, such as in annual reports. 
10.4 
Medically-Attended Adverse Event Severity and Relationship to Study Treatment 
10.4.1 
Severity Grading of Medically-Attended Adverse Events and Abnormal 
Laboratory Test Results 
 
The severity of MAEs and laboratory abnormalities will be graded based on the United States 
Food and Drug Administration’s (FDA) Guidance for Industry: Center for Biologics Evaluation 
and Research (CBER) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials in Appendix 3 (with the exception of malaise, 
which will be graded per CTCAE v4.03), with the modification that, by convention, all fatal 
MAEs will be graded as Grade 5 (Fatal). 
 
All MAEs not listed in the CBER toxicity grading scale will be graded as shown in Table 10-1. 
 
Table 10-1: 
Grading Scale for Medically-Attended Adverse Events Not Included 
in the CBER Guidance on Toxicity Grading for Healthy Volunteers in 
Vaccine Clinical Trials 
 
MAE Severity 
Definition 
Grade 1 – Mild 
No interference with activity 
Grade 2 – Moderate 
Some interference with activity, not requiring medical intervention 
Grade 3 – Severe 
Prevents daily activity and requires medical intervention 
Grade 4 – Potentially life-threatening 
Emergency room visit or hospitalization 
Grade 5 
Death 
 
 
For all MAEs and SAEs, if there is a change in the severity after onset, the event should be 
reported as a single entry with the maximum severity grading captured. 
10.4.2 
Relationship of Medically-Attended Adverse Events to Study Treatment 
 
The investigator will determine the relationship of the MAE to study treatment using the 
definitions provided in Table 10-2. 


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Table 10-2 
Definitions for Relationship of Medically-Attended Adverse Events to 
Trial Treatment 
 
Relationship to 
Trial Treatment 
Definition 
Not Related 
Another cause of the event is most plausible; or clinically plausible temporal sequence 
is inconsistent with the onset of the event and the trial treatment administration; or a 
causal relationship is considered biologically implausible. 
Possibly Related 
An event that follows a reasonable temporal sequence from administration of the trial 
treatment or a known or expected response pattern to the suspected drug, but that could 
readily have been produced by a number of other factors. 
Probably Related 
An event that follows a reasonable temporal sequence from administration of the trial 
treatment, and there is a biologically plausible mechanism for trial treatment causing or 
contributing to the MAE, and the event could not be reasonably explained by the known 
characteristics of the subject’s clinical state. In addition, the relationship may be 
confirmed by improvement on stopping the trial treatment and reappearance of the event 
on repeated exposure. 
MAE = medically-attended adverse event. 
 
The investigator will follow all MAEs observed during the study until the MAEs are considered 
resolved, stabilized, or until the subject has completed the study. The sponsor may request 
additional follow-up on specific unresolved MAEs. 
 
If the SAE is assessed as possibly or probably related to study treatment, it must be followed 
until it is considered stable or resolved, including beyond EOS Visit. 
 
Any SAE assessed as not related to study treatment will be followed as clinically indicated until 
its resolution or, if nonresolving, until it is considered chronic or stable, or until study 
completion. 
 
The sponsor may request additional follow-up on specific unresolved MAEs. 
 
10.5 
Reporting and Documentation of Pregnancy 
 
Any subject who becomes pregnant or begins breastfeeding during the study will be discontinued 
from all study treatments and will be followed for pregnancy outcome. Follow-up information 
should be actively sought by the investigator and submitted to Dynavax or designee as soon as it 
becomes available. The investigator will complete the pregnancy reporting form and all other 
relevant eCRFs. Uncomplicated pregnancies are not considered an MAE/SAE. A complicated 
pregnancy or a pregnancy with an adverse outcome may meet criteria for an MAE or SAE and 
would then also be reported according to the appropriate requirements. 


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A subject who becomes pregnant will be instructed to report the pregnancy to the study site as 
soon as possible. The subject should be followed by the investigator through the pregnancy 
(including beyond EOS) for outcomes. A report of the pregnancy will be completed by the 
investigator or designee and will document details of the pregnancy, outcome of pregnancy, and 
details of delivery. 
 
Pregnancies and breastfeeding that occur from Day 1 through the end of the study (Week 68) 
must be reported by the investigator. The sponsor or designee must be notified as soon as 
possible once the study site learns of a pregnancy or breastfeeding. Pregnancy report forms 
provided by the sponsor or designee must be completed and submitted to Dynavax or designee. 
The contact information for reporting pregnancy is provided in the Study Reference Manual. 
11.0 
STATISTICAL METHODS 
 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary or exploratory objectives and/or hypotheses, or to 
the statistical methods related to those objectives and/or hypotheses, then those changes, along 
with an explanation as to when and why they occurred, will be listed in the Clinical Study Report 
(CSR) for the study. Post-hoc exploratory analyses will be clearly identified in the CSR. 
Handling of missing data, if any, will be outlined in the study Statistical Analysis Plan. 
Additional details of the statistical analyses to be performed will be provided in the study 
Statistical Analysis Plan. 
11.1 
Sample Size Considerations 
 
The sample size calculation is based on approximately 100 subjects in the per-protocol 
population (Table 11-1). With an expected 15% loss to follow up prior to week 20, 
approximately 115 subjects will be enrolled. This sample size would allow estimating 
immunogenicity response at the following accuracy levels depending on the observed 
immunogenicity responses. 
Table 11-1: 
Sample Size Estimates 
 
N 
If Observed 
Immunogenicity 
Response is 
Width of the Resulting 95% 
Confidence Interval 
Lower Limit of the Resulting 95% 
Confidence Intervala 
100 
80.0% 
0.165 
70.8% 
100 
86.0% 
0.145 
77.6% 
100 
90.0% 
0.127 
82.4% 
100 
95.0% 
0.096 
88.7% 
N = number of subjects 
a 
Calculation based on exact method (Clopper-Pearson) 
Note: Approximately 115 subjects will be enrolled to meet the N of 100 evaluable subjects in the per-protocol population. 


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11.2 
Study Analysis Populations 
 
The Safety Population will comprise all subjects who received at least 1 study injection, 
excluding subjects who have no on-study safety data. 
 
The Per-protocol (PP) Population for the immunogenicity analysis will comprise all subjects who 
receive all study injections, have no major protocol violations (to be specified in the Statistical 
Analysis Plan), and have anti-HBs levels obtained within the study visit window at Week 20. 
 
The modified intent-to-treat (mITT) population for the immunogenicity analysis will comprise 
all subjects who receive at least 1 study injection and have at least 1 post-injection 
immunogenicity evaluation. 
11.3 
Demographic and Baseline Characteristics 
 
Demographic and baseline characteristics will be listed by subject and summarized. Descriptive 
summary statistics (sample size, mean, median, SD, and range, when appropriate) will be 
provided for the continuous variables such as age, weight, and height. Count and percentage will 
be reported for categorical variables such as sex, race, and ethnicity. 
11.4 
Immunogenicity Analyses 
 
Immunogenicity data will be analyzed based on the PP Population. The SPR at specified 
timepoints will be estimated. The associated 2-sided 95% confidence interval will be calculated 
using the Clopper-Pearson method. 
11.5 
Safety Analyses 
 
Safety data will be analyzed descriptively and will be based on the Safety Population. The most 
important safety parameters will be presented for all sites combined. Summary statistics will be 
used to describe the incidence of all post-injection reactions and MAEs (including SAEs, deaths, 
AMIs, and AESIs; further details regarding safety reporting of AMIs and AESIs are provided in 
Section 9.4.7.2). The incidence and proportion of injection site reactions and MAEs will be 
summarized. MAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) System of Organ Class (SOC) and Preferred Term (PT). 
 
The incidence of AMIs and major adverse cardiovascular events will be analyzed in subjects 
initiating hemodialysis after enrollment in the study and in subjects undergoing hemodialysis at 
the time of enrollment in the study. 


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11.6 
Interim Analysis 
 
A preliminary analysis may be performed to assess the primary immunogenicity objective of the 
SPR at Week 20 after approximately 50 subjects have completed their Week 20 visit. Further 
details will be outlined in the Statistical Analysis Plan. 
12.0 
DATA QUALITY ASSURANCE 
 
The study sites will be monitored by Dynavax or its designee according to GCP and standard 
operating procedures. Prior to initiation of the study, representatives from Dynavax or its 
designee will review with the site personnel information about the investigational product, 
proper storage of study treatments, protocol requirements, and monitoring requirements. During 
and after the study, periodic site visits will be made to monitor for compliance, including 
verification of the accuracy and completeness of data recorded on the eCRFs, source documents, 
and study treatments accountability records. 
13.0 
ETHICS 
13.1 
Institutional Review Board/Independent Ethics Committee 
 
The protocol and informed consent documents must be reviewed and approved by an 
appropriately composed IRB. The study will not be initiated at a site until appropriate written 
IRB approval of the protocol, ICF, and all recruiting materials (if applicable) is obtained by the 
investigator. Copies should be reviewed and approved by Dynavax prior to submission to the 
IRB. The investigator will submit periodic reports on the progress of the study as required by the 
IRB, in accordance with applicable governmental regulations, and in agreement with the policy 
established by Dynavax. In addition, the investigator will inform the IRB of any protocol 
amendments and administrative changes and will obtain appropriate written IRB approval of all 
protocol amendments. 
13.2 
Ethical Conduct of the Study 
 
This study will be conducted in accordance with the International Council for Harmonisation 
(ICH) E6(R2) GCP guidelines and applicable local legal and regulatory requirements. 
 
The study will be submitted to required clinical trial registries such as www.clinicaltrials.gov. 
 
13.3 
Informed Consent 
 
The investigator is responsible for obtaining informed consent from each subject participating in 
the study in compliance with US CFR Title 21, Part 50, Title 45 Part 46, and ICH and IRB 
guidelines. Prior to initiation of the study at the site, the ICF, and any other study information to 


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be provided to the subject must be reviewed and accepted by Dynavax and approved by the 
governing IRB. The investigator or authorized designee will discuss the purpose and pertinent 
details of the study with each subject, and the subject must demonstrate understanding, sign, and 
date the appropriate IRB-approved ICF before undergoing any study-specific procedures. The 
ICF must be personally signed and dated by the subject and by the person who conducted the 
informed consent discussion. Additional signature requirements may exist. The original signed 
and dated ICF will be retained with the subject’s study records, and a copy of the signed ICF will 
be given to the subject. The investigator or designee will maintain a log of all subjects who sign 
the ICF. At a minimum, the log will include a subject identifier, the dates of informed consent 
and screening procedures, the outcome of the screening, and the reason the subject did not enroll 
in the study, if applicable. 
13.4 
Subject Confidentiality 
 
The investigator is responsible for maintaining the privacy and confidentiality of the subject’s 
medical or health information collected during the study. The investigator is also responsible for 
ensuring that all use, review and disclosure of subject’s medical or health information is in 
accordance with Health Insurance Portability and Accountability Act (HIPAA) regulations and 
the ICF approved by the IRB and signed by the subject. Specifically, all data collected about a 
subject during the study will be identified only by a number and the subject’s initials. 
14.0 
DATA HANDLING AND RECORD KEEPING 
14.1 
Source Documents 
 
The investigator must maintain detailed records of all study participants who are enrolled in the 
study or who undergo screening. Source documents include, but are not limited to, subject 
medical records and investigator’s subject study files, as well as all test results. 
 
Data collection is the responsibility of the study site staff under the supervision of that site’s 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The following minimum information should be 
entered into the enrolled subject’s source documents: 
• The date the subject entered the study and the subject number 
• The study protocol number and the name Dynavax 
• The date that informed consent was signed 
• Evidence that informed consent was obtained before the subject underwent any trial-specific 
procedures 


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• Evidence that the subject meets study eligibility requirements (eg, medical history, study 
procedures, evaluations) 
• 
The dates of all study-related subject visits 
• Evidence that study-required procedures and/or evaluations were completed 
• Use of any concurrent medications 
• Documentation of study treatment accountability 
• Occurrence and status of any MAEs 
• The date the subject exited the study, and a notation as to whether the subject completed the 
study or was discontinued early, including the reason for discontinuation 
• Any deviations from the protocol 
14.2 
Direct Access to Source Data/Documents 
 
Qualified individuals designated by Dynavax or its representative will monitor all aspects of the 
study at regular intervals throughout the study and following study completion. This monitoring 
is for the purpose of verifying adherence to the protocol including appropriate storage of study 
treatments, completeness and exactness of the data being entered onto the eCRFs, and 
compliance with the FDA or other regulatory agency regulations. The investigator and 
investigator’s institution agree to allow these monitors access to all study records, eCRFs, and 
corresponding portions of the subject’s clinical study files; to allow access to the clinical 
supplies, dispensing, and storage areas; and if requested, to assist the monitors. The investigator 
further agrees to permit direct access to source data/documents for study-related monitoring, 
audits, IRB/Independent Ethics Committee (IEC) review, and regulatory inspection(s). 
In certain circumstances, a secondary audit may be conducted by members of Dynavax’s Quality 
Assurance group or by Dynavax’s designated representative. The investigator will be notified if 
this is to take place, and advised as to the nature of the audit. 
14.3 
Case Report Forms 
 
Electronic CRFs (eCRFs) will be used at the clinical study site to collect study data for screen 
failures and enrolled subjects. When data are available, authorized clinical study site personnel 
will carefully and accurately record the data on the eCRF. Sites must ensure that all source 
documents are maintained according to ICH/GCP guidance and support the data that are entered 
onto the eCRFs. 
 
The eCRF data will be captured in a system validated according to procedures that comply with 
21 CFR Part 11 and ICH GCP Guidelines E6 (R2). The eCRFs will be reviewed and signed by 


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the principal investigator or someone clinically qualified and identified on the delegation log as 
someone that can sign-off on the eCRF. 
14.4 
Data Handling 
 
The sponsor may designate a Contract Research Organization (CRO) to perform data 
management. The CRO will write a data management plan outlining the data management 
systems, procedures, and agreements between the CRO and sponsor. The plan will be reviewed 
and signed by a representative of the sponsor’s data management department. 
 
Outside the electronic data capture (EDC) system, when appropriate, the CRO will receive FDA 
21 CFR 11 compliant external lab data transfers from a validated laboratory information 
management system. After database lock, the investigator will receive a copy of the subject data 
for archiving at the study site. 
 
The standard procedures for handling and processing eCRF records including identification of 
data errors and data clarification process will be followed per Good Clinical Practice (GCP) and 
the Sponsor's (or designee's) SOPs. 
 
Complete details of data preparation and management will be described in a separate study Data 
Management Plan. 
14.5 
Coding of Medically-Attended Adverse Events, Drugs, and Diseases 
 
MAEs and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Prior and concomitant medications will be coded according to the World 
Health Organization Drug Dictionary. 
14.6 
Record Retention 
 
The investigator must retain all records relating to the conduct of this study (including subject’s 
study records, receipt and disposition of all investigational materials, subject exclusion logs, 
signed consent forms, eCRFs, all correspondence, and other supporting documentation) for at 
least 2 years after a marketing application for this indication is approved; or if an application is 
not filed or not approved for the drug for this indication, for at least 2 years after clinical 
development for the drug has been formally discontinued and the appropriate regulatory or 
health authorities have been notified. However, in certain instances, documents may need to be 
retained for a longer period if required by regulatory requirements or by an agreement with 
Dynavax. 


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The investigator may withdraw from the responsibility of retaining records only after transferring 
custody of the records to another individual who will accept responsibility for them. A written 
notice of transfer must be provided to Dynavax prior to or no later than 10 days after transfer. 
 
The investigator must allow representatives of the FDA, the governing IRB, or other regulatory 
agencies to inspect all study records. If informed of such an inspection, the investigator will 
notify Dynavax immediately. 
 
The investigator must obtain written approval from Dynavax prior to the destruction of any 
records relating to the conduct of this study. 
15.0 
USE OF INFORMATION AND PUBLICATION 
 
It is understood by the investigator that the information generated in this study is the property of 
Dynavax. It is understood that the investigator is obliged to provide Dynavax with complete test 
results, all study data, and access to all study records. 
 
All efforts should be made for abstracts and publications to be jointly authored by investigators 
and Dynavax. Dynavax will be furnished with a copy of any proposed publication. Dynavax’s 
comments shall be given without undue delay, and not later than within 60 days. 
 
Results from the investigation shall not be made available to any third party by the investigators 
or any of their staff. 
 
It is understood by the investigator that the information generated in this study may be used by 
Dynavax in connection with the development of the product and therefore may be disclosed to 
government agencies in various countries. 
 
Dynavax recognizes the importance of communicating medical study data, and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences. 
 
Any results of medical investigations with Dynavax’s products and all publications, lectures, 
presentations, and manuscripts based thereon shall be exchanged and discussed by the 
investigators and Dynavax’s representatives prior to submission for publication or presentation. 
Due regard shall be given to Dynavax's legitimate interests, eg, manuscript authorship, obtaining 
optimal patent protection, coordinating and maintaining the proprietary nature of submissions to 
health authorities, coordinating with other ongoing studies in the same field, and protecting 
confidential data and information. 
 
Dynavax will be furnished with a copy of any proposed publication and allowed to make 
comments. In cases of publications or presentations of material arising from multicenter clinical 


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investigations, Dynavax is to serve as coordinator and referee. Individual investigators who are 
part of a multicenter investigation may not publish or present data that are considered common to 
a multicenter investigation without the consent and the prior review of Dynavax. In case of 
disagreement among the investigators participating in a multicenter investigation, Dynavax will 
be the final arbiter. If Dynavax’s comments are not accepted, the senior author of the manuscript 
and Dynavax’s representatives shall promptly meet and endeavor to agree mutually on the final 
wording and disposition of the publication. The above procedure also applies to information on 
prematurely discontinued and other incomplete studies. 
Results from investigations shall not be made available to any third party by the investigating 
team outside the publication procedure as outlined previously. Dynavax will not quote from 
publications by investigators in its scientific information or promotional material without full 
acknowledgment of the source (ie, author and reference). 


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16.0 
REFERENCES 
Buti, M., L. Viladomiu, R. Jardi, A. Olmos, J. A. Rodriguez, J. Bartolome, R. Esteban and J. 
Guardia (1992). "Long-term immunogenicity and efficacy of hepatitis B vaccine in hemodialysis 
patients." Am J Nephrol 12(3): 144-147. 
 
Center for Biologics Evaluation and Research (2007). Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials, U.S. Department of Health and Human Services, Food and Drug Administration. 
 
Centers for Disease Control and Prevention (1985). "Recommendations for protection against 
viral hepatitis. Recommendation of the Immunization Practices Advisory Committee. Centers for 
Disease Control, Department of Health and Human Services." Ann Intern Med 103(3): 391-402. 
 
Centers for Disease Control and Prevention (2001). "Recommendations for preventing 
transmission of infections among chronic hemodialysis patients." MMWR Recomm Rep 50(RR- 
5): 1-43. 
 
Chaves, S. S., D. Daniels, B. W. Cooper, S. Malo-Schlegel, S. Macarthur, K. C. Robbins, J. F. 
Kobetitsch, A. McDaniel, J. F. D'Avella and M. J. Alter (2011). "Immunogenicity of hepatitis B 
vaccine among hemodialysis patients: effect of revaccination of non-responders and duration of 
protection." Vaccine 29(52): 9618-9623. 
 
Floreani, A., V. Baldo, M. Cristofoletti, G. Renzulli, A. Valeri, C. Zanetti and R. Trivello (2004). 
"Long-term persistence of anti-HBs after vaccination against HBV: an 18 year experience in 
health care workers." Vaccine 22(5-6): 607-610. 
 
Girndt, M. and N. H. Litjens (2010). "Unmet Needs and New Promises in Hepatitis B 
Vaccination for Chronic Kidney Disease Patients." European Nephrology 4: 14-18. 
 
Jilg, W., B. Lorbeer, M. Schmidt, B. Wilske, G. Zoulek and F. Deinhardt (1984). "Clinical 
evaluation of a recombinant hepatitis B vaccine." Lancet 2(8413): 1174-1175. 
 
Keating, G. M. and S. Noble (2003). "Recombinant hepatitis B vaccine (Engerix-B): a review of 
its immunogenicity and protective efficacy against hepatitis B." Drugs 63(10): 1021-1051. 
 
Miller, E. R., M. J. Alter and J. I. Tokars (1999). "Protective effect of hepatitis B vaccine in 
chronic hemodialysis patients." Am J Kidney Dis 33(2): 356-360. 
 
National Cancer Institute (2010). Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03. National Cancer Institute, National Institutes of Health, U.S. Department of Health 
and Human Services. 


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National Institutes of Health (2017). United States Renal Data System. 2017 USRDS Annual 
Data Report: Epidemiology of kidney disease in the United States. N. I. o. D. a. D. a. K. 
Diseases. Bethesda, MD. 
 
Navarro, J. F., J. L. Teruel, M. L. Mateos, R. Marcen and J. Ortuno (1996). "Antibody level after 
hepatitis B vaccination in hemodialysis patients: influence of hepatitis C virus infection." Am J 
Nephrol 16(2): 95-97. 
 
Schillie, S., C. Vellozzi, A. Reingold, A. Harris, P. Haber, J. W. Ward and N. P. Nelson (2018). 
"Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the 
Advisory Committee on Immunization Practices." MMWR 67(No. RR-1-36)(1): 1-36. 
 
Sezer, S., F. N. Ozdemir, G. Guz, Z. Arat, T. Colak, S. Sengul, M. Turan, A. Haberal and R. 
Erdal (2000). "Factors influencing response to hepatitis B virus vaccination in hemodialysis 
patients." Transplant Proc 32(3): 607-608. 


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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS 
 
Study Period: 
Screening 
Study Treatment 
Treatment Follow-up 
Early 
Discontinuationa 
Visit: 
0 
1 
2 
3 
4 
5 
6 h 
7 h 
8 
End of Study 
Day: 
-28 to -1 
1 
29 
57 
113 
141 
197 
295 
477 
Week: 
-4 
0 
4 
8 
16 
20 
28 
h 
42h 
68 
Visit window (days) from visit date: 
0 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
28+ days after last 
injection 
Informed consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics 
X 
Medical and medication historyb 
X 
X 
Height and weightc 
X 
Physical examinationd 
X 
X 
X 
X 
X 
X 
X 
Hematology by central laboratory 
X 
Serum chemistry by central laboratory 
X 
HIV and hepatitis screen (HIV, HBsAg, anti-HBc, anti-HBs, 
anti-HCV, anti-HIV-1/2) 
X 
Serum pregnancy test (for WOCBP)e 
X 
Serum or urine pregnancy test (for WOCBP)e,f 
X 
X 
X 
X 


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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS (CONT’D) 
 
Study Period: 
Screening 
Study Treatment 
Treatment Follow-up 
Early 
Discontinuationa 
Visit: 
0 
1 
2 
3 
4 
5 
6 h 
7h 
8 
End of Study 
Day: 
-28 to -1 
1 
29 
57 
113 
141 
197 
295 
477 
Week: 
-4 
0 
4 
8 
16 
20 
28 
h 
42 
h 
68 
Visit window (days) from visit date: 
0 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
28+ days after last 
injection 
Anti-HBs (quantitative) and stored serum and plasma aliquotg 
X 
X 
X 
X 
X 
X 
X 
Confirmation of eligibility prior to each injection 
X 
X 
X 
X 
Study injection (HEPLISAV-B®)i 
X 
X 
X 
X 
30 minute post-injection observationj 
X 
X 
X 
X 
Instruction to subjects on collection of oral temperature and 
PIRsk 
X 
X 
X 
X 
Assessment of SAEsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of MAEs, AESIs, and AMIsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MAE = medically-attended adverse event; AESI = adverse event of special interest; AMI = acute myocardial infarction; anti-HBc = antibodies to hepatitis B core antigen; anti-HBs = 
antibodies to hepatitis B surface antigen; anti-HCV = antibody to hepatitis C virus; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; PIR = post-injection 
reaction; SAE = serious adverse event; WOCBP = women of child-bearing potential. 


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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS (CONT’D) 
 
Footnotes 
 
Early Discontinuationa 
The assessments at the Early Discontinuation Visit should occur 28 days or more after the last study injection. 
Medical and medication historyb 
Medical and medication history are all medical events occurring and medications received by the subject prior to the first study injection. 
Height and weightc 
Height and weight are only collected at Screening. 
Physical examinationsd 
A full physical examination (excluding pelvic/genital, rectal, and breast examination) will be conducted at Screening, and a targeted 
physical examination based on subject-reported symptoms (excluding pelvic/genital, rectal, and breast examination) will be conducted 
at each study injection visit and End-of-Study (EOS) Visit or Early Discontinuation Visit. If a subject discontinues study treatment, 
subsequent targeted physical examination is only required at EOS Visit or Early Discontinuation Visit. 
Serum pregnancy test (for WOCBP)e 
All female subjects, regardless of age, are considered to be women of child bearing potential (WOCBP) except if they have been 
post-menopausal for at least 1 year or surgically sterile for at least 1 year. Samples will be collected prior to study drug injection. All 
pregnancy test results must be negative prior to injection. 
Urine pregnancy test (for WOCBP)e,f 
All female subjects, regardless of age, are considered to be women of child bearing potential (WOCBP) except if they have been 
post-menopausal for at least 1 year or surgically sterile for at least 1 year. Samples will be collected prior to study drug injection. All 
pregnancy test results must be negative prior to injection. Dipstick can be used for urine pregnancy test. 
Anti-HBs (quantitative) and stored serum 
and plasma aliquotg 
There must be a minimum of 21 days between any study injection and the subsequent anti-HBs sample collection. On treatment days, 
samples will be collected prior to study injection. Extra aliquots of serum and plasma will be collected and may be stored frozen for future 
use. 
Weeks 28 and 42 h 
Week 28 and 42 assessments (assessment of SAEs; MAEs, AESIs, AMIs; and concomitant medication) will be completed via telephone 
call. 
Study injection (HEPLISAV-B®)i 
Blood collection and HEPLISAV-B administration must be performed prior to the start of dialysis on study visit days. 
30 minute post-injection observationj 
May be completed while the subject is receiving dialysis. 
Instruction to subjects on collection of 
oral temperature and PIRsk 
Subjects will be provided with a diary to record oral temperature and post-injection reactions. 
Assessment of MAEs, SAEs, AMIs, and 
AESIs l 
SAEs will be collected and followed through EOS Visit. If the SAE is assessed as possibly or probably related to study treatment, it must be 
followed until it is considered stable or resolved, including beyond EOS Visit. MAEs, AMIs, and AESIs will be collected and followed 
through EOS Visit. Further details regarding safety monitoring of AMIs and AESIs are provided in Section 9.4.7.2. 
Concomitant medicationsm 
Concomitant medications are all medications and non-study vaccines received by the subject from the first injection through Week 28 or 
Early Discontinuation. Use of vitamins and dietary supplements will not be collected unless they are indicated as a concomitant therapy for 
conditions directly related to undergoing hemodialysis. After Week 28, only prescription medication or over-the-counter drug taken by the 
subject for the treatment of MAEs, SAEs, AMIs, or AESIs will be recorded on the eCRF through EOS Visit (further details regarding safety 
monitoring of AMIs and AESIs are provided in Section 9.4.7.2). 


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APPENDIX 2: 
HEPLISAV-B® UNITED STATES PACKAGE INSERT 
 


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APPENDIX 3: 
TOXICITY GRADING SCALE FOR HEALTHY ADULT AND 
ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE 
VACCINE CLINICAL TRIALS 
 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Erythema/Rednessa 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative dermatitis 
Induration/Swellingb 
2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or prevents 
daily activity 
Necrosis 
Pain 
Does not interfere 
with activity 
Repeated use of non- 
narcotic pain reliever 
> 24 hours or 
interferes with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room 
(ER) visit or 
hospitalization 
Feverc (°C) 
38.0 – 38.4 
38.5 – 38.9 
39.0 – 40 
> 40 
(°F) 
100.4 – 101.1 
101.2 – 102.0 
102.1 – 104 
> 104 
Malaise 
Uneasiness or lack of 
well being 
Uneasiness or lack of 
well being; limiting 
instrumental ADL 
A grade is not 
available 
A grade is not 
available 
Headache 
No interference with 
Repeated use of non- Significant; any use 
ER visit or 
activity 
narcotic pain reliever of narcotic pain 
hospitalization 
> 24 hours or some 
reliever or prevents 
interference with 
daily activity 
activity 
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Significant: prevents 
daily activity 
ER visit or 
hospitalization 
Fatigue 
No interference with 
activity 
Some interference 
with activity 
Significant: prevents 
daily activity 
ER visit or 
hospitalization 
Sources: (Center for Biologics Evaluation and Research 2007, National Cancer Institute 2010). 
a 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
b 
Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
c 
Oral temperature; no recent hot or cold beverages or smoking. Subject should be at rest for vital sign measurements. 


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APPENDIX 4: 
LIST OF ADVERSE EVENTS OF SPECIAL INTEREST 
 
Each subject will be assessed for these autoimmune, hypersensitivity, and inflammatory diseases 
during the trial. The following AESIsa will be evaluated and reported to FDA: 
Gastrointestinal disorders 
• Celiac disease 
• Crohn’s disease 
• Ulcerative colitis 
• Ulcerative proctitis 
 
Liver disorders 
• Autoimmune cholangitis 
• Autoimmune hepatitis 
• Primary biliary cirrhosis 
• Primary sclerosing cholangitis 
 
Metabolic diseases 
• Addison’s disease 
• Autoimmune thyroiditis (including Hashimoto thyroiditis) 
• Diabetes mellitus type 1 
• Grave’s or Basedow’s disease 
 
Musculoskeletal disorders 
• Antisynthetase syndrome 
• Dermatomyositis 
• Juvenile chronic arthritis (including Still’s disease) 
• Mixed connective tissue disorder 
• Polymyalgia rheumatic 
• Polymyositis 
• Psoriatic arthropathy 
• Relapsing polychondritis 
• Rheumatoid arthritis 
• Scleroderma, including diffuse systemic form and CREST syndrome 
• Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s Syndrome) 
and undifferentiated spondyloarthritis 
• Systemic lupus erythematosus 
• Systemic sclerosis 


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Neuroinflammatory disorders 
• Acute disseminated encephalomyelitis, including site specific variants: eg, non-infectious 
encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis 
• Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy) 
• Guillain-Barré syndrome, including Miller Fisher syndrome and other variants 
• Tolosa Hunt syndromeb 
• Immune-mediated peripheral neuropathies and plexopathies (including chronic 
inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and 
polyneuropathies associated with monoclonal gammopathy) 
• Multiple sclerosis 
• Myasthenia gravis, including Eaton-Lambert syndrome 
• Narcolepsy 
• Optic neuritis 
• Transverse Myelitis 
 
Skin disorders 
• Alopecia areata 
• Autoimmune bullous skin diseases (including pemphigus, pemphigoid and dermatitis 
herpetiformis) 
• Cutaneous lupus erythematosus 
• Erythema nodosum 
• Morphoea 
• Lichen planus 
• Psoriasis 
• Rosacea 
• Sweet’s syndrome 
• Vitiligo 
 
Vasculitides 
• Large vessels vasculitis including: giant cell arteritis such as Takayasu’s arteritis and 
temporal arteritis 
• Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, Kawasaki’s 
disease, microscopic polyangiitis, Wegener’s granulomatosis, Churg-Strauss syndrome 
(allergic granulomatous angiitis), Buerger’s disease (thromboangiitis obliterans), necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type 
unspecified), Henoch-Schonlein purpura, Behcet’s syndrome, leukocytoclastic vasculitis 


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Others 
• Antiphospholipid syndrome 
• Autoimmune hemolytic anemia 
• Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, membranoprofilerative glomerulonephritis, 
and masangioproliferative glomerulonephritis 
• Autoimmune myocarditis/cardiomyopathy 
• Autoimmune thrombocytopenia 
• Goodpasture syndrome 
• Idiopathic pulmonary fibrosis 
• Pernicious anemia 
• Raynaud’s phenomenon 
• Sarcoidosis 
• Sjögren’s syndrome 
• Stevens-johnson syndrome 
• Uveitis 
 
 
a 
List provided to Dynavax Technologies by FDA on 30 January 2019 
b 
Added by Dynavax 

SAP_001.pdf: 
 
DV2-HBV-24 
STATISTICAL ANALYSIS PLAN  
An Open-label, Single Arm Study, Evaluating the 
Immunogenicity and Safety of HEPLISAV-B® in Adults 
With End-Stage Renal Disease Undergoing Hemodialysis 
NCT03934736 
 
Amendment 2: Version 2.1: 15 September 2020 
Amendment 1: Version 2: 02 September 2020 
Original Version: Version 1: 25 February 2020 


Dynavax Technologies Corporation 
STATISTICAL ANALYSIS PLAN 
 
Study Title: 
An Open-label, Single Arm Study, Evaluating the 
Immunogenicity and Safety of HEPLISAV-B® in 
Adults with End-Stage Renal Disease Undergoing 
Hemodialysis 
Protocol Identifier: 
DV2-HBV-24 
Phase 
Phase 1 
Investigational Product: 
HEPLISAV-B® 
Indication: 
Prevention of Hepatitis B Virus Infection 
Sponsor: 
Dynavax Technologies Corporation 
2100 Powell Street Suite 900 
Emeryville, CA 94608 
United States of America 
Reference Numbers: 
United States IND 12692 
 
 
 
 
Amendment 2: 
Version 2.1: 15 September 2020 
Based on Protocol Version: 
Amendment 4: 17 April 2020 
 
Amendment 1: 
Version 2: 02 September 2020 
Original Version: 
Version 1: 25 February 2020 
 
 
 


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Statistical Analysis Plan 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND TERMS ................................................................... 4 
1.0 
INTRODUCTION .................................................................................................. 6 
2.0 
STUDY OVERVIEW .............................................................................................. 6 
3.0 
STUDY OBJECTIVES .......................................................................................... 8 
3.1 
Primary Objectives ....................................................................................... 8 
3.2 
Secondary Objectives ................................................................................... 8 
4.0 
ANALYSIS VARIABLES ..................................................................................... 8 
5.0 
SAMPLE SIZE CONSIDERATIONS .................................................................. 8 
6.0 
ANALYSIS POPULATIONS ................................................................................ 9 
6.1 
Enrolled Population ....................................................................................... 9 
6.2 
Safety Population ......................................................................................... 9 
6.3 
Efficacy Population ...................................................................................... 9 
7.0 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS ........................... 9 
7.1 
Definitions and Computations ...................................................................... 9 
7.2 
Conventions ................................................................................................ 10 
7.3 
Rules for Missing Data ............................................................................... 11 
8.0 
TIMING OF ANALYSES ................................................................................... 12 
9.0 
STATISTICAL METHODS................................................................................ 12 
9.1 
Patient Disposition ..................................................................................... 13 
9.2 
Protocol Deviations .................................................................................... 13 
9.3 
Demographics and Baseline Characteristics .............................................. 13 
9.4 
Prior and Concomitant Medications ............................................................ 14 
9.5 
Medical History .......................................................................................... 14 
9.6 
Immunogenicity Analyses .......................................................................... 14 
9.7 
Safety Analyses .......................................................................................... 14 
9.8 
Other Analyses ........................................................................................... 17 
9.9 
Interim Analysis ......................................................................................... 17 
9.10 
Reporting Output ........................................................................................ 17 
10.0 
REVISION HISTORY ......................................................................................... 18 
11.0 
REFERENCES ...................................................................................................... 18 
12.0 
LIST OF TABLES ............................................................................................... 19 
13.0 
LIST OF FIGURES ............................................................................................. 20 
14.0 
LIST OF PATIENT DATA LISTINGS ............................................................. 21 


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LIST OF ABBREVIATIONS AND TERMS 
 
Abbreviation or Term 
Definition 
 
AE 
adverse event 
AESI 
adverse event of special interest 
AMI 
acute myocardial infarction 
anti-HBs 
antibodies against hepatitis B surface antigen 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
CBER 
Center for Biologics Evaluation and Research 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
EOS 
End of Study (visit) 
FDA 
United States Food and Drug Administration 
GMC 
geometric mean concentration 
GRF 
glomerular filtration rate 
HBV 
hepatitis B virus 
MAE 
medically-attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat (population) 
ODS 
output delivery system 
PT 
Preferred Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System of Organ Class 
SPR 
seroprotection rate 
TEMAE 
treatment emergent medically-attended adverse event 
TFL 
tables, figures, listings 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
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Abbreviation or Term 
Definition 
 
WHO 
World Health Organization 
 


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Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
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1.0 
INTRODUCTION 
 
This statistical analysis plan contains definitions of analysis populations and endpoints, 
outlines the timing of statistical analyses, and provides a comprehensive description of 
statistical analyses to be implemented to assess the safety and immunogenicity in patients on 
hemodialysis as described in Protocol DV2-HBV-24 (Amendment 4: 17 April 2020): “An 
Open-label, Single Arm Study, Evaluating the Immunogenicity and Safety of HEPLISAV- 
B® in Adults With End-Stage Renal Disease Undergoing Hemodialysis”. 
2.0 
STUDY OVERVIEW 
 
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Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 7 of 21 
 
 
Day: 
Week: 
-28 
-4 
1 29 
0 4 
57 
8 
113 141 197 295 477 
16 20 
28 42 
68 
N = 100 
X X 
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In this study, the safety and immunogenicity in patients on hemodialysis will be evaluated 
further to investigate an optimal dosing regimen for this patient population. An optimal 
dosing regimen for HEPLISAV B that induces higher rates of protection, earlier onset of 
protective immunity, and longer duration of protection in hemodialysis patients would be an 
important advance in vaccine development given the ongoing risk of HBV infection in the 
hemodialysis setting and consequences of HBV infection in this highly compromised patient 
population. 
 
This study will consist of a 4-injection (0.5 mL per injection) regimen of HEPLISAV-B at 
Weeks 0, 4, 8, and 16. It is anticipated that a fourth dose of HEPLISAV-B will provide 
improved seroprotection aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa for hemodialysis patients. 
Eligible subjects will receive HEPLISAV-B at Weeks 0, 4, 8 and 16 and will be followed 
through Week 68 (Figure 2-1). The study is designed to evaluate the immunogenicity over 
the 20-week period and safety over the 68-week period. 
Figure 2-1: 
Study Flow Diagram 
 
 
Screening 
HEPLISAV-B 
Treatment 
Follow-Up 
 
 
 
 
 
 
 
 
 
X = study injection 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 8 of 21 
 
 
For the primary immunogenicity endpoint, SPR will be evaluated at Week 20, 4 weeks after 
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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
• To evaluate the safety of HEPLISAV-B with respect to clinically significant adverse 
events 
• To evaluate the immunogenicity induced by HEPLISAV B at Week 20 as measured by 
the seroprotection rate (SPR) 
3.2 
Secondary Objectives 
• To evaluate the immunogenicity of HEPLISAV-B as measured by the percentage of 
subjects with anti-HBs concentration ≥100 mIU/mL 
• To evaluate the immunogenicity of HEPLISAV-B as measured by the anti HBs 
geometric mean concentration (GMC) 
• To evaluate the immunogenicity of HEPLISAV-B at each study visit through 20 weeks 
after the first dose of study vaccine as measured by the SPR 
4.0 
ANALYSIS VARIABLES 
Primary Endpoints 
• Proportion of subjects with treatment-emergent MAEs 
• Proportion of subjects with treatment-emergent SAEs, acute myocardial infarctions 
(AMIs), or deaths 
• Proportion of subjects with treatment-emergent immune-mediated adverse events of 
special interest (AESIs) 
• SPR at Week 20 
Secondary Endpoints 
• Proportion of subjects with anti-HBs concentration ≥100 mIU/mL 
• Anti-HBs geometric mean concentration (GMC) 
• SPR at each study visit through 20 weeks after the first dose of study vaccine 
5.0 
SAMPLE SIZE CONSIDERATIONS 
 
The sample size calculation is based on approximately 100 subjects in the per-protocol 
population. With an expected 15% loss to follow up prior to week 20, approximately 115 
subjects will be enrolled. This sample size would allow estimating immunogenicity response 
at the following accuracy levels depending on the observed immunogenicity responses 
(Table 5-1). 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 9 of 21 
 
 
Table 5-1: 
Sample Size Estimates 
 
N 
If Observed 
Immunogenicity 
Response is 
Width of the Resulting 
95% Confidence Intervala 
Lower Limit of the Resulting 95% 
Confidence Intervala 
100 
80.0% 
0.165 
70.8% 
100 
86.0% 
0.145 
77.6% 
100 
90.0% 
0.127 
82.4% 
100 
95.0% 
0.096 
88.7% 
N = number of subjects 
a 
Calculation based on exact method (Clopper-Pearson) 
Note: Approximately 115 subjects will be enrolled to meet the N of 100 evaluable subjects in the per-protocol population. 
 
 
 
6.0 
ANALYSIS POPULATIONS 
6.1 
Enrolled Population 
 
The enrolled population is defined as all patients who enrolled in the study. 
 
6.2 
Safety Population 
 
The safety population will comprise all subjects who received at least 1 study injection, 
excluding subjects who have no on-study safety data. 
6.3 
Efficacy Population 
 
The per-protocol (PP) population for the immunogenicity analysis will comprise all subjects 
who receive all study injections, have no major protocol deviations (see Section 9.2), and 
have anti-HBs levels obtained within the study visit window at Week 20. PP population is 
defined for Week 20 visit, but will be used in analyses at other visits where applicable. 
 
The modified intent-to-treat (mITT) population for the immunogenicity analysis will 
comprise all eligible subjects who receive at least 1 study injection and have at least 1 post- 
injection immunogenicity evaluation. 
7.0 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS 
7.1 
Definitions and Computations 
Study Day 
 
Study day will be calculated in reference to the date of first injection (Day 1). For visits 
conducted on or after the first injection date, study day is calculated as (visit date – first 
injection date + 1). For visits conducted before the first injection date, study day is calculated 
as (visit date – first injection date). There will be no Day 0. 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 10 of 21 
 
 
Date of First Injection and Date of Last Injection of Study Vaccine 
 
The date of the first injection of study vaccine is defined as the date a patient receives the 
first injection of the study vaccine. The date of the last injection of study vaccine is the date a 
patient receives the last injection of the study vaccine. 
Treatment-Emergent Period 
 
In this trial, only medically attended adverse events (MAEs), AEs for which a subject seeks 
medical attention at a doctor’s office, clinic, study site, emergency room, or is hospitalized, 
will be collected. 
 
The reporting period for all non-serious MAEs begins at the time of the first study injection 
(Day 1) through EOS Visit. All MAEs will be captured on the MAE eCRF. 
 
Any SAE that occurs from the time the consent is signed through EOS Visit, whether or not 
the SAE is related to the study treatment, must be reported. 
 
The treatment-emergent period is defined as time from the first study injection through EOS 
visit. 
7.2 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
 
• 1 year = 365.25 days. Year is calculated as (days/365.25) rounded up to 1 significant 
digit. 
• 1 month = 30.4375 days. Month is calculated as (days/30.4375) rounded up to 
1 significant digit. 
• Age will be calculated by the following SAS code: 
If only year of birth is given, then Age = (Year of Screening – Year of Birth). Otherwise 
age = floor ((intck('month', birth_date, consent_date) - 
(day(consent_date) < day(birth_date))) / 12); 
• 1 pound = 0.454 kg 
• 1 inch = 2.54 cm 
• Missing safety data will not be imputed unless otherwise specified. 
• For immunogenicity results, anti-HBs concentrations, are obtained using the Elecsys 
Anti‑HBs II assay. For concentration reported as <value, half of the value will be used in 
calculation. For concentration reported as >value, value+1 will be used in calculation. 
• For safety analyses, percentages will be calculated based on the number of patients in the 
analysis population. 


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DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 11 of 21 
 
 
• For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with nonmissing data as the denominator unless otherwise specified. 
• For other continuous endpoints, the summary statistics will include mean, standard 
deviation, median, and range (minimum and maximum). 
• For categorical endpoints, the summary statistics will include counts and percentages. 
• MAEs and medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17 or higher. 
• Prior therapies and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
7.3 
Rules for Missing Data 
 
Missing data will not be imputed, except for missing date information for AEs and 
concomitant medications. The imputed dates will be used to determine the treatment- 
emergent period. For AEs with a partial date, available date parts (year, month, and day) of 
the partial date will be compared with the corresponding date components of the start date 
and end date of the treatment-emergent period to determine if the event is treatment 
emergent. When in doubt, the AE will be considered treatment emergent by default. 
The following rules will be applied to impute partial dates for AEs: 
 
• If start date of an AE is completely or partially missing, impute as follows: 
• If both month and day are missing and year = year of first dose date, then set to first 
dose date. 
• If both month and day are missing and year ≠ year of first dose date, then set to 
January 1. 
• If day is missing and month and year = month and year of first dose date, then set to 
first dose date. 
• If day is missing and month and year ≠ month and year of first dose date, then set to 
first of the month. 
• If start date is completely missing and AE end date is on or after the first dose date, 
set to first dose date. 
• If start date is completely missing and AE end date is prior to the first dose date, do 
not impute an AE start date. 
• If end date of an AE is partially missing, impute as follows: 
• If both month and day are missing, then set to December 31. 
• If only day is missing, then set to last day of the month. 
• If end date is completely missing, do not impute. 


Dynavax Technologies 
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Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 12 of 21 
 
 
When the start date or end date of a medication is partially missing, the date will be imputed 
to determine whether the medication is prior or concomitant (or both). The following rules 
will be applied to impute partial dates for medications: 
• If start date of a medication is partially missing, impute as follows: 
• If both month and day are missing, then set to January 1. 
• If only day is missing, then set to the first of the month. 
• If end date of a medication is partially missing, impute as follows: 
• If both month and day are missing, then set to December 31. 
• If only day is missing, then set to last day of the month. 
• If start date or end date of a medication is completely missing, do not impute. 
 
Listings will show the original date information without imputation, but derived parameters 
(TEAE indicator and duration of AE) will be flagged to indicate the type of imputation 
performed. 
8.0 
TIMING OF ANALYSES 
 
A preliminary analysis may be performed to assess the primary immunogenicity objective of 
the SPR at Week 20 after approximately 50 subjects have completed their Week 20 visit (see 
Section 9.9). 
 
A final immunogenicity report with data up to Week 20 will be produced including 
demographics, baseline characteristics, medical history, vaccine exposures, immunogenicity 
data and post-injection reaction data. These data will be verified as complete and final 
following database lock process, and major protocol deviations up to Week 20 have been 
identified. Safety analysis of MAEs and concomitant medications with non-fully validated 
and non-final data will be included in this report. Status of these data will be footnoted where 
applicable. 
 
Final analyses will be carried out after the last participant has completed their last study visit, 
the study database has been authorized by Dynavax as complete and final, and major 
protocol deviations have been identified. Any changes to the frozen data in the final 
immunogenicity report with data up to Week 20 will follow post database lock change 
process according to BRK-SOPaaaaa Clinical Study Database Lock-Unlock Authorization. 
9.0 
STATISTICAL METHODS 
 
This is an open-label, single arm study, evaluating the immunogenicity and safety of 
HEPLISAV-B® in adults with end-stage renal disease undergoing hemodialysis. No pre- 
specified hypothesis testing will be performed. All analyses of demographics and baseline 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 13 of 21 
 
 
characteristics, medical history, vaccine exposure, immunogenicity and safety will be 
summarized in a descriptive manner. 
 
All confidence intervals are two-sided 95% confidence intervals unless otherwise specified. 
 
In general, continuous variables will be summarized by sample size, mean, standard 
deviation, median, quartiles, minimum and maximum, and categorical variables will be 
summarized by counts and percentages. All data processing, summarization, and analyses 
will be performed using SAS Version 9.3 or higher. Specifications for tables, graphs, and 
data listings will be provided in the tables, figures, listings (TFL) specifications document if 
needed. 
9.1 
Patient Disposition 
 
Patient disposition will be summarized for all enrolled patients including patients in the 
safety, PP and mITT populations and patients discontinuing the study along with the reasons 
for discontinuation (as documented on the case report form Study Completion). 
 
A listing of patients discontinuing the study after enrollment will be produced. 
 
9.2 
Protocol Deviations 
 
For the purpose of selecting subjects for the per-protocol population, a major protocol 
deviation is defined as one of the following: 
• not meeting one or more enrollment criteria, 
• anti-HBs serum sample obtained outside protocol specified visit window 4 weeks 
following the fourth study injection (Week 20 ± 7 days) 
• 28 days prior to Injection 1 and through Week 20: received prohibited concomitant 
medications comprising systemic corticosteroids, other immunomodulators or immune 
suppressive medications (with the exception of inhaled steroids), immunoglobulin, DNA 
plasmids or oligonucleotides, or any other investigational medication. 
 
A listing of patients with major protocol deviations will be provided describing their 
deviations. Any exclusions from analysis populations due to protocol deviations and other 
reasons will also be listed. 
9.3 
Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics will be listed by subject and summarized. 
Descriptive summary statistics (sample size, mean, median, SD, and range, when 
appropriate) will be provided for the continuous variables such as age, weight, height and 
BMI. Count and percentage will be reported for categorical variables such as sex, race, and 
ethnicity. 
 
Listings will be provided for these parameters for all patients. 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 14 of 21 
 
 
9.4 
Prior and Concomitant Medications 
 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (Version 201506 or higher). Prior medications are drugs and 
therapies used before the first dose date. Medications or therapies are considered concomitant 
if exposure occurs after the first dose date. The number and percentage of patients with 
concomitant medications will be presented alphabetically by anatomical therapeutic chemical 
(ATC) class and by decreasing order of frequency of preferred terms within each ATC class 
for the safety population. Patients taking the same medication multiple times will be counted 
once per medication. 
All medications recorded on the case report form will be listed. 
 
9.5 
Medical History 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA V17.0 or higher). Medical history will be summarized by System of Organ Class 
(SOC) and Preferred Term (PT) for safety population. All medical history data will be 
provided in a listing. 
9.6 
Immunogenicity Analyses 
 
Immunogenicity data will be analyzed based on the PP population by visit for all visits 
through 20 weeks with immunogenicity data collected. 
 
The SPR will be estimated. The associated 2-sided 95% confidence interval will be 
calculated using the Clopper-Pearson method. 
 
Proportion of subjects with anti-HBs concentration ≥100 mIU/mL and associated 2-sided 
95% confidence interval will also be calculated using Clopper-Pearson methods. 
 
Anti-HBs geometric mean concentration (GMC) and associated 2-sided 95% confidence 
interval will be calculated by exponentiating the mean and confidence interval in log10 of the 
anti-HBs concentration assuming Normal distribution. 
 
Analyses based on the mITT population may also be conducted. 
 
9.7 
Safety Analyses 
 
Vaccine exposure and compliance will be summarized descriptively for safety population. 
 
Safety data will be analyzed descriptively and will be based on the safety population. The 
most important safety parameters will be presented for all sites combined. Summary statistics 
will be used to describe the incidence of all post-injection reactions and MAEs (including 
SAEs, deaths, AMIs, and AESIs; further details regarding safety reporting of AMIs and 
AESIs are provided in Protocol Section 9.4.7.2). The incidence and proportion of post- 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 15 of 21 
 
 
injection reactions and MAEs will be summarized. MAEs will be coded using the MedDRA 
SOC and PT. 
 
The incidence of AMIs and major adverse cardiovascular events will be analyzed in subjects 
initiating hemodialysis after enrollment in the study and in subjects undergoing hemodialysis 
at the time of enrollment in the study. 
 
The treatment-emergent period is defined in Section 7.1. 
 
Local and systemic post-injection reactions are to be recorded on the subject diary. If they 
persist longer than 7 days (i.e., 8 days or longer) and are medically attended (i.e., subject 
seeks medical attention), they should also be recorded and reported as MAEs, per protocol 
Section 10.2. The severity of the post-injection reactions will be graded using the Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials. 
 
Local reactions include redness, swelling and pain, and systemic reactions include malaise 
(not feeling well), headache, myalgia (body aches) and fatigue (feeling tired). 
 
Post-injection reactions reported from day 1 to day 7 will be summarized by maximal 
severity and by vaccine group. The severity of local reactions, including redness and swelling 
will be categorized as none, 1 to ≤10mm, >10mm to ≤25mm, >25 to ≤50mm, >50 to 
≤100mm and >100mm (severe local reactions). 
 
The severity of pain and systemic reactions including malaise, headache, myalgia and fatigue 
occurring up to 7 days after each vaccination will be categorized as none, mild (no 
interference with activity), moderate (some interference with activity), severe (significant, 
prevents daily activity). 
 
Temperature will be categorized as <38°C (no fever), 38-38.4°C, 38.5-38.9°C, 39-40°C and 
>40°C. 
 
Each local and systemic reaction will also be categorized as none vs. any. 
 
All MAEs will be coded to preferred term and system organ class using MedDRA 17.0 or 
higher. An MAE that started or increased in severity during the treatment-emergent period 
will be considered a TEMAE. Severity of TEMAEs and laboratory abnormalities will be 
graded based on the United States Food and Drug Administration’s (FDA) Guidance for 
Industry: Center for Biologics Evaluation and Research (CBER) Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(with the exception of malaise, which will be graded per CTCAE v4.03), with the 
modification that, by convention, all fatal MAEs will be graded as Grade 5 (Fatal). All MAEs 
not listed in the CBER toxicity grading scale will be graded as shown in Table 9-1. 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 16 of 21 
 
 
Table 9-1: 
Grading Scale for Medically-Attended Adverse Events Not 
Included in the CBER Guidance on Toxicity Grading for Healthy 
Volunteers in Vaccine Clinical Trials 
 
MAE Severity 
Definition 
Grade 1 – Mild 
No interference with activity 
Grade 2 – Moderate 
Some interference with activity, not requiring medical intervention 
Grade 3 – Severe 
Prevents daily activity and requires medical intervention 
Grade 4 – Potentially life-threatening 
Emergency room visit or hospitalization 
Grade 5 
Death 
 
A study vaccine-related TEMAE is defined as any TEMAE with at least a possible 
relationship to the study vaccine as assessed by the investigator or that is missing the 
assessment of causal relationship whose relationship to the study vaccine could not be ruled 
out. 
 
Patients with multiple occurrences of events for a given preferred term, system organ class, 
or overall will only be counted once at the worst severity and strongest relationship to study 
vaccine for each preferred term, system organ class, and overall, respectively. MAEs that are 
continuous but change in grade, relationship, or seriousness will be counted as 1 event. 
TEMAEs of unknown severity will be categorized separately. A TEMAE of unknown 
relationship will be considered to be probably related to study vaccine. 
 
Incidences and percentages of subjects experiencing each reaction will be presented by 
severity. Summary tables showing the occurrence of any local or systemic reaction overall 
and at each time point will also be presented. 
Tabular summaries including numbers and percentages of the following adverse events will 
be provided: 
 
• 
All TEMAEs 
• 
TEMAEs of Grade 3 or above 
• 
All treatment-related MAEs 
• 
Treatment-related MAEs of Grade 3 or above 
• 
All treatment-emergent SAEs 
• 
All treatment-related SAEs 
• 
All TEMAEs leading to premature discontinuation of HEPLISAV 
• 
All SAEs leading to death 
• 
All AMI 


Dynavax Technologies 
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Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 17 of 21 
 
 
• 
All AESI 
Listings will be provided for all TEAEs. 
 
9.8 
Other Analyses 
 
No other analyses are planned. 
 
9.9 
Interim Analysis 
 
A preliminary analysis may be performed to assess the primary immunogenicity objective of 
the SPR at Week 20 after approximately 50 subjects have completed their Week 20 visit. The 
scope of the analysis is limited to the estimates of the SPR at Week 20. Limited demographic 
and safety data may be presented along with the SPR estimates. The list of analyses for this 
interim analysis will be highlighted in the Table of Contents of Tables, Figures and Listings 
document. 
9.10 
Reporting Output 
 
All outputs will be produced using SAS® version 9.3 or later. The REPORT procedure will 
be used to produce all tables and listings whenever possible. The SGPLOT procedure will be 
used to produce all figures whenever possible. All statistical appendices (supportive SAS 
output) will be output directly from the appropriate SAS procedure. 
 
Post-text tables, listings, and statistical appendices will be produced as RTF files using 
output delivery system (ODS) and Times New Roman or a similar font size 8 or larger. Data 
will be presented in RTF tables with data in individual cells. Figures will be produced as 
RTF files using ODS and simplex font. For all outputs, the page numbering will be applied to 
ensure that when the RTF files are combined, the page numbering remains fixed. 
 
All tables, listings and statistical appendices will be produced to landscape orientation and 
will be incorporated into a Word 2010 or later document (margins: top 1.5”, left, right and 
bottom 1”) using 8pt font or larger. 
 
Vaccine name for tables and figures will be as follows: 
 
• 
HEPLISAV-B 


Dynavax Technologies 
DV2-HBV-24 
Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 18 of 21 
 
 
10.0 
REVISION HISTORY 
 
Version Date 
Author 
Comments/Rationale for Revision 
1.0 
25FEB2020 
aaaaaaaa 
New Document 
2.0 
02SEP2020 
aaaaaaaa 
Update for Protocol Amendment 4 
2.1 
15SEP2020 
aaaaaaaa 
COVID-19 Specific Update [1] on Major 
Protocol Deviations/PP Population 
definition: “vaccine given outside protocol 
specified visit window at Weeks 4, 8 and 16 
(± 7 days)” are not Considered as Major 
Protocol Deviations for PP Population 
Exclusion Purpose. 
 
11.0 
REFERENCES 
[1] FDA Guidance for Industry: Statistical Considerations for Clinical Trials During the 
COVID-19 Public Health Emergency, June 2020 
https://www.fda.gov/media/139145/download 


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Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 19 of 21 
 
 
12.0 
LIST OF TABLES 
List of tables will be provided in a separate Table of Contents of Tables, Figures and Listings 
document. 


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Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 20 of 21 
 
 
13.0 
LIST OF FIGURES 
 
List of figures will be provided in a separate Table of Contents of Tables, Figures and 
Listings document. 


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Statistical Analysis Plan 
15 September 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 21 of 21 
 
 
14.0 
LIST OF PATIENT DATA LISTINGS 
List of listings will be provided in a separate Table of Contents of Tables, Figures and 
Listings document.