A Phase 2 Randomized Blinded Placebo Controlled Comparison of the Safety Pharmacokinetics and Pharmacodynamics of a Single Dose of SYN023 Administered With Licensed Rabies Vaccines in Healthy Adult Subjects
Phase: PHASE1
Conditions: Human Rabies
Sponsor: Synermore Biologics Co., Ltd.

 
 
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SYN023 
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A Phase 2 randomized blinded single dose comparison of the safety 
pharmacokinetics and pharmacodynamics of rabies immune globulin, and 
SYN023 in healthy adult subjects receiving rabies vaccines 
 
 
Investigational Product:  
 
SYN023 
 
Protocol Number:  
 
 
SYN023-002 
 
US FDA IND Number: 
 
 
BB-IND-121522 
 
 
Sponsor: 
Synermore Biologics Co., Ltd 
6F, No 5-6, Aly 22, Ln 513, Ruiguang Rd. 
Neihu Dist., Taipei City 11492 
Taiwan 
Phone: 011.886.02.2659.0988 
Fax: 
011.866.02.2659.0950 
 
Sponsor Representative: 
Eric Tsao, Ph.D. 
Chief Executive Officer 
 
Signature 
 
 
 
 
 
 
 
Date 
 
Version and Date:  
 
 
Version 2.0 (21 June 2016) 
Version Superseded 
 
 
Version 1.0 (12 May 2016) 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Agreement: 
I, the undersigned, have reviewed this protocol and agree to conduct this protocol in accordance 
with Good Clinical Practices (ICH-GCP), the ethical principles set forth in the Declaration of 
Helsinki, and with local regulatory requirements.   
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
Printed Name  

 
 
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SYN023 
Protocol SYN-023-002  
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 TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
STUDY ABSTRACT .................................................................................................................... 8 
1 
INTRODUCTION........................................................................................................... 10 
1.1 
Background ............................................................................................................. 10 
1.2 
Description of SYN023 ........................................................................................... 11 
1.3 
Nonclinical Experience with SYN023 .................................................................... 11 
1.4 
Clinical Experience with Anti-infective Monoclonal Antibody 
Preparations ............................................................................................................. 12 
1.5 
Clinical Experience with SYN023 .......................................................................... 12 
1.6 
Rationale for Study .................................................................................................. 14 
2 
STUDY OBJECTIVES AND DESIGN ......................................................................... 14 
2.1 
Objectives ................................................................................................................ 14 
2.2 
Design ...................................................................................................................... 15 
3 
STUDY PROCEDURES ................................................................................................ 15 
3.1 
Schedule of Subject Treatments and Evaluations ................................................... 15 
3.2 
Subject Selection ..................................................................................................... 16 
3.2.1 
Recruitment and Informed Consent .......................................................... 17 
3.2.2 
Screening................................................................................................... 17 
3.2.3 
Inclusion Criteria ...................................................................................... 17 
3.2.4 
Exclusion Criteria ..................................................................................... 18 
3.2.5 
Screening Clinical Assessments and Laboratory Tests ............................ 19 
3.2.5.1 
Window Period for Select Screening Laboratory 
Tests ......................................................................................... 20 
3.3 
Study Randomization and Sentinel Subjects ........................................................... 20 
3.4 
Blinding ................................................................................................................... 20 
3.4.1 
Unblinding for Clinical Emergencies ....................................................... 21 
3.5 
Medicinal Product and Study Drug Administration ................................................ 21 
3.5.1 
SYN023 (Study Drug) .............................................................................. 22 
3.5.2 
Rabies Immune Globulin, (HyperRab ST® Study Drug) .......................... 22 
3.5.3 
Rabies Vaccine RVa (Chicken Fibroblast Rabies Vaccine 
RabAvert®) ................................................................................................ 23 
3.5.4 
Rabies Vaccine RVi (Human Diploid Cell Rabies Vaccine 
Imovax®) ................................................................................................... 23 
3.6 
Study Evaluations .................................................................................................... 23 
3.6.1 
Efficacy Evaluations ................................................................................. 23 
3.6.2 
Immunology Laboratory Evaluations ....................................................... 23 
3.6.3 
Safety Evaluations .................................................................................... 24 

 
 
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3.6.3.1 
Pre-Study Study Drug and Post-Study Drug 
Administration Clinical Monitoring of Subjects ...................... 24 
3.6.3.2 
Recognition of Anaphylaxis ..................................................... 24 
3.6.3.3 
Treatment of Anaphylaxis ........................................................ 25 
3.6.3.4 
Recognition and Evaluation of Immune Complex 
Illness ....................................................................................... 26 
3.6.3.5 
Clinical Assessments and Laboratory Tests ............................. 26 
3.6.3.6 
Adverse Events......................................................................... 27 
3.6.3.7 
Concomitant Medications ........................................................ 27 
3.6.4 
Window Periods for Clinical Laboratory, ECG, Immunology 
and Pharmacodynamic Blood Specimens ................................................. 27 
3.6.5 
Subject Follow-up and Contact ................................................................. 27 
3.6.6 
Loss to Follow-up ..................................................................................... 28 
3.6.7 
Replacement of Subjects ........................................................................... 28 
4 
STUDY MEDICINAL PRODUCTS ............................................................................. 28 
4.1 
SYN023 ................................................................................................................... 28 
4.1.1 
Receipt and Storage .................................................................................. 28 
4.1.2 
SYN023 Preparation ................................................................................. 29 
4.1.3 
Disposal of Unused Supplies .................................................................... 29 
4.2 
RIG (HyperRab ST®) ............................................................................................... 29 
4.2.1 
Receipt and Storage .................................................................................. 29 
4.2.2 
RIG Preparation ........................................................................................ 29 
4.2.3 
Disposal of Unused Supplies .................................................................... 30 
4.3 
RVi (Imovax®) ........................................................................................................ 30 
4.3.1 
Receipt and Storage .................................................................................. 30 
4.3.2 
RVi Preparation ........................................................................................ 30 
4.3.3 
Disposal of Unused Supplies .................................................................... 30 
4.4 
RVa (RabAvert®) .................................................................................................... 31 
4.4.1 
Receipt and Storage .................................................................................. 31 
4.4.2 
RVa Preparation ........................................................................................ 31 
4.4.3 
Disposal of Unused Supplies .................................................................... 31 
4.5 
Accountability ......................................................................................................... 31 
5 
SAFETY ........................................................................................................................... 32 
5.1 
Responsibilities for Ensuring the Safety of Trial Subjects ..................................... 32 
5.1.1 
Principal Investigator ................................................................................ 32 
5.1.2 
Study Sponsor ........................................................................................... 32 
5.1.3 
Medical Monitor ....................................................................................... 32 
5.1.4 
Safety Monitoring Committee .................................................................. 32 
5.1.5 
Institutional Review Boards and Ethics Committees................................ 33 
5.1.6 
National Regulatory Authority ................................................................. 33 
5.2 
Safety Surveillance During the Study ..................................................................... 33 
5.3 
Definition of Adverse Event ................................................................................... 33 

 
 
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5.4 
Assessing Severity ................................................................................................... 34 
5.5 
Assessing Causal Relationship (Relatedness) ......................................................... 35 
5.6 
Definition of Adverse Reaction ............................................................................... 37 
5.7 
Solicited Adverse Events and Injection Site Reactions .......................................... 37 
5.8 
Assessing “Seriousness” and Serious Adverse Events ........................................... 38 
5.9 
Assessing Expectedness .......................................................................................... 38 
5.10 Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) ............ 38 
5.11 Reporting of Serious Adverse Events ..................................................................... 39 
5.12 Other Events Requiring Immediate Reporting ........................................................ 40 
5.13 Adverse Event Treatment, Follow-up, and Outcome .............................................. 40 
5.14 Follow-up of Subjects Who Become Pregnant ....................................................... 41 
5.15 Subject Daily Temperature Monitoring .................................................................. 42 
6 
PAUSING AND STOPPING RULES ........................................................................... 42 
6.1 
Safety Pausing Rules ............................................................................................... 42 
6.2 
Safety Stopping Rules ............................................................................................. 43 
7 
STATISTICAL CONSIDERATIONS .......................................................................... 43 
7.1 
Subject Populations ................................................................................................. 43 
7.2 
Demographics and Protocol Compliance ................................................................ 44 
7.3 
Efficacy or Pharmacodynamic (Serum Rabies Virus Neutralizing 
Activity) Analyses ................................................................................................... 44 
7.4 
Immunogenicity: Anti-SYN023 Antibodies ........................................................... 44 
7.5 
Pharmacokinetic Analyses ...................................................................................... 45 
7.6 
Safety Analyses ....................................................................................................... 45 
7.6.1 
Adverse Events ......................................................................................... 45 
7.6.2 
Clinical Laboratory and Vital Sign Parameters ........................................ 46 
7.7 
Sample Size Considerations .................................................................................... 46 
7.8 
Plan for Statistical Summaries and Analyses .......................................................... 47 
7.8.1 
Preliminary Data Reviews ........................................................................ 47 
7.8.2 
Final Study Report .................................................................................... 47 
7.9 
Computer Methods .................................................................................................. 47 
8 
DATA COLLECTION, MONITORING, AND RECORD RETENTION................ 47 
9 
HUMAN SUBJECTS ...................................................................................................... 48 
9.1 
Ethics and Regulatory Considerations .................................................................... 48 
9.2 
Institutional Review Board or Independent Ethics Committee ............................... 49 
9.3 
Informed Consent .................................................................................................... 49 
10 
STUDY COMPLETION ................................................................................................ 50 
11 
PUBLICATIONS ............................................................................................................ 50 
12 
CHANGES IN THE PROTOCOL ................................................................................ 51 

 
 
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12.1 Changes to Version 2.0 from Version 1.0. .............................................................. 51 
REFERENCES ............................................................................................................................ 54 
APPENDIX A 
Detailed Description of Selected Study Visits ....................................... 56 
APPENDIX B 
SAE Reporting Scheme .......................................................................... 58 
APPENDIX C 
Sponsor’s Representative ....................................................................... 59 
APPENDIX D 
Protocol Facility and Contact List......................................................... 60 
APPENDIX E 
Toxicity Table .......................................................................................... 62 
 

 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term
AE
adverse event
ADCC
antibody directed cellular cytotoxicity
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
AUC0-last
area under the curve time 0 to last time point
AUC0-inf,
area under the curve time 0 to infinity
HCG
beta human chorionic gonadotropin 
BUN
blood urea nitrogen
BP
blood pressure
HIV
human immunodeficiency virus
ICI
immune complex illness
CBC
complete blood count
CDC
Centers for Disease Control
Cmax, 
maximum concentration
Clp
plasma clearance
CFR
code of federal regulations
Cr
creatinine
CRF
case report form
CPK
creatinine phosphokinase
CV
coefficient of variation
ECG
electrocardiogram
eCRFs
electronic case report form
EDC
electronic data capture
FDA
U.S. Food and Drug Administration
HASYN023
human anti-SYN023 antibodies
HIV
human immunodeficiency virus
IEC
independent ethics committee
IgA
Immunoglobulin A
IgG1κ
Immunoglobulin G type 1 kappa 
IM
intramuscular
IRB
Institutional review board
IU
International units
λz
terminal elimination rate constant
LLN
lower limit of normal
kg
kilogram 
MedDRA
medical dictionary for regulatory activities
mL
milliliter

 
 
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mAb
monoclonal antibody
PD
pharmacodynamic
PEF
peak expiratory flow
PK
pharmacokinetic
PEP
post-exposure prophylaxis
PT(INR)
prothrombin time (international normalized ratio)
PTT
partial thromboplastin time
RFFIT
rapid fluorescent foci inhibition test
RVNA
rabies virus neutralizing activity
RIG
rabies immune globulin
RVa
RabAvert®
RVi
Imovax®
SAE
serious adverse event
SAP
statistical analysis plan
SMC
safety monitoring committee
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse event 
Tmax
time till maximum concentration
t1/2
half-life
ULN
upper limit of normal
WHO
World Health Organization
 
 

 
 
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STUDY ABSTRACT 
 
TITLE: A Phase 2 randomized blinded single dose comparison of the safety pharmacokinetics 
and pharmacodynamics of rabies immune globulin, and SYN023 in healthy adult subjects 
receiving rabies vaccines 
 
RATIONALE: 
The lowest dose of SYN023 tested in Protocol SYN023-001(0.3 mg/kg) exceeded rabies virus 
neutralizing activity (≥ 0.5 IU/mL) in the serum for at least 35 days.  The two higher doses of 1.0 
mg/kg and 3.0 mg/kg exceeded rabies virus neutralizing activity for 84 days.  This means that the 
lowest dose of SYN023 administered to humans will likely produce a bridge of rabies 
neutralizing activity until the rabies neutralizing response to vaccination becomes therapeutic, 
usually in two to three weeks after vaccination. Since high levels of antibody have the potential 
to impair the immune response to the rabies vaccine it is important to evaluate the potential of 
0.3 mg/kg SYN023 to inhibit the immune response of the two licensed rabies vaccines Imovax® 
and Rabavert®. 
 
OBJECTIVES: 
Primary Objective 
Compare the rabies virus neutralizing activity induced by licensed rabies vaccines Imovax® (RVi) 
and Rabavert® (RVa) co-administered with human rabies immune globulin (RIG) or 0.3 mg/kg 
of SYN023. 
 
Secondary Objective(s) 
 Compare the safety RVi and RVa administered with RIG or SYN023 
 Determine the pharmacokinetics of SYN023 
 Determine the immunogenicity of SYN023 
 
DESIGN: 
This is a Phase 2 single site, randomized, blinded comparison of the immunogenicity, of RVi and 
RVa when administered RIG or SYN023.   After sentinel subjects are evaluated for each regimen 
subjects will be randomized into one of four dose regimens with a ratio of 1:1:1:1 (Table 2.1-1).  
The trial is planned at one site. All injections will be given intramuscularly  
 
Table 2.1-1Treatment Allocation 
Treatment Allocation 
Number of subjects 
RVi + RIG 
40 
RVa + RIG 
40 
RVi + SYN023 0.3 mg/kg 
40 
RVa + SYN023 0.3 mg/kg 
40 
Total  
160 
 

 
 
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The labeled RVi and RVa regimens for post exposure prophylaxis are both five dose regimens. 
The initial dose of RVi and RVa will be co-administered with Study Drug (either RIG or 0.3 
mg/kg SYN023) on Study Day 0.   Rabies virus neutralizing activity (RVNA) and blood levels 
of SYN023 will be measured for the remainder of the trial while the rest of the post-exposure 
RVi and RVa doses are given.  It is anticipated that RVNA will remain high during RVi and 
RVa administration and through the end of the study at Study Day 112.  Pharmacodynamic 
efficacy will be defined as RVNA measured above 0.5 IU/mL with RVi and RVa for the 
duration of the trial.  SYN023 concentrations and anti-SYN023 antibodies will also be measured. 
 
ANALYSIS OF SAFETY 
Safety monitoring will include vital signs (blood pressure, temperature, pulse, oximetry and 
respiration rates), physical examination, electrocardiogram (ECG) and clinical laboratory tests 
(serum chemistry, hematology, troponins, creatinine phosphokinase [CPK], human anti-SYN023 
antibodies [HASYN023], and urinalysis). Adverse events will be recorded throughout the study 
and will be coded using MedDRA (Medical Dictionary for Regulatory Activities) terminology. 
Visual assessment of the injection site will be performed prior to and 30 minutes post-injection 
after all injections. Solicited local (induration, pain, redness and swelling) and systemic reactions 
are reviewed over follow-up visits during the twenty eight (28) days following administration. 
Adverse events are captured and recorded from the time of first administration through Day 42. 
Serious adverse events (SAEs) are captured and recorded from the time of administration through 
Day 112. 
 
 Safety analyses will be performed using the Safety Population, as defined in section 7.1. Both 
count and percent summaries will be presented by treatment group for all subjects.  Descriptive 
statistics (number of subjects, mean, standard deviation, percent coefficient of variation, median, 
minimum, and maximum) will be used to summarize all safety and laboratory data. 
 
ANALYSIS OF EFFICACY 
RVNA of >0.5 IU/mL will be used as a pharmacodynamic surrogate of efficacy.   
 
ANALYSIS OF IMMUNOLOGY 
Anti-SYN023 antibodies (i.e., anti-CTB011 and anti-CTB012 antibodies) will be determined on 
Study Days 0, and 7 through 112, or the last blood specimen available for subjects who leave the 
study prior to Day 112.  The development of anti-SYN023 antibodies will be analyzed as a 
continuous measure across categorical groups by treatment assignment, with descriptive statistics. 
Exploratory immunological analyses may be conducted on any collected sera. 
 
ANALYSIS OF PHARMACOKINETICS 
All PK analyses of serum SYN023 concentrations will be based on subjects who received 
study drug. Individual analyses will be performed and descriptive statistics will be used to 
describe the results of individual analyses. PK parameters for SYN023 mAb will be estimated 
using non-compartmental analysis. Cmax, Tmax, AUC0-last, AUC0-inf, t1/2, Clp, and λz will 
be calculated when possible.  

 
 
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1 
INTRODUCTION 
 
1.1 
Background 
Rabies is an acute lethal zoonotic disease transmitted from animals to humans. Rabies is known 
to be present in more than 150 countries and territories and on every continent except Antarctica, 
and all mammals are believed to be susceptible to infection with the virus. In the US, multiple 
rabies virus variants are maintained in wild mammalian reservoir populations such as raccoons, 
skunks, foxes, and bats. Infected domestic and wild animals spread rabies to humans via saliva or 
scratches (Gompf ,  2014). Although the US has been declared free of canine rabies virus variant 
transmission, in developing countries, the primary route of transmission to humans is via the bite 
of a rabid dog (Manning et al. 2008).  There are currently no known effective rabies antiviral 
drugs.  
 
Once the clinical signs of rabies manifest, the mortality rate approaches 100%.  Therefore, post-
exposure prophylaxis against rabies infection is of critical importance.  Rabies vaccination alone 
is used for preexposure prophylaxis (Fishbein, 1989).  Studies on the development of rabies virus 
neutralizing activity through immunization indicate that on Day 7 post vaccination most 
individuals lack adequate rabies virus neutralizing activity while by Day 14 after immunization 
virtually all individuals vaccinated with a modern vaccine have adequate rabies neutralizing 
activity (Grandien 1976, Vodopija 1988a)   
 
The rabies mortality from rabid wolf attacks in Iran in 1955 was 1/24 (4.2%) when both 
vaccination and rabies antisera were used prior to disease manifestations versus 3/5 (60%) when 
vaccine alone was employed (Baltazard 1955).  A study by the same investigator from 1974 
found that a rabies vaccine from human diploid cells combined with mule derived anti-rabies 
antiserum yielded 0% rabies mortality in 44 bitten individuals without disease manifestations 
even with delays of up to 14 days (Bahmanyar 1976). Delays of up to 4 days in the initiation of 
rabies immune globulin after anti-rabies vaccination have demonstrated no inhibition of the 
RVNA activity in blood (Khawplod 1996).  Since those experiences post-exposure prophylaxis 
through the combined administration of a rabies vaccines and rabies immune globulin (RIG) is 
the standard of care.   
 
The passive administration of RIG is intended to provide an immediate supply of virus 
neutralizing antibodies to bridge the gap until the induction of active immunity in response to 
vaccine administration. The use of RIG provides rapid passive immunity that persists for a short 
time (half-life of approximately 21 days) (Manning et al. 2008). There is sometimes an 
interaction between RIG and the immune response elicited by the rabies vaccine thus the dose of 
rabies immune globulin must be evaluated to insure no significant inhibition (Vodopija 1988b). 
 
Two anti-rabies immunoglobulin (Ig) formulations prepared from hyperimmunized human 
donors have been approved by the FDA: HyperRab® S/D (Grifols Therapeutics) and Imogam® 

 
 
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Rabies-HT (Sanofi Pasteur).  Since both human RIG preparations are considered equivalent 
HyperRab® S/D will be used as the RIG in this trial.  
 
1.2 
Description of SYN023 
SYN023 is a mixture of two anti-rabies humanized monoclonal IgG1κ antibodies, CTB011 and 
CTB012, which bind to distinct and non-overlapping antigenic sites on the rabies glycoprotein. 
N355 and H389 are the critical binding residues for CTB011 and H289, L290 and V291 are the 
critical residues for CTB012.  As with RIG, the goal of treatment with SYN023 is to rapidly 
establish protective levels of anti-rabies antibody in individuals exposed to the rabies virus.  
Since RIG is derived from pooled sera of human donors or horses vaccinated against rabies 
(human rabies immune globulin and equine rabies immune globulin, respectively), there is a 
limited supply, particularly in endemic areas. Thus, there is an urgent need for improved 
approaches to the critical initial treatment period.  SYN023, a mixture of two anti-rabies 
humanized monoclonal IgG1κ antibodies, CTB011 and CTB012, has been shown to neutralize 
more than 15 contemporary clinical isolates of rabies viruses collected in China, and the 10 
predominant strains in the US. 
 
1.3 
Nonclinical Experience with SYN023 
Nonclinical studies with SYN023 and its component antibodies CTB011 and CTB012 showed 
that both antibodies exhibited high affinity for the rabies virus glycoprotein target and that the 
two antibodies bind to distinct, non-overlapping sites on the surface of the virus. SYN023 and the 
component antibodies exhibited potent neutralizing activity against a wide spectrum of rabies 
virus strains from both the US and China and importantly, SYN023 did not attenuate or impact 
the nature or timing of the immune response to rabies vaccine in an established hamster model. 
SYN023 provided improved post-exposure prophylaxis (PEP) relative to vaccine alone, and 
provided early-phase passive immune protection that served as a bridge in both hamster and dog 
disease models until active immunity was produced by the rabies vaccine. 
The antibodies comprising SYN023 both exhibited half-lives of a week or more in rats and dogs, 
with >90% bioavailability in both males and females. Dose-dependent exposure was observed in 
both rats and dogs with increasing doses of SYN023. 
SYN023 was safe and well-tolerated in male and female rats following three repeated weekly IM 
doses at up to 10 mg/kg, and no mortality or toxicity were observed. SYN023 and the component 
antibodies did not bind specifically to any human tissues, and neither CTB011 nor CTB012 
exhibited any apparent in vitro cytotoxicity, antibody-dependent cell-mediated cytotoxicity 
(ADCC) or complement-dependent cytotoxic activity in normal, non-rabies-infected cells. As 
anticipated, SYN023 did exhibit potent complement-dependent cytotoxic activity against rabies- 
infected BSR hamster cells, demonstrating the specificity of SYN023 antibodies for rabies virus 
and virus-infected cells, and that the antiviral activity likely involves a complement-dependent 
mechanism. It is important to note that neither of the component SYN023 antibodies bound 

 
 
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specifically to any human tissue, and there is no endogenous target for the SYN023 product in 
normal, healthy human tissues, such that no specific or non-specific toxicity is anticipated for 
SYN023. 
Animal PEP studies have demonstrated that in hamsters, doses of antibody combinations as low 
as 0.3 mg/kg provided complete protection against rabies challenge, whereas in dogs, doses of 
SYN023 as low as 0.03 mg/kg in tandem with rabies vaccine also provided complete protection 
against lethal rabies challenge.  These findings suggest that doses of SYN023 as low as 0.005-
0.01 mg/kg, at least in dogs, should produce levels of RVNA of at least 0.5 IU/mL, which are 
generally considered sufficient for complete protection against lethal rabies challenge when 
administered in concert with rabies vaccine. 
 
1.4 
Clinical Experience with Anti-infective Monoclonal Antibody Preparations 
SYN023 is a mixture of monoclonal antibodies that are directed against an infectious agent and 
do not exhibit cross-reactivity with human tissues.  Palivizumab (Synagis, MedImmune Inc.) is a 
monoclonal antibody that is directed against an infectious agent, respiratory syncytial virus that 
lacks cross-reactivity with human tissues.  Palivizumab has been on the market since1998 and 
continues to remain effective and exhibit an acceptable safety profile.  
 
1.5 
Clinical Experience with SYN023 
 
SYN023 administration exhibited an acceptable safety profile in protocol SYN023-001. There 
were no SAEs or acute allergic reactions and local toxicity was mild.  SYN023 antibody 
concentrations are pending for Study SYN023-001, however RVNA determinations are final.   
All five subjects in each dose group of protocol SYN023-100 lacked RVNA prior to SYN023 
injection and exhibited measurable RVNA after administration thus, it is reasonable to conclude 
that the RVNA was the result of SYN023 antibody injection. If this is true then the two higher 
doses of 1.0 mg/kg and 3.0 mg/kg exceeded rabies virus neutralizing activity for 84 days and the 
mean level of the lowest dose of SYN023 tested in Protocol SYN023-001 (0.3 mg/kg) exceeded 
rabies virus neutralizing activity (≥ 0.5 IU/mL) by over five-fold in the serum for at least 28 days 
(Table 1.5-1).  The descriptive statistics including mean, standard error and 95% confidence 
intervals were calculated by SAS 9.4 (Cary, NC, USA) and figure 1.5-1was generated using 
Graphpad Prism 5.0 (San Diego, CA, USA 
 
 
 
 
 
 
 
 

 
 
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Table 1.5-1  Mean RVNA activity in IU by dose level in Phase I study of SYN023. 
Five subjects in each group.   
 
Dose 
Level  
mg/kg
Study Day 
0 
1 
3 
7 
14 
28 
35 
84 
0.3
0.00 ± 0.00
2.70 ±0.43
3.68 ±0.56 
4.44 ±1.09
3.78 ±0.41
2.82±0.61
1.82 ±0.93
0.22 ±0.25
1.0
0.00 ± 0.00
8.88 ±3.13
10.02 ±2.07 17.00 ±8.81
11.2 ±3.24
10.3±3.37
11.64 ±3.86
2.22 ±1.06
2.0
0.02 ± 0.00
13.40 ±8.19
27.60 ±3.31 35.00 ±2.40
35.6 ±3.85
13.80 ±7.61 10.14 ±2.12
3.76 ±1.07
 
These results are graphically presented for the lowest dose group as means ± 95% confidence 
interval (Figure 1.5-1).  Rabies neutralizing activity from IM injection Study Day 0 was 
measurable and several-fold above the minimum inhibitory level of 0.5 IU/mL on Study Days 1, 
3, 7, 14 and 28.  
 
Dose 0.3 mg/kg
Rabies Virus Neturalizing Antibodies
10
20
30
40
50
60
70
80
90
-1
0
1
2
3
4
5
6
0.5
Time (Days)
Neutralizing Activities (IU/mL)
 
Figure 1.5-1 SYN023 Rabies Virus Neutralizing Activity over time (95% CI) 
 
 
The lowest dose of SYN023 tested in Protocol SYN023-001(0.3 mg/kg) in humans exceeded 0.5 
IU/mL of RVNA in the serum of all volunteers for at least 35 days.  The two higher doses of 1.0 
mg/kg and 3.0 mg/kg exceeded serum rabies virus neutralizing activity for 84 days (Table 1.5-1).  
This means that the lowest dose tested in humans will produce a bridge of RVNA long enough 
for the neutralizing response from vaccination to become therapeutic, usually within 14 days.  
Since high levels of antibody have the potential to impair the immune response to the rabies 
vaccine it is important to evaluate the potential of the lowest SYN023 dose active in animal (0.3 
mg/kg) to inhibit the immune response of the two licensed rabies vaccines Imovax® and 
Rabavert®.  SYN023-001 was a single dose study.  Any effects of anti-SYN023 antibodies on 
RVNA are reflected in the RVNA values and seem to have a negligible inhibitory effect. The 
overall RVNA needed for protection will be known with certainty in the current SYN023-002 

 
 
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study.  When the human SYN023-001 pharmacokinetic values are available it will be possible to 
correlate the RVNA provided by a known amount of SYN023 to develop a RVNA-per-mg-
SYN023 value that might be useful in the current study to estimate the relative contribution of 
SYN023 to the overall RVNA induced by vaccination. In any event such as estimation can be 
made during the Study Day 0 through Study Day 7 interval when vaccine induced RVNA is 
unlikely to be present. 
 
 
1.6 
Rationale for Study 
Monoclonal antibodies (mAbs) offer the advantages of batch-to-batch consistency and large- 
scale production, and may therefore provide a solution to the current global shortage of RIG. 
However, as mentioned, there are several strains of the rabies virus that predominate in various 
regions of the US and the world; their prevalence is tracked by the Centers for Disease Control 
and Prevention (CDC) and the World Health Organization (WHO). A single target epitope may 
not be present on all strains of the rabies virus. As a result, it is of critical importance for the 
antibody product to account for the genetic variability of the rabies viruses and offer effective 
broad spectrum neutralization activities. Accordingly, administration of a mixture of mAbs with 
complementary specificity and functionality would be preferable to administration of a single 
mAb.  
Consensus definitions of adequate rabies virus neutralizing antibody reference values have been 
developed to define an appropriate, intact adaptive host response to vaccination: RVNA of 0.5 
international units (IU) per milliliter (mL) or complete virus neutralization at a 1:5 serum 
dilution by RFFIT (Centers for Disease Control and Prevention 1999). The goal of RIG and 
SYN023 is to rapidly establish protective rabies virus neutralizing levels in the rabies exposed 
person. RVNA appears to be adequate at the 0.3 mg/kg dose level and since this is clinically 
important and logically correlated directly with the SYN023 antibody administered the SYN023-
002 study may be started despite the ongoing analysis of a RVNA-per-mg-SYN023 value that 
might be important in the SYN023-002 analysis. 
 
 
 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Objectives 
Primary Objective 
Compare the rabies virus neutralizing activity induced by licensed rabies vaccines Imovax® (RVi) 
and Rabavert® (RVa) co-administered with human rabies immune globulin (RIG) or 0.3 mg/kg 
of SYN023. 
 
Secondary Objective(s) 
 Compare the safety RVi and RVa administered with RIG or SYN023 
 Determine the pharmacokinetics of SYN023 

 
 
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 Determine the immunogenicity of SYN023 
  
2.2 
Design 
This is a Phase 2 single site, randomized, blinded comparison of the immunogenicity, of RVi and 
RVa when administered RIG or SYN023.   Subjects will be randomized into one of four dose 
regimens with a ratio of 1:1:1:1 (Table 2.2-1).  The trial is planned at one site. All injections will 
be given intramuscularly  
 
 
 
 
Table 2.2-1Treatment Allocation 
 
Treatment Allocation 
Number of subjects 
RVi + RIG 
40 
RVa + RIG 
40 
RVi + SYN023 0.3 mg/kg 
40 
RVa + SYN023 0.3 mg/kg 
40 
Total  
160 
 
The RVi and RVa regimens for post exposure prophylaxis are both five dose regimens. The 
initial dose of RVi and RVa will be co-administered with Study Drug (either RIG or 0.3 mg/kg 
SYN023) on Study Day 0.   Rabies virus neutralizing activity (RVNA) and blood levels of 
SYN023 will be measured for the remainder of the trial while the rest of the post-exposure RVi 
and RVa doses are given.  It is anticipated that RVNA will remain high during RVi and RVa 
administration and through the end of the study at Study Day 112.  Pharmacodynamic efficacy 
will be defined as RVNA measured above 0.5 IU/mL with RVi and RVa for the duration of the 
trial and no more than 10% lower for SYN023 compared to RIG at any time point through Study 
Day 35.  SYN023 concentrations and anti-SYN023 antibodies will also be measured.  
3 
STUDY PROCEDURES 
3.1 
Schedule of Subject Treatments and Evaluations 
A Summary Schedule of Evaluations depicting all visit-specific procedures is provided in Table 
3.1-1.  All scheduled phlebotomy samples must be collected prior to administration of any study 
specified vaccine, RIG or SYN023.   See Appendix A for a more detailed description of the 
evaluations.  
 

 
 
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Table 3.1-1 Summary Schedule of Subject Treatment and Evaluations 
Study Visit Day  
Scre
en
-2
0
1 
3 
7 
14
28
35
42
84
112
Visit Windowd
0
0
0
0
1
1
3
4
4
8
11
Written informed consent
X
 
Eligibility criteria verification
X
 
Medical history
X
 
Physical examination 
X
 
ECGe
X
X
X
X
X
X
X
 
X
Urine toxicology screen
X
 
Urine HCG (all females)e 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
Serum HCG (all females)a 
 
5 
 
 
 
 
 
 
 
 
 
 
Serum Hepatitis B, C tests
3
 
Serum HIV-1,2 tests
3
 
Rabies Vaccine administration
X
X
X
X
X
 
Study Drug Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
Urinalysise
X
X
X
X
X
X
X
X
X 
X
Serum Anti-rabies activitye
10
10
10
10
10
10
10
10
10
10
Serum chemistryb,e
10
10
10
10
10
10
10
 
10
CBC, differential, plateletse 
7
7
7
7
7
7
7
 
7
PT (INR), PTTe 
5
5
5
 
5
Serum IgA
7
 
SYN023 Pharmacokineticse 
14
7
7
7
7
7
7
7
7
Anti-SYN023 antibodiese 
5
5
5
5
5
5
5
5
Weight
X
X
 
X
Vital signs & oximetry
X
X
X
X
X
X
X
 
X
Interval history
X
X
X
X
X
X
X
X 
X
X
Focused physical examination
X
X
X
X
X
X
X
X 
X
X
Solicited adverse events (incl. 
con. meds.)
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Unsolicited adverse events (incl. 
con. meds.)
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serious adverse events (incl. con. 
meds.)
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Site of injection examination
X
X
X
X
X
X
X
X 
X
Lymphadenopathy
X
X
X
X
X
X
X
X 
X
Per visit phlebotomy volume
35
5
51
34
34
39
39
39
22
22
22
37
Cumulative phlebotomy volumec.
35
40
91
125
159
198
237 
276
298
310 
332
369
a. 
Results must be known before Study Drug administration 
b. Serum Chemistry: creatinine phosphokinase (CPK), troponin, total bilirubin, AST, ALT, ALP, creatinine, blood 
urea nitrogen, sodium, potassium, chloride, bicarbonate, calcium. Note minimum serum chemistry labs for 
screening visit are: AST, ALT, ALP and creatinine although other labs monitored for safety may be collected if 
part of panel.  
c. 
The cumulative phlebotomy volume is approximate. 
d. Visit window refers to acceptable variation in days either early or late from scheduled visits in without a 
protocol violation. 
e. 
Must be obtained on day of visit but prior to any injections. 
 
3.2 
Subject Selection 

 
 
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3.2.1 
Recruitment and Informed Consent 
Various methods of recruitment may be used such as advertising, referrals, or solicitation of 
subjects previously known to the clinical site.  Interested subjects will be invited to participate in 
the informed consent process.  Informed consent will be obtained by the use of a written consent 
form approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
and signed and dated by the subject at the time of consent.  Potential subjects will be interviewed 
to ensure that the subjects meet all entry criteria relating to history.  The clinical investigator or 
designee will conduct the consent discussion on an individual basis with each subject and will 
allow adequate time for all questions to be addressed.  Written informed consent will be obtained 
prior to conducting any study-related procedures.  A copy of the signed consent form shall be 
given to the subject prior to Study Day 0. 
 
3.2.2 
Screening 
A sequential site specific volunteer number will be assigned to each subject for identification 
purposes. Informed consent will then be obtained. Then the subject will be screened to assess 
eligibility for the study.   
 
A screening log will be maintained by the site that records all subjects for whom consent was 
obtained and who entered the screening process. The screening log will record the sex, age and 
racial or ethnic identity of the candidate subjects.  Abnormal results and findings resulting in 
ineligibility will be discussed with the subject, who will be referred for follow-up care with their 
healthcare provider if necessary. Only screening information from consented, eligible and dosed 
individuals will be entered into the study database.  Eligibility for entry into the study will be 
based on the inclusion and exclusion criteria described below.  The investigator must document 
confirmation of eligibility prior to randomization.  The serum chemistry labs for screening visit 
that determine eligibility are: AST, ALT, ALP and creatinine. These are a subset of the larger 
clinical safety laboratory analytes. Other serum chemistry values (total bilirubin, BUN etc.) that 
are collected for safety monitoring (Table 3.1-1) will be collected for Study Day 0 baseline 
values but are not part of the inclusion/exclusion criteria as such. 
 
3.2.3 
Inclusion Criteria 
Subjects must meet all of the following criteria at the time of subject ID assignment: 
 
1. Male or female subjects between 18 and 50 years of age, inclusive 
2. Body mass index between 18 and 30 kg/m², inclusive 
3. Female subjects physically capable of pregnancy (i.e., not sterilized and still menstruating 
or within 1 year of the last menses if menopausal) must: 
a. Agree to avoid pregnancy from 28 days prior to Study Day 0 through the duration 
of the study. 

 
 
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b. If in a sexual relationship with a man, use an acceptable method of avoiding 
pregnancy during this period. Acceptable methods of avoiding pregnancy include: 
the use of at least two forms of contraception, including use by a partner of a 
barrier method (e.g., male condom with intravaginal spermicide) as one form of 
contraception. 
4. Women of childbearing potential must have a negative serum pregnancy test within 48 
hours preceding receipt of the first dose. 
5. Can understand and sign the informed consent document, can communicate with the 
investigator and provide updated contact information as needed for the duration of the 
study, has no current plans to move from the study area for the duration of the study, and 
can understand and comply with the requirements of the protocol. 
 
3.2.4 
Exclusion Criteria 
Subjects must have none of the following at the time of subject ID assignment: 
1. Oral temperature ≥37.5°C at screening 
2. Complete blood count (CBC) and platelet count abnormal values (>5% above the 
upper limit of normal [ULN] or >5% below the lower limit of normal [LLN] per local 
laboratory parameters) at screening with exception of absolute lymphocyte count. 
3. Abnormally elevated aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), total bilirubin, alkaline phosphatase (ALP), or creatinine (Cr) values at 
screening (however a single test AST, ALT or ALP may be >10% above the ULN per 
local laboratory parameters) 
4. Abnormal PT (INR) PTT 
5. Abnormal screening urinalysis result that is, per the investigator, clinically significant, 
or a screening urine dipstick result of ≥2+ protein 
6. Positive screening urine test for illicit drugs (opiates, cocaine, amphetamines 
methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol, PCP, 
MDMA, and methadone) 
7. History or evidence of autoimmune disease 
8. History or evidence of any past, present, or future possible immunodeficiency state, 
including laboratory evidence of human immunodeficiency virus (HIV) 1  or 2  
infection 
9. History or evidence of chronic hepatitis 

 
 
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10. History or evidence of rabies infection 
11. History or evidence of any other acute or chronic disease that, in the opinion of the 
investigator, may interfere with the evaluation of the safety or immunogenicity of the 
drug or compromise the safety of the subject; for example a clinically relevant history 
of respiratory, thyroid, gastrointestinal, renal, hepatic, hematological, lymphatic, 
oncologic, cardiovascular, psychiatric, neurological, musculoskeletal, genitourinary, 
infective, inflammatory, immunological, dermatological or connective tissue disease 
12. History or evidence of allergic disease or reaction, including adverse responses to 
therapeutic monoclonal antibodies that, in the opinion of the investigator, may 
compromise the safety of the subject 
13. History of non-compliance that, in the opinion of the investigator, will make it 
unlikely that the subject will comply with the protocol 
14. Previous exposure to rabies vaccine 
15. Receipt of an immunoglobulin or blood product within 90 days prior to Study Day 0 
16. Receipt of immunosuppressive medications other than inhaled or topical 
immunosuppressant drugs within 45 days prior to Study Day 0 
17. Body weight greater than 90 kg.  
18. History or evidence of  IgA deficiency 
 
3.2.5 
Screening Clinical Assessments and Laboratory Tests 
Unless noted otherwise, the window period within which all screening evaluations must be 
completed, and the results reviewed by the investigator to confirm eligibility of subjects, is 28 
days prior to Study Day 0.   
 
Subjects will provide a detailed medical history and subjects will undergo a physical 
examination.  The assessment will include the determination of any surgeries or medically 
significant procedures planned to occur during the entire study period.  Demographic 
characteristics (date of birth, gender, and race/ethnicity) will also be collected.  Any new 
abnormal findings will be discussed with the subject and referral will be made for follow-up care 
if necessary. 
 
Screening laboratory tests (See Table 3.1-1) will be performed during the screening process.  
Results from some of these laboratory tests (HIV, Hepatitis B and C, serum IgA) may serve as 
study-entry baseline values if not required for Study Day 0.  Values from specimens obtained at 
on or after Study Day -2 will not be required to be redrawn prior to study start on Study Day 0 
and the values will serve as baseline values.  Eligibility is determined by screening laboratory 

 
 
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tests.  All laboratory tests for Study Day 0 must be drawn prior to study drug administration. 
Abnormal results and findings that make the subject ineligible will be discussed with the subject 
and the subject will be referred for follow-up care with their healthcare provider if necessary.  
All screening laboratory specimens will be processed according to laboratory SOPs available 
from the clinical laboratory(ies) designated for the study.  Information about the laboratory(ies), 
including any instructions for performing and interpreting specific tests, will be maintained in the 
investigator’s study files. 
 
3.2.5.1 Window Period for Select Screening Laboratory Tests 
Select laboratory evaluations must be performed on specimens obtained within two days (Study 
Day -2) prior to study entry on Study Day 0, and the results must be known and eligibility 
confirmed prior to study entry on Study Day 0.  Screening tests that must be obtained ≤ 48 hours 
prior to receipt of SYN023 or RIG on Study Day 0 include the following:  serum βHCG for 
women only.  The results from tests performed on specimens collected within 48 hours prior to 
study entry on Study Day 0 may serve as both screening and Study Day 0 evaluations. 
 
If blood specimens for serum anti-rabies activity, SYN023 pharmacokinetics (pre dose) and anti-
SYN023 antibodies are also taken within two days prior to study entry on Study Day 0, these 
specimens may be used as the Study Day 0 evaluations for subjects who subsequently are 
randomized. 
 
3.3 
Study Randomization and Sentinel Subjects  
 
Subjects will be randomized to the study based on a randomly-generated sequence of subject 
identification numbers (randomization schedule).  The randomization schedule will be prepared 
by a statistician who will not be involved in the analysis of the study in order to maintain the 
blind of the study team.  A subject is considered randomized when a subject identification 
number has been assigned to them on Study Day 0. The first four subjects entered into the study 
(sentinel subjects) will be randomized such that a subject each receives one of the four possible 
regimens.  Safety information on these sentinel subjects through study day 14 will be collected 
and reviewed by the medical monitor and principal investigator before the reminder of the trial is 
enrolled.   
 
Subjects who withdraw from the study or are discontinued may be replaced by modification of 
the remaining randomization schedule. Unless there is reason to pause the study, based on the 
study pausing rules as outlined in Section 6.1, then the principal investigators may proceed to 
enroll all of the subjects. 
 
3.4 
Blinding 
Because of different volumes for RIG and SYN023 this study is incompletely blinded.  In a strict 
sense it is a single blind study since the subject will not be told which treatment he or she is 
receiving.  The sponsor and the medical monitor are unblinded.  The statistician is unblinded. 

 
 
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The other unblinded persons on the study are the study drug manager or pharmacist (and 
designee, if appointed) and the study monitor(s).  All unblinded persons must take care to not 
reveal individual subject treatment regimen assignments to any other member of the study team.  
The subject, the principal investigator and most of the study team remain blinded to reduce bias 
in safety assessment.  
 
The study drug manager or pharmacist (and designee) must have no other clinical or regulatory 
responsibilities associated with the conduct of the study during the entire study period.  With the 
exception of the medical monitor, unblinded study personnel must not participate in the 
evaluation of adverse events.  A Delegation of Authority Log will be maintained by the site and 
will identify the individual(s) authorized to function as the study drug manager, i.e., individuals 
with access to study blinding information.   
 
The randomization schedule will be provided by the unblinded statistician to the study drug 
manager in a sealed tamper-evident envelope.  Access to the randomization schedule during the 
study will be provided only to the study drug manager (or designee in the pharmacy), the study 
monitor, and the sponsor’s investigational product manager (and/or designee).  The 
randomization schedule and all pharmacy source documents and dose preparation records that 
can link a subject identification number with a treatment assignment must remain secure (e.g., in 
the pharmacy with access limited to only unblinded persons) until notification from the sponsor 
that the study has been unblinded. 
 
Labels accompanying the syringes of prepared study drug doses will not indicate which vaccine 
is in the syringe.  Identical syringes and needles will be used for preparation and administration 
of each study drug.  
 
3.4.1 
Unblinding for Clinical Emergencies  
 
If there is an urgent clinical requirement to know a subject’s treatment assignment, the 
investigator (in consultation with the medical monitor, if possible) will make a written request 
(handwritten is acceptable) to the Study Drug manager for urgent unblinding of a subject’s 
treatment.  The request must include the subject identification number, the date, a brief 
justification of the clinical requirement to the vaccine manager in the research pharmacy, and the 
investigator’s signature.  The request will be kept in the study file.  
 
Upon receipt of proper written request, the vaccine manager or designee will disclose the 
treatment group to the investigator.  The sponsor must be notified immediately of any clinically 
required break of the study blind on an Immediately Reportable Event Form. 
 
3.5 
Medicinal Product and Study Drug Administration 
There are four substances administered as part of this study.  There are two study drugs SYN023 
and rabies immune globulin (RIG): HyperRab ST® Grifols.   SYN023 is investigational agent 
that has been administered previously to human subjects in a Phase 1 trial.  RIG is licensed and 

 
 
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commercially available.  SYN023 was tolerated acceptably in the initial human study thus 
enrollment of this study may be parallel between the different study groups. Vaccination will 
occur within 75 minutes after Study Drug administration.  RVi, RVa, SYN023 and RIG will be 
administered by intramuscular injection. Generally antibodies should be administered on the 
right side of the body and vaccinations on the left aside of the body to avoid administration in the 
same site. 
 
3.5.1 
SYN023 (Study Drug) 
One or more IM injections of the calculated dose of SYN023 should be administered in any of 
the acceptable injection sites on the RIGHT side of the body on Study Day 0. If for some reason 
left sided administrations sites must be used a record must be kept of the site and care taken to 
not administer SYN023 at a rabies vaccination site.  SYN023 is supplied at a concentration of 10 
mg/mL.  For example a dose calculation for a 70 kg person receiving SYN023 at the dose of 0.3 
mg/kg would require a dose of 21mg resulting in a dose volume of 2.1 mL.  This would need to 
be administration into injection sites as described below.  A needle no smaller than 21-gauge and 
1.0 to 3.0 inches in length depending on subject size should be used to draw up the dose of 
SYN023.  Aspiration of SYN023 from the vial should be done gently to avoid foaming. 
SYN023 is to be administered as one or more IM injections in one of three possible injection site: 
the gluteus medius (ventrogluteal injection site/hip), the vastus lateralis (thigh), rectus femoris 
(thigh) and the deltoid muscle.  Doses of up to 5 mL may be given as a single injection into the 
hip and thigh muscles.  Doses up to 3 mL may be given if required in the deltoid muscle.  No 
more than one injection may be administered into each muscle. Only a single deltoid 
administration is permitted in any subject. Injections into the gluteus maximus (buttocks) will not 
be performed. 
When selecting the site of injection, known paths of nerves, arteries and veins are to be avoided. 
If available ultrasound assessment of thickness of fat pad and survey of nerve and blood vessel 
paths may be employed. The needle should be inserted into the skin at a 90° angle. Before 
SYN023 is administered, aspirate gently by pulling back on the plunger. If blood is drawn into 
the syringe, the needle is in a blood vessel and must be moved. Remove the needle from the 
muscle, re-insert it in a new location in the same muscle, and repeat the aspiration step before 
administering SYN023.   If a dose of SYN023 is drawn up and cannot be administered 
immediately, the syringe may be stored at 2º to 8º C and used within 3 hours. 
 
3.5.2 
Rabies Immune Globulin, (HyperRab ST® Study Drug) 
RIG should be administered on the Right side of the body.  If for some reason left sided 
administrations sites must be used a record must be kept of the site and care taken to not 
administer RIG at a rabies vaccination site. The dose of RIG should be calculated based on body 
weight: 0.133 mL/kg.  The calculated dose should be administered as one or more IM injections 
in one of three possible injection sites: the gluteus medius (ventrogluteal injection site/hip), the 
vastus lateralis (thigh), rectus femoris (thigh) and the deltoid muscle. For example, a 70 kg 
person has a calculated dose of 9.31 mL.  Since doses of up to 3 mL are recommended for the 
deltoid muscle, this will require dividing the dose between two injection sites.  Doses of up to 5 

 
 
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mL may be given as a single injection into the hip and thigh muscles.  Doses up to 3 mL may be 
given if required in the deltoid muscle.  No more than one injection may be administered into 
each muscle. Only a single deltoid RIG administration is permitted in any subject. Injections into 
the gluteus maximus (buttocks) will not be performed. 
When selecting the site of injection, known paths of nerves, arteries and veins are to be avoided. 
If available ultrasound assessment of thickness of fat pad and survey of nerve and blood vessel 
paths may be employed. The needle should be inserted into the skin at a 90° angle. Before RIG is 
administered, aspirate gently by pulling back on the plunger.  RIG should not be administered 
intravenously.  If blood is drawn into the syringe, the needle is in a blood vessel and must be 
moved. Remove the needle from the muscle, re-insert it in a new location in the same muscle, 
and repeat the aspiration step before administering RIG.  RIG should be administered 
immediately, as soon as possible after the dose is constituted.  
3.5.3 
Rabies Vaccine RVa (Chicken Fibroblast Rabies Vaccine RabAvert®) 
The 1 mL dose of the chicken fibroblast rabies vaccine should be administered on the LEFT side 
of the body in Left deltoid muscle or in the Left vastus lateralis (thigh) or rectus femoris (thigh). 
Five doses of the vaccine should be administered on Study Days 0, 3, 7, 14 and 28. The vaccine 
should be administered as soon as possible after dose constitution.  RVa should be administered 
within 75 minutes after Study Drug. 
 
3.5.4 
Rabies Vaccine RVi (Human Diploid Cell Rabies Vaccine Imovax®) 
The 1 mL dose of the human diploid cell rabies vaccine should be administered on the LEFT 
side of the body in Left deltoid muscle or in the Left vastus lateralis (thigh) or rectus femoris 
(thigh). Five doses of the vaccine should be administered on Study Days 0, 3, 7, 14 and 28. The 
vaccine should be administered as soon as possible after dose constitution.  RVi should be 
administered within 75 minutes after Study Drug. 
 
3.6 
Study Evaluations 
3.6.1 
Efficacy Evaluations  
This is not an efficacy trial. A pharmacodynamic measurement of serum rabies virus neutralizing 
activity in international units will be used as a surrogate of protection. Refer to Table 3.11 for the 
day on which rabies virus neutralizing activity should be drawn. Refer to the Analytical 
methodology information sheet (provided under separate cover) for further instructions and 
additional information on specimen collection and processing. 
3.6.2 
Immunology Laboratory Evaluations 
A summary of immunologic assays to be performed on blood specimens is shown in Table 3.6-2.  
Staff at the clinical research site will refer to the most current version of the analytical 
methodology information sheet (provided under separate cover) for further instructions and 
additional information on specimen collection and processing. 

 
 
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Table 3.6-2 Summary of Immunology Laboratory Evaluations 
Sample type 
 
Assay 
Study Days 
Serum for pharmacokinetics
SYN023 concentration 
0, 1, 3, 7, 14, 28, 35, 42, 84
Serum for anti-SYN023 antibodies
Anti-SYN023 antibodies
0,7,14, 28, 35, 42, 84, 112
 
3.6.3 
Safety Evaluations 
Electrocardiograms are performed to monitor subject safety (Table 3.1-1).  Laboratory 
evaluations for subject safety are clinical chemistry evaluations, CBC, platelet counts and 
differential counts, PT(INR) an PTT and urinalyses,  Please refer to Table 3.1-1 for a list of 
laboratory tests for monitoring of safety.  Additional laboratory tests may be required for 
evaluation of specific adverse events such as anaphylaxis and immune complex diseases (see 
chapters 3.6.3.2)  
 
3.6.3.1 Pre-Study Study Drug and Post-Study Drug Administration Clinical 
Monitoring of Subjects 
Hypersensitivity reactions are a potential adverse effect of all medicinal products administered in 
this protocol including monoclonal antibodies. Allergic reactions to vaccination are possible, 
therefore, appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available and a medically qualified study team member trained to recognize and 
treat anaphylaxis must be present in the clinic during the entire vaccination procedure and post-
vaccination monitoring period. Appropriate drugs include intravenous fluids, epinephrine, 
antihistamines, corticosteroids, inhaled oxygen and drugs required for the treatment of cardiac 
arrest such as antiarrythmics and pressors.  Appropriate equipment includes devices for blood 
pressure monitoring, oximetry, maintenance of airway and intratracheal intubation and, removal 
of secretions and cardiac defibrillation. 
 
Grade ≥3 hypersensitivity reactions are Immediately Reportable Events. 
 
Subjects will have vital signs and oximetry taken prior to Study Drug administration.  Before 
after and between  each medicinal product  administration vital signs and oximetry will be 
monitored every 30 minutes  At every clinical contact the subject will be asked how they are 
feeling and if they have noticed any new adverse symptoms or manifestations.   
 
Subjects will remain in the clinic under close observation for at least 240 minutes after receiving 
rabies vaccination that is administered after Study Drug.  Vital signs and oximetry will be 
repeated every 30 minutes during the 240 minute monitoring period before subjects leave the 
clinic.   
 
3.6.3.2 Recognition of Anaphylaxis 
When the diagnosis of anaphylaxis is considered the following laboratory 
tests should be obtained: plasma tryptase, plasma histamine and urinary N-

 
 
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methyl histamine.  Anaphylaxis is highly likely when any one of the 
following 3 criteria are fulfilled (Sampson et al. 2006): 
 
 Acute onset of an illness (minutes to several hours) with involvement of the 
skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, 
swollen lips-tongue-uvula) 
 
AND AT LEAST ONE OF THE FOLLOWING 
 
o Respiratory compromise (e.g., dyspnea, wheeze-
bronchospasm, stridor, reduced PEF, hypoxemia) 
o Reduced BP or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 
 
 Two or more of the following that occur rapidly after exposure to a likely 
allergen for that patient (minutes to several hours): 
o Involvement of the skin-mucosal tissue (e.g., generalized 
hives, itch-flush, swollen lips-tongue-uvula) 
o Respiratory compromise (e.g., dyspnea, wheeze-
bronchospasm, stridor, reduced PEF, hypoxemia) 
o Reduced BP or associated symptoms (e.g., hypotonia 
[collapse], syncope, incontinence) 
o Persistent gastrointestinal symptoms (e.g., crampy abdominal 
pain, vomiting) 
 
 Reduced BP after exposure to known allergen for that patient 
(minutes to several hours): 
o Infants and children: low systolic BP (age specific) or greater 
than 30% decrease in systolic BP 
o Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
 
3.6.3.3 Treatment of Anaphylaxis 
Epinephrine is the treatment of choice for anaphylaxis.  Aqueous epinephrine, 0.01 mg/kg   
(maximum dose, 1.5 mg) administered intramuscularly every 5 to 15 minutes as necessary, is the 
recommended dosage for controlling symptoms and maintaining blood pressure.  The 5-minute 
interval between injections can be liberalized to permit more frequent injections if deemed 
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Intramuscular administration of injectable epinephrine in the anterior lateral thigh is preferred 
over subcutaneous injection.   
 
Intravenous epinephrine is an option for patients with severe hypotension or cardiac arrest 
unresponsive to intramuscular doses of epinephrine and fluid resuscitation. Although there is no 
precisely established dosage or regimen for intravenous epinephrine in anaphylaxis, 5 to 10 mg 
intravenous bolus (0.2 mg/kg) doses for hypotension and 0.1 to 0.5 mg administered 
intravenously in the presence of cardiovascular collapse have been suggested. Other treatments 
should be combined with epinephrine such as: fluid resuscitation, recumbent posture, oxygen, 
inhaled adrenergic agents, vasopressors, H1 and H2 histamine antagonists, corticosteroids, and 
glucagon for individuals on β adrenergic blocking agents. (Sampson et al. 2006) 
 
3.6.3.4 Recognition and Evaluation of Immune Complex Illness 
Simultaneous presence of antibodies directed at circulating antigens may result in illness.  
Immune complex illness (ICI) results from the deposition of antibody-antigen complexes on the 
microvasculature with the resulting activation of compliment and release of inflammatory 
mediators and tissue injury. These manifestations may result when anti-rabies antibodies such as 
those in RIG are administered in temporal proximity to rabies vaccine.  They may also result 
when repetitive vaccination induces antibodies to the administered antigens.  ICI manifests itself 
with inflammation and evidence of vascular injury.  Syndromes of allergic vasculitis 
(leukocytoclastic vasculitis or Henoch-schonlein vasculitis in the case of IgA) and glomerular 
injury may beobserved.  Clinical manifestations of headache, anorexia and fever occur early 
followed by a petechial rash (palpable purpura) or larger purpura and cutaneous edema more 
frequent in the dependent regions of the body.  Joint pain, rash and abdominal pain are common.  
The urinary findings may reflect an active glomerular process with hematuria, proteinuria and 
RBC casts.   Acute glomerular histologic lesions of hypercellularity, necrosis, crescent formation 
and leukocyte infiltration are seen.  Ultimately a reduction in renal function and elevated serum 
creatinine reflects this glomerular damage.  ICI is treated by the cessation of antigen or antibody 
administration or the suppression of endogenously produced antigen.  Prednisone has been used 
in the treatment of ICI (Salmon 2012). 
  
3.6.3.5 Clinical Assessments and Laboratory Tests 
Abnormal Clinical Assessments and Laboratory Tests 
Results from clinical laboratory tests obtained on the study must be reviewed by the investigator 
(or a designee who is a medically qualified study team member) within 72 hours of receiving the 
results to determine if abnormalities exist.  If the laboratory value is abnormal and has increased 
in toxicity grade (see Appendix E for toxicity grading scales) from baseline values, it must be 
reported as an adverse event and repeated promptly to demonstrate resolution.  Additional 
laboratory tests may be performed if the investigator deems them to be necessary to fully 
evaluate an adverse event.  In the event that the investigator elects to order non-protocol-
specified laboratory tests, the investigator must record the rationale for the tests and a 
determination of clinical significance of the result in the source documents.  The investigator 
must keep the medical monitor informed of adverse events of clinical significance.   

 
 
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Abnormal results and findings will be discussed with the subject, or the subject will be referred 
for follow-up with their healthcare provider if necessary. 
 
3.6.3.6 Adverse Events 
The collection periods for adverse events are: 
Unsolicited adverse events: 42 days after Study Drug Administration 
Solicited adverse events: 
28 days after Study Drug Administration 
Serious adverse events: 
Entire study period (i.e., 112 days) 
 
For this study, solicited adverse events are listed in section 5.7. 
 
3.6.3.7 Concomitant Medications 
The collection of information on concomitant medications used by subjects following 
vaccination will coincide with the collection period of adverse events.  The collection period for 
concomitant medications will be through 14 days following the last vaccination.  The collection 
period for concomitant medications associated with the treatment of serious adverse events (SAE) 
will be Study Days 0-112 
 
Concomitant medication includes prescription and non-prescription drugs or other treatments, 
and any monoclonal or polyclonal antibodies other than the study antibodies.  The name of the 
medication, treatment start and stop dates (or ‘ongoing’), route of administration, and indication 
must be recorded on the concomitant medications case report form (CRF).  The indication 
recorded on the concomitant medications CRF must correspond to a medical term/diagnosis 
recorded on the adverse event (AE) CRF, or to a pre-existing condition noted in the subject’s 
medical history, or be noted as prophylaxis, e.g., dietary supplement. 
 
3.6.4 
Window Periods for Clinical Laboratory, ECG, Immunology and 
Pharmacodynamic Blood Specimens 
There is no window for clinical laboratory tests earlier than Study Day 7.  After Study Day 7 the 
window is approximately 10% of the Study Day number. For example At Study Day 7 the 
window is 0.7 days that rounds to 1 day.  At Study Day 14 the window is 1.4 days that rounds to 
1 day. At Study Day 42 the window is 4.2 days that rounds to 4 days. 
 
3.6.5 
Subject Follow-up and Contact 
All subjects who are assigned a subject identification number and receive study drug will be 
followed according to the protocol unless consent is withdrawn.  Subjects will be instructed to 
contact a study team member to report new diagnoses or new or worsening adverse events and to 
come to the study clinic if medical attention is needed, provided the urgency of the situation 
permits.  For emergencies and other unscheduled visits to a medical facility other than the study 
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During each clinic visit, the subject will be reminded to notify a study team member of the 
following:   
 
The occurrence of Aes and SAEs during the respective reporting periods  
 
Receipt of any concomitant medications during the applicable reporting period 
 
Plans to move or if contact information changes  
 
If subject has decided to withdraw from the study 
 
Change in general health status  
 
Any other change in status that may affect the subject’s participation (e.g., plan to participate 
in another investigational study) 
 
All deviations from protocol procedures, evaluations, and/or visits must be categorized and 
documented as they occur.  Each deviation must be documented on a Protocol Deviation Form.  
When possible, missed visits and procedures must be rescheduled and performed at the nearest 
possible time point to the original schedule. 
 
3.6.6 
Loss to Follow-up 
If the site’s study team members are unable to establish contact with a subject who misses a 
scheduled study visit, the clinical site must make every possible effort to re-establish contact and 
document such efforts.  If contact is re-established, then the subject will resume participation in 
the study.  If contact with the subject cannot be re-established by the subject’s calculated Study 
Day 112 visit date, then a determination of “lost to follow-up” can be made. 
 
3.6.7 
Replacement of Subjects 
Subjects who fail to complete the study through Study Day 28 may be replaced at the discretion 
of the sponsor. 
4 
STUDY MEDICINAL PRODUCTS 
4.1 
SYN023 
SYN023 will be supplied by Synermore Biologics. 
 
4.1.1 
Receipt and Storage 
Upon receipt of study drug supplies, the study drug manager must immediately inspect all vials 
for damage.  SYN023 will be shipped with a continuous temperature-monitoring device.  Any 
damage or discrepancies from the packing list must be documented and promptly discussed with 
the sponsor and the study monitor to determine the appropriate action.  SYN023 must be stored 
upright at 2- 8° C in a secured location with no access for unauthorized personnel.  Refer to the 
most recent version of the Project Specific Procedures or detailed instructions regarding study 
drug storage. 
 

 
 
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4.1.2 
SYN023 Preparation 
After cleaning of the vial top with an alcohol swab, the proper dose of SYN023 is withdrawn 
slowly from the vial with a 21 gauge needle. After cleaning of the vial top with an alcohol swab, 
the proper dose of SYN023 is withdrawn slowly from the vial with a 21 gauge needle avoiding 
foaming. Study drug should be inspected for particulate matter and discarded if present.   If more 
than one vial of SYN023 is required the dose may be accumulated from a second vial. SYN023 
must be allowed to sit at room-temperature for at least 15 minutes before intramuscular 
administration to allow the SYN023 to warm before administration.  A constituted SYN023 dose 
if not administered immediately must be stored at temperature of 2°-8° C and administered 
within two hours after dose constitution.   Refer to the most recent version of the Project Specific 
Procedures for detailed instructions regarding study drug preparation.  
 
4.1.3 
Disposal of Unused Supplies 
Upon completion of the study, the sponsor must provide authorization for any unused study drug 
and supplies to be disposed of according to the facility’s SOPs.  Any disposal of study drug 
conducted at the clinical site must be documented in the study file. 
 
 
4.2 
RIG (HyperRab ST®) 
RIG (HyperRab ST®, Grifols Therapeutics) will be supplied by inVentiv or the sponsor. 
 
4.2.1 
Receipt and Storage 
Upon receipt of study drug supplies, the study drug manager must immediately inspect all vials 
for damage.  RIG will be shipped with a continuous temperature-monitoring device.  Any 
damage or discrepancies from the packing list must be documented and promptly discussed with 
the sponsor and the study monitor to determine the appropriate action.   RIG liquid will be stored 
at 2-8° C in a secured location. RIG that has been frozen should not be used.  Refer to the most 
recent version of the Project Specific Procedures for detailed instructions regarding study drug 
storage. 
 
4.2.2 
RIG Preparation 
RIG is packaged in 2 mL and 10 mL single dose vials. After cleaning of the vial top with an 
alcohol swab, the proper dose of RIG is withdrawn slowly from the vial with a 21 gauge needle 
avoiding foaming. Study drug should be inspected for particulate matter and discarded if present.   
If more than one vial of RIG is required the dose may be accumulated from a second vial. RIG 
must be allowed to sit at room-temperature for at least 15 minutes before intramuscular 
administration to allow the RIG to warm before administration.  A constituted RIG dose if not 
administered immediately must be stored at temperature of 2°-8° C and administered within two 
hours after dose constitution.   Refer to the most recent version of the Project Specific 
Procedures for detailed instructions regarding study drug preparation. 
 

 
 
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4.2.3 
Disposal of Unused Supplies 
Upon completion of the study, the sponsor must provide authorization for any unused RIG and 
supplies to be disposed of according to the facility’s SOPs.  Any disposal of study drug 
conducted at the clinical site must be documented in the study file. 
 
4.3 
RVi (Imovax®)  
RVi (Imovax®) will be supplied by inVentiv or the sponsor. 
 
4.3.1 
Receipt and Storage 
Upon receipt of study drug supplies, the study drug manager must immediately inspect all vials 
of RVi for damage.  The RVi vaccine will be shipped with a continuous temperature-monitoring 
device.  Any damage or discrepancies from the packing list must be documented and promptly 
discussed with the sponsor and the study monitor to determine the appropriate action.  
Unreconstituted RVi will be stored at 2-8° C in a secured location. Refer to the most recent 
version of the Project Specific Procedures for detailed instructions regarding study drug storage. 
 
4.3.2 
RVi Preparation 
 
RVi (Imovax®) is supplied in a tamper evident unit dose box with:  
 One vial of freeze-dried vaccine containing a single dose  
 One sterile syringe containing diluent.  
 A separate plunger is provided for insertion and use 
 One sterile disposable needle for reconstitution.  
 
Cleanse the vaccine vial stopper with a suitable germicide. Do not remove the stopper or the 
metal seal holding it in place. Attach the plunger and reconstitution needle to the syringe and 
reconstitute the freeze-dried vaccine by injecting the diluent into the vaccine vial. Gently swirl 
the contents until completely dissolved and withdraw the total contents of the vial into the 
syringe. Remove the reconstitution needle and discard. Attach a sterile needle of your choice that 
is suitable for intramuscular injection of the subject. An RVi dose, once constituted should be 
allowed to sit at room-temperature for 15 minutes to allow warming and then administered.  If 
unable to be administered immediately after room-temperature warming it should be stored at 2-
8° C and should be administered within 2 hours of constitution.  Refer to the most recent version 
of the Project Specific Procedures for detailed instructions regarding study drug preparation. 
 
4.3.3 
Disposal of Unused Supplies 
Upon completion of the study, the sponsor must provide authorization for any unused study drug 
and supplies to be disposed of according to the facility’s SOPs.  Any disposal of study drug 
conducted at the clinical site must be documented in the study file. 
 

 
 
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4.4 
RVa (RabAvert®)  
RVa will be supplied by inVentiv or the sponsor. 
 
4.4.1 
Receipt and Storage 
Upon receipt of study drug supplies, the study drug manager must immediately inspect all vials 
of RVa for damage.  The Rva vaccine will be shipped with a continuous temperature-monitoring 
device.  Any damage or discrepancies from the packing list must be documented and promptly 
discussed with the sponsor and the study monitor to determine the appropriate action.  
Unreconstituted RVa will be stored at 2-8° C in a secured location.  Refer to the most recent 
version of the Project Specific Procedures for detailed instructions regarding study drug storage. 
 
4.4.2 
RVa Preparation 
 
RVa (RabAvert®) is supplied in a tamper evident unit dose box with:  
 One vial of freeze-dried vaccine containing a single dose  
 One sterile syringe containing diluent.  
 A separate plunger is provided for insertion and use 
 One sterile disposable needle for reconstitution.  
 
Cleanse the vaccine vial stopper with a suitable germicide. Do not remove the stopper or the 
metal seal holding it in place. Attach the plunger and reconstitution needle to the syringe and 
reconstitute the freeze-dried vaccine by injecting the diluent into the vaccine vial. Gently swirl 
the contents until completely dissolved and withdraw the total contents of the vial into the 
syringe. Remove the reconstitution needle and discard. Attach a sterile needle of your choice that 
is suitable for intramuscular injection of the subject. An RVa constituted dose should be allowed 
to sit at room-temperature for 15 minutes to allow warming and then administered.  If unable to 
be administered immediately after room-temperature warming it should be stored at 2-8° C 
administered within 2 hours of constitution.  Refer to the most recent version of the Project 
Specific Procedures for detailed instructions regarding study drug preparation.  
 
4.4.3 
Disposal of Unused Supplies 
Upon completion of the study, the sponsor must provide authorization for any unused study drug 
and supplies to be disposed of according to the facility’s SOPs.  Any disposal of study drug 
conducted at the clinical site must be documented in the study file. 
 
 
4.5 
Accountability 
The study drug manager is required to maintain accurate study drug accountability records.  
Instructions and forms to be completed and kept for accountability will be provided to the study 
drug manager.  If the study drug manager wishes to use site-specific accountability forms, these 
must be reviewed and approved in advance by the sponsor.  Upon completion of the study, all 

 
 
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study drug management records will be copied and the copies returned to the sponsor or its 
designee.  The originals must be maintained at the clinical site with the rest of the study records. 
5 
SAFETY 
5.1 
Responsibilities for Ensuring the Safety of Trial Subjects 
The national regulatory authority, the sponsor (Synermore), the institution(s) through which the 
research is performed and all members of the principal investigator’s clinical team share 
responsibility for ensuring that participants in this trial are exposed to the least possible risk of 
adverse events that may result from participation in this protocol.  
 
5.1.1 
Principal Investigator 
The principal investigator has a personal responsibility to closely monitor trial subjects and an 
inherent authority to take whatever measures necessary to ensure their safety.  The principal 
investigator has the authority to terminate, suspend or require changes to a clinical trial for safety 
concerns and may delay an individual’s study drug administration or pause study drug 
administration in the whole trial if the investigator has some suspicion that the study drug might 
place a subject at significant risk.  The principal investigator determines severity and causality 
with respect to the study drug for each adverse event.  For blinded studies the principal 
investigator is blinded, in which case the study drug may consist of a placebo, an active control, 
or the investigational product.  
 
5.1.2 
Study Sponsor 
The sponsor (Synermore) also has an institutional responsibility to ensure subject safety.  This 
responsibility is vested in a medical monitors and a safety monitoring committee.   
 
5.1.3 
Medical Monitor 
The local medical monitor is the sponsor’s representative and is a licensed physician or surgeon 
in their country of residence.  The local medical monitor reviews the safety of the product for 
protocols in a specific region and determines expectedness of the adverse event.  The local 
medical monitor may make a sponsor’s assessment of severity and causality for adverse events 
that may upgrade the degree of severity and causality determined by the principal investigator.  
The local medical monitor, unlike the principal investigator, is unblinded for the study.  
 
5.1.4 
Safety Monitoring Committee 
 
If study drug administration is paused (see safety pausing rules in Section 6.1) by the principal 
investigator, the local medical monitor, or the global medical monitor, an SMC will be convened.  
The SMC composition is described in an SMC charter.  The voting members cannot be directly 
involved with the conduct of the study.  Voting members cannot be employees of the sponsor.  
Additional subject area experts may be present to provide expertise if requested by the SMC.  
The SMC may review an individual SAE or it may choose to review adverse events, serious 

 
 
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adverse events, solicited adverse events, and laboratory and vital signs data.  The SMC may 
unblind any amount of safety information needed to conduct their assessment.  Only the SMC 
and the independent statistician responsible for preparing these analyses would be unblinded 
during these reviews.  All procedures associated with this review, including objectives, data 
handling, and elements to be included for review will be documented in SMC minutes.  
 
Based on its review and the protocol stopping rules (Section 6) the SMC will make 
recommendations in the SMC minutes to the sponsor regarding further conduct of the study and 
further administration of study drug.  The conclusions of the SMC will be communicated to the 
investigators and the Institutional Review Boards/Ethics Committees and the national regulatory 
authority.  The sponsor agrees to abide by the decision of its SMC and any directives issued by 
the national regulatory authority, the Institutional Review Board or Ethics Committee.   
 
5.1.5 
Institutional Review Boards and Ethics Committees 
The Institutional Review Board or Ethics Committee has institutional responsibility for the safety 
of research subjects.  The Institutional Review Board or Ethics Committee has the authority to 
terminate, suspend or require changes to a clinical trial.   
 
5.1.6 
National Regulatory Authority 
Since the national regulatory authority (such as the FDA for United States) receives all expedited 
safety reports it also has the authority to terminate, suspend or require changes to a clinical trial.   
 
5.2 
Safety Surveillance During the Study 
Subjects will be monitored and safety data collected by way of clinical interviews and 
examinations, evaluations of daily diaries conducted by study team members, and through 
reports of laboratory evaluations.  Time points and the specific data collected for each of these 
evaluations are described in Section 3 and the protocol appendices. The Medical Monitor will 
make the SMC aware of new safety data when it becomes available. 
 
5.3 
Definition of Adverse Event 
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, disease, 
syndrome, abnormal laboratory finding, or concurrent illness that emerges or worsens after 
receipt of study drug relative to the subject’s pretreatment baseline, whether or not it is 
considered to be related to the medicinal product. 
 
All conditions that exist prior to administration of the study drug (pre-existing conditions) will be 
recorded in the subject’s medical history to establish baseline.  Day-to-day fluctuations in pre-
existing conditions that do not represent a clinically significant change in the subject’s status will 
not necessarily be reported as adverse events. 
 

 
 
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Any adverse change from the subject’s baseline condition (determined from screening 
evaluations conducted to confirm study eligibility) that occurs following the administration of 
the study drug will be considered an adverse event.  This includes the occurrence of a new 
adverse event or the worsening of a baseline condition, whether or not considered related to the 
study drug.  Intermittent conditions such as headaches in adults or irritability in infants may be 
present on Study Day 0 but may represent an adverse event if the intensity or duration of the 
event is worse than usual following receipt of study drug.  Adverse events include but are not 
limited to: adverse changes from baseline that represent increases in toxicity grade according to 
the Toxicity Table (see protocol appendices), adverse changes in the general condition of the 
subject, signs and symptoms noted by the subject after study drug administration; concomitant 
disease with onset or increased severity after study drug administration, and changes in 
laboratory safety parameters occurring after study drug administration.   
 
The reporting period for all adverse events is specified in Table 3.1-1.  Adverse events will 
be reported on the Adverse Event CRF using a recognized medical term or diagnosis that 
accurately reflects the event.  Adverse event evaluations will be reviewed by the principal 
investigator or by a designated medically qualified practitioner.  Adverse event CRF pages are to 
be completed by members of the study team designated in writing by the principal 
investigator.  The onset and resolution dates of the event and action taken in response to the 
event will be documented.  All adverse events must be followed until resolution is demonstrated.  
The resolution date will be recorded on the CRF as the last date on which the subject 
experienced the adverse event.  If an adverse event resolution date is uncertain the principal 
investigator should estimate the completion date based on medical judgment and interview of the 
subject.  Approximate dates of resolution from interviews may be taken as adverse event 
resolution dates.  Some examples of estimation of adverse event resolution are:  1) an 
asymptomatic laboratory abnormality on one visit that has not been followed-up between visits 
but has resolved by the next visit may be assumed to have resolved by the midpoint of the inter-
visit interval; 2) A resolved adverse event that was treated may be assumed to have been 
resolved by the end of treatment.  Adverse events that are still present at the end of the trial 
should be recorded as ongoing.  Information recorded on the CRF must be substantiated in the 
source documents.  If an adverse event evolves into a condition that becomes “serious,” it will be 
designated as serious on the Adverse Event CRF and a supplemental SAE report form will be 
completed.  
 
5.4 
Assessing Severity 
The safety concepts of “severity” and “seriousness” are distinct concepts (see Section 5.8).  
Severity refers to a degree of clinical manifestation.  “Seriousness” refers to defined outcomes 
from an adverse event.  A severe adverse event is not always serious and a serious adverse event 
is not always severe.  
 
For all adverse events, the investigator (or designee, who is a healthcare professional; is someone 
the investigator deems qualified to review adverse event information, to provide a medical 
evaluation of the event, and to classify the event based upon medical judgment and the severity 

 
 
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categories described below) is responsible for assessing the severity of the event and the causal 
relationship of the event to the study drug. 
 
The severity of all adverse events, including clinical findings and abnormal laboratory values, 
will be classified as one of the following grades:  
1. Mild  
2. Moderate  
3. Severe   
 
A Toxicity Table is provided in the protocol appendices for the assessment of severity of 
specified adverse events.  The Toxicity Table Adverse Event Grades do not correlate directly 
with the classical severity grades of mild, moderate and severe.  FOR THE PURPOSES OF 
RECORDING EVENTS ON THE CRF, Toxicity Table Grade 1 events will be considered mild 
in severity, Toxicity Table Grade 2 events will be considered moderate in severity, and both 
Toxicity Table Grade 3 and 4 events will be considered as severe.  In the Toxicity Table certain 
local reactions such as erythema (redness) and swelling are graded according to size.  Laboratory 
values are graded according to level of deviation from the normal range.   
 
For adverse events not listed in the Toxicity Table determination of severity requires some level 
of interpretation as outlined below.  The degree of incapacity caused by the adverse event and 
the level of medical intervention required for treatment may be helpful in assessing the overall 
severity of the adverse event.  
For example: 
 
“Mild” events are generally regarded as noticeable but have no impact on normal activities; 
they may or may not require over-the-counter treatment managed by the subject.   
 
“Moderate” events generally have some impact on an individual’s normal activities and may 
require general symptomatic medical intervention by a healthcare professional or by the 
subject.   
 
“Severe” adverse events may be incapacitating, leading to suspension of normal daily 
activities, and would generally require more immediate medical evaluation and intervention 
by a healthcare professional.   
 
A change in severity of an adverse event will not be recorded as a new adverse event.  Only the 
highest severity level that occurs during the entire period of the adverse event will be recorded 
on the CRF with the onset and resolution dates encompassing the entire duration of the event.   
 
5.5 
Assessing Causal Relationship (Relatedness) 
For all adverse events, the investigator and the sponsor (the medical monitor) will determine a 
causal relationship, to the study drug without knowledge, for the blinded principal investigator, 
of whether SYN023, placebo, or active control was administered. Serious Adverse Events 
considered related to other medicinal products administered during the trial such as RIG or the 
rabies vaccine may occur and are subject to reporting to the manufacturer who will have a post-
marketing reporting obligation to the FDA if the event is unexpected. A number of factors will 
be considered in making this assessment, including:  1) the temporal relationship of the event to 

 
 
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the administration of the study drug 2) whether an alternative etiology has been identified and 3) 
biological plausibility.  The investigator will use the following guidelines to assess the causal 
relationship of an adverse event to study drug:   
 
 
Not Related to study drug (i.e., there is no evidence of a causal relationship; another etiology 
is known to have caused the adverse event.  The alternative etiology should be documented 
in the subject’s study record). 
 
Unlikely Related to study drug (i.e., there is less than a reasonable possibility that the 
adverse event was caused by study drug). 
 
Possible relationship to study drug (i.e., there is a reasonable possibility that the adverse 
event was caused by study drug.  There must be a plausible mechanism for the event to be 
related to study drug.  The evidence is inadequate to accept or reject, or favors rejection of, a 
causal relationship; an association exists between the event and the study drug but there may 
also be an alternative etiology, such as characteristics of the subject’s clinical status or 
underlying condition).   
 
Probable relationship to study drug (i.e., it is likely that the adverse event was caused by 
administration of the study drug.  The evidence favors acceptance of a causal relationship; an 
association exists between the event and receipt of the study drug and there is a plausible 
mechanism for the event to be related to the study drug, and an alternative etiology is not 
apparent). 
 
Definite relationship to study drug (i.e., the study drug is known to be the cause of the 
adverse event.  The evidence establishes a causal relationship; an association exists between 
the event and receipt of the study drug and there is a plausible mechanism for the event to be 
related to the study drug, and causes other than the study drug have been ruled out).  
 
The principal investigator and the local medical monitor both determine causality.  It is expected 
that communication and consultation may occur in the assessment of the causality of adverse 
events.  The greatest degree of causal relationship (definite > probable > possible > unlikely 
related > not related) determined by either the investigator or local medical monitor after their 
discussions will determine the ultimate classification of the adverse event.  Definite, probable 
and possible are considered to be related.  Not related and unlikely related are considered to be 
unrelated. 
 
Every effort should be made by the investigator to determine the existence of any pre-existing 
conditions (e.g., headache in adults or rashes in infants on Study Day 0 with onset prior to study 
vaccination) that must be taken into consideration when assessing causal relationship of an 
adverse event.  Pre-existing conditions should be recorded in the CRF as baseline history and 
substantiated by appropriate source documentation.  Intermittent conditions such as headaches in 
adults or irritability in infants may not be present on Study Day 0 but may represent an adverse 
event if the intensity or duration of the event is worse than usual following study drug. 
 

 
 
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5.6 
Definition of Adverse Reaction 
An adverse reaction is an adverse event judged to be related to study drug (see Section 5.3 for 
adverse event definition). 
 
Related adverse events (adverse reactions) are defined as those judged by the investigator 
or local medical monitor to be possibly, probably, or definitely related to study drug.  
 
5.7 
Solicited Adverse Events and Injection Site Reactions 
Solicited adverse events are events the subject is specifically asked about.  These adverse events 
are commonly observed soon after receipt of study antibody.  For this study, solicited adverse 
events to be collected include:  to be collected include the following:  injection site (s) pain, 
tenderness, redness swelling, warmth, skin disruption and regional lymphadenopathy.  Non-local 
solicited symptoms include headache, arthralgia, myalgia, rash, pruritus, urticaria, dyspnea, chest 
pain, cough, fever and chills.   Solicited adverse events of local injection site reactions (i.e., pain 
at injection site, redness at injection site, or swelling at injection site will be considered causally 
related to study drug (adverse reaction). 
 
The reporting period during which solicited adverse events will be evaluated is specified in 
Table 3.1-1.  The solicited adverse event reporting period begins with the day of vaccination.   
Adverse events and solicited adverse events including assessment of local injection site reactions 
will be assessed by the investigator for severity, causal relationship to the study drug, possible 
etiologies, and whether the event meets criteria as a serious adverse event (and therefore requires 
immediate notification to the medical monitor).   
 
Presence of ulceration and/or scarring at the site of injection and axillary lymphadenopathy of 
the injection arm(s) in adults or localized lymphadenopathy (e.g., groin) of the thigh injections 
are considered to be adverse events that are causally related to the study drug and are of special 
interest.  Site of injection ulceration (including presence of drainage) and axillary 
lymphadenopathy will be actively evaluated during each clinic visit through study day 28.  These 
events will be recorded on the Adverse Event CRF. 
 
In the event that the clinical presentation meets the definition of a serious adverse event, an 
SAER form must be completed and the event reported per protocol instructions.  
  

 
 
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5.8 
Assessing “Seriousness” and Serious Adverse Events 
Seriousness refers to the outcome of an adverse event.  Seriousness is determined by both the 
principal investigator and the local medical monitor.  If either principal investigator or local 
medical monitor determines an event to be serious, it will be classified as such.  If any of the 
following outcomes are present then the adverse event is serious: 
 
 
It results in death (i.e., the AE caused or led to the fatality).  Serious does not describe an 
event which hypothetically might have caused death if it were more severe. 
 
It was immediately life-threatening (i.e., the AE placed the subject at immediate risk of 
dying.  It does not refer to an event which hypothetically may have led to death if it were 
more severe).  
 
It required inpatient hospitalization or prolonged hospitalization beyond the expected length 
of stay.  Hospitalizations for scheduled treatments and elective medical/surgical procedures 
related to a pre-existing condition that did not increase in severity or frequency following 
receipt of study drug, are not serious by this criterion.  Hospitalization is defined as a 
hospital admission or an emergency room visit for a period greater than 24 hours.  
 
It resulted in a persistent or significant disability/incapacity (i.e., substantial reduction of the 
subject’s ability to carry out activities of daily living). 
 
It resulted in a congenital anomaly or birth defect (i.e., an adverse finding in a child or 
fetus of a subject exposed to the study drug prior to conception or during pregnancy). 
 
Other medically important conditions that may not result in death, threaten life or require 
hospitalization (i.e., the AE does not meet any of the above serious criteria) may be 
considered a serious adverse event when, based on appropriate medical judgment, they may 
jeopardize the subject and require medical or surgical intervention to prevent one of the 
serious outcomes listed in these criteria (e.g., allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not 
result in hospitalization, or the development of drug dependency or drug abuse). 
 
A serious adverse event is an adverse event meeting the outcome criteria for seriousness 
regardless of relationship to an administered medicinal product. 
 
5.9 
Assessing Expectedness 
Expected adverse events are adverse events consistent with the applicable product information 
provided by the sponsor (the investigator’s brochure for an investigational product).  The sponsor, 
in the person of the local medical monitor, determines expectedness.  If the assessment is that the 
adverse event is expected no further action is required.  If the local medical monitor’s 
assessment is that the adverse event is unexpected, then the event may represent a SUSAR or 
expedited SAE (see Sections 5.10 and 5.11). 
 
5.10 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
When an adverse event is judged to be related to an investigational product, such as SYN023 and 
also is judged to be serious and unexpected, it is a SUSAR (suspected unexpected serious 
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5.11 
Reporting of Serious Adverse Events 
Serious adverse events, which include SUSARs, are reported to the sponsor and to Drug 
Safety Solutions for the entire study period (see protocol appendices).  SUSARs are 
reported even after the trial is over, if the sponsor, local medical monitor or principal 
investigator becomes aware of them.  The site will be provided with specific reporting 
procedures including the Adverse Event CRF and any supplemental reporting forms to be used.  
Serious adverse events will be reported on the Adverse Event CRF using a recognized medical 
term or diagnosis that accurately reflects the event.   
 
Serious adverse events will be assessed by the investigator and the local medical monitor 
according to their roles (as described in Sections 5.1.1 and 5.1.3) for severity, causal relationship 
to the study drug, and expectedness.  The onset and resolution dates of the event and the action 
taken in response to the event will be documented.  If the event has not resolved by the final 
study visit, it will be documented as “ongoing” on the CRF, however, follow-up of the SAE must 
continue until resolved.  Information recorded on the CRF must be substantiated in the source 
documents. 
 
The SAE Report form completed for that event must be faxed by the principal investigator 
or his/her designee, within 24 hours (one calendar day) of the clinical site becoming aware 
of the event, to the local medical monitor and to Drug Safety Solutions.  The AE CRF 
should be completed with all information known at the time; the Supplemental SAE Report 
(paper form) should be completed and both forms faxed (even if all information concerning 
the event is not yet known) within the first 24 hours of awareness of the event.    
 
Fatal or life-threatening serious adverse events that the investigator suspects are related to 
the study drug should be telephoned to the medical monitor immediately upon the 
investigator’s awareness of the event.  If the medical monitor is required by the protocol or 
chooses to suspend enrollment s/he shall immediately create a written memorandum for 
record to the study file and telephonically notify the sponsor of this act. 
 
Contact information for all safety personnel are contained in the Team Contact List which 
will be stored on site in the Site Regulatory Binder and maintained by the study sponsor.   
 
Investigators must not wait to collect additional information to fully document the event before 
notifying the local medical monitor and Drug Safety Solutions of a serious adverse event.  The 
initial notification should include the following (at minimum):  
 
 
Protocol number and name and contact number of the investigator 
 
Subject ID number (and initials and date of birth, if available) 
 
Date subject received study drug     
 
Serious adverse event(s) and date of event onset 
 
Current status of subject  
 

 
 
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The sponsor has authorized Drug Safety Solutions to execute its responsibilities for safety report 
submission to the appropriate regulatory authorities within specific time periods of being notified 
of the event (within 7 or 15 calendar days depending the character of the SUSAR); therefore, it is 
important that the investigator submit additional information requested as soon as it becomes 
available.   
 
The sponsor will notify the SMC of all SUSARs within 3 working days of becoming aware of an 
event and will provide all follow-up information in a timely manner. 
 
5.12 
Other Events Requiring Immediate Reporting 
The investigator must report the following events by faxing the appropriate form to the medical 
monitor within 24 hours of becoming aware of the event:   
 
 
Withdrawal of consent during the study (Immediately Reportable Event Form) 
 
Emergency unblinding (Immediately Reportable Event Form) 
 
Protocol violation affecting the safety of a subject or involving the vaccination process 
(Immediately Reportable Event Form) 
 
Adverse event thought to be an allergic reaction to the study drug (Immediately Reportable 
Event Form, unless event meets SAE criteria)  
 
Any event that, in the opinion of the investigator, precludes further administration of the 
study drug (Immediately Reportable Event Form, unless meets SAE criteria)  
 
Pregnancy (Immediately Reportable Event Form, and Pregnancy Notification Form) 
 
5.13 
Adverse Event Treatment, Follow-up, and Outcome 
Treatment of any adverse events will be determined by the investigator using his/her best 
medical judgment and according to current clinical practice guidelines.  All treatments as well as 
follow-up will be recorded in the appropriate CRF.   
 
Adverse events will be considered resolved when the condition returns to normal or returns to 
the subject’s baseline status as established on Study Day 0, or when the condition has stabilized 
with the expectation that it will remain chronic. 
 
The investigator will continue follow-up on adverse events, including laboratory abnormalities 
and solicited adverse events, until the event has resolved, is otherwise satisfactorily explained, or 
the subject completes the study. 
  
Follow-up for serious adverse events must continue until resolution and the outcome reported to 
the sponsor, even if this extends beyond the serious adverse event reporting period (i.e., after the 
final study visit).  For analysis purposes, the outcome for serious adverse events will be 
determined on the final study visit. 
 

 
 
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Outcome of all adverse events will be classified as one of the following: 
 
Resolved  
 
Resolved with sequelae 
 
Ongoing 
 
Death 
 
If at any time after completion of the serious adverse event reporting period (the final study visit) 
the investigator becomes aware of a serious adverse event that is suspected by the investigator to 
be related to the study drug, the event must be reported to the sponsor. 
 
5.14 
Follow-up of Subjects Who Become Pregnant  
 
If a subject becomes pregnant during the study, she should be encouraged to continue in the 
study for safety follow-up.  Follow-up should continue for pregnancy outcome including 
premature terminations, and data are to be included in the safety reports.  
 
The investigator must notify the local medical monitor of the pregnancy immediately (even if 
already known to have resulted in spontaneous or elective abortion) by faxing the Pregnancy 
Notification Form to the medical monitor.  At a minimum, the estimated date of conception, the 
estimated due date, and the date the subject received the study drug should be provided.   
 
If a subject becomes pregnant, she will not have any interventions done as normally mandated by 
the protocol.  The subject will undergo all other evaluations according to the Summary 
Schedule(s) of Evaluations.      
 
The health status of the mother and child, the date of delivery, and the child’s sex, birth weight 
and multiparity should be reported to the safety monitor after delivery, using a Pregnancy 
Notification Form.  If delivery occurs before the final study visit, the subject should continue to 
be followed for SAEs through the final study visit unless withdrawal of consent has occurred.  If 
delivery occurs after the final study visit, the investigator should attempt to maintain contact with 
the subject to obtain information after delivery.       
 
Pregnancy will not be recorded as an adverse event.  However, pregnancy outcomes will be 
recorded in the World Wide Safety Database.  If the pregnancy results in a miscarriage or a 
planned termination, the event (spontaneous abortion or elective abortion) will be reported as an 
adverse event or serious adverse event per the investigator’s judgment (e.g., if it was a medically 
important or life-threatening event that meets the definition of a serious adverse event).  
 
A congenital anomaly or birth defect (i.e., an adverse finding in a child or fetus of a subject 
exposed to the study drug before conception or during pregnancy) must be reported as a serious 
adverse event. 
 

 
 
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If it is determined after completion of the study that a subject became pregnant during the study, 
the subject should notify the investigator.  The pregnancy must be reported to the local medical 
monitor and the status of the mother and child after delivery will be obtained and reported, when 
possible.     
 
5.15 
Subject Daily Temperature Monitoring 
Subjects will receive a digital thermometer to be used during the specified post-vaccination. 
Temperature should be taken and the time recorded as soon as possible after awakening and 
before the ingestion of hot or cold liquids during the solicited adverse event period after Study 
Drug administration.      
 
6 
PAUSING AND STOPPING RULES 
These rules govern the pausing and stopping of study drug administration at any time during the 
study such as between doses (for multiple dose studies) for an individual, between individuals 
within a single dose group, and between dose groups. 
 
6.1 
Safety Pausing Rules 
The principal investigator and/or local medical monitor will pause administration of study drug 
in the trial if: 
1. It is determined that a SUSAR occurred 
OR 
2. It is determined that a serious adverse event OR a Toxicity Grade 3 or 4 event (except for 
elevated CPK and visually interpreted urine dipstick findings) OR an adverse event pattern of 
concern occurred AND is judged to be POSSIBLY, PROBABLY or DEFINITELY related to 
study drug 
 
If the principal investigator and/or local medical monitor pauses administration of study drug in 
the study, he or she will record this in a memorandum to the study file and notify the sponsor 
who will then convene the SMC.  The FDA must be notified if the Study is paused for safety 
reasons.  The FDA must be notified if the Study is then resumed.  If additional clinical 
information becomes available that reduces the principal investigator’s assessment of causality, 
severity or toxicity grade such that study pausing is no longer required, then the principal 
investigator, with the agreement of the local medical monitor, may resume study drug 
administration, record this in a memorandum to the study file, and notify the sponsor. 
 
Since the medical monitor reviews data from all the sponsor’s trials, he or she may become 
aware of an adverse event pattern of concern not appreciated by the principal investigator or 
local medical monitor.  If the global medical monitor independently determines that an adverse 
event pattern of concern that is judged to be POSSIBLY, PROBABLY or DEFINITELY related 
to study drug has occurred, the global medical monitor will pause administration of study drug in 
the trial, record the study pause in a memorandum to the study file, and notify the local medical 
monitor, principal investigator and sponsor who will convene the SMC.  

 
 
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6.2 
Safety Stopping Rules 
The rules for stopping further enrollment and study drug administration by the SMC are below: 
 
Death in any subject unless the SMC determines it is UNRELATED to SYN023 
 
An anaphylactic reaction to SYN023 in any subject 
 
A severe (Toxicity Grade 3 or 4) or serious adverse event (except for CPK elevations and 
visually interpreted urine dipstick findings) unless the SMC determines it is UNRELATED 
to SYN023. 
 
A potentially life-threatening adverse event or serious adverse event unless the SMC 
determines it is UNRELATED to SYN023. 
 
A pattern of significant symptoms, physical findings or laboratory abnormalities (adverse 
events) that, although individually minor, collectively represent a safety concern in the 
opinion of the investigator or the medical monitor and are judged by the SMC to be 
DEFINITELY, PROBABLY or POSSIBLY related to SYN023  
 
The SMC may recommend resumption of study drug administration if the study pause was for 
reasons less severe than those in the SMC stopping rules.  The SMC may recommend resumption 
of enrollment if it judges that changes to the study protocol will eliminate or greatly reduce the 
safety risks specified in the stopping rules.  In the absence of study protocol changes the SMC 
must follow the SMC study stopping rules.  
 
If a decision to resume study enrollment and study drug administration is made the SMC will 
record their judgment in a memorandum to the study file and notify the sponsor.  The SMC 
memorandum will be forwarded to the medical monitor and principal investigator.  The clinical 
site will be allowed to resume activities upon receipt of written notification from the sponsor.  
The U.S. FDA will be informed in writing when: 
1. The study is stopped  
2. The decision is made by the SMC to resume or discontinue study activities 
 
7 
STATISTICAL CONSIDERATIONS 
The planned statistical analyses for this study are outlined below.  A detailed statistical analysis 
plan will be created and finalized prior to database lock and preparation of any unblinded 
preliminary data review and for preparation of the final study report (see Section 8). 
 
7.1 
Subject Populations 
The safety population will consist of all randomized subjects who received at least one dose of a 
study drug.  
 
The per-protocol population for efficacy or pharmacodynamic analyses will consist of all 
randomized subjects who received all scheduled doses of study drug and remained on study for 
at least 28 days.  The intent-to-treat population for efficacy analyses will consist of all 
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7.2 
Demographics and Protocol Compliance 
Demographic parameters (age, sex, and race) and other baseline characteristics will be 
summarized by treatment group for all subjects in the safety population. Detailed demographic 
descriptions will be provided in the statistical analysis plan (SAP). 
 
Listings of randomized subjects who missed any dose of study drug and of subjects with protocol 
deviations (to be defined in the statistical analysis plan) will be provided. 
 
7.3 
Efficacy or Pharmacodynamic (Serum Rabies Virus Neutralizing Activity) 
Analyses 
Analysis of Pharmacodynamics 
Criteria for Pharmacodynamic Similarity Acceptance 
Rabies Virus Neutralizing Activity plotted against time will be created. Pharmacodynamic 
parameters for SYN023 mAb will be estimated using non-compartmental analysis. Cmax, Tmax, 
AUC0-last, AUC0-inf will be calculated. For the comparison of RIG to SYN023 with RVi and 
RVa vaccines:  The 90% confidence intervals for the ratio of geometric means (RIG/SYN023) 
must be 80% to 125% .  An ANOVA of the in-transformed AUC0-inf  will be run to determine the 
90% confidence interval on the difference between treatments. The confidnce interval limits 
derived on the log scale will be back-transformed to the raw AUC scale for comparison to the 
acceptance criteria.  
To investigate any interference of SYN023 to the immune response generated by the vaccine, a 
non-inferority test of the AUC14-last between RIG and SYN023 for each vaccine can be 
performed. The one-sided 90% confidence interval derived on the log transformed AUC from an 
ANOVA would be compared to the lower acceptance criterion of 80%.  
Additionally, a non-inferiority test of the level of RVNA between RIG and SYN023 for each 
vaccine at selected time points, such as 14 or 28 days, can be performed using a Wilsoxon rank 
sum approach with a non-inferiority of 10% of the level associated with RIG. Pharmacodynamic 
efficacy will be defined as RVNA measured above 0.5 IU/mL with RVi and RVa for the 
duration of the trial and no more than 10% lower for SYN023 compared to RIG at any time point 
through Study Day 35.   
7.4 
Immunogenicity: Anti-SYN023 Antibodies 
All immunogenicity analyses will be based on subjects who received at least one dose of Study 
Drug.  Immunogenicity will be summarized for all time points as collected and as available.  No 
imputation for missing data will be performed.  Data will be transformed as appropriate prior to 
analysis.  The development of anti-SYN023 antibodies will be analyzed on a continuous scale as 
a categorical variable by treatment assignment, with descriptive statistics.  
 

 
 
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7.5 
Pharmacokinetic Analyses 
All PK analyses of serum SYN023 concentrations will be based on subjects who received study 
drug. Individual analyses will be performed and descriptive statistics will be used to describe the 
results of individual analyses. PK parameters for SYN023 mAb will be estimated using 
non-compartmental analysis. Cmax, Tmax, AUC0-last, AUC0-inf, t½, Clp, and λz will be calculated 
when possible. Anti-SYN023 antibodies (i.e., anti-CTB011 and anti-CTB012 antibodies) will be 
determined on Study Day 0 and Study Day 7 through 112, or for subjects who leave the study 
prior to Day 112, the last blood specimen available. 
 
7.6 
Safety Analyses 
Safety analyses will be performed using the safety population as defined in Section 7.1.  Count 
(percentage) summaries will be presented by treatment group for all subjects in the safety 
population. 
 
7.6.1 
Adverse Events 
The safety profile of SYN023 will be described by treatment group.  The primary variable for 
evaluation of the safety profile will be the number and percentage of unsolicited and solicited 
adverse events recorded at all available post-vaccination time points.  For all presentations of 
adverse events, additional summaries based on reporting period of adverse events following each 
study vaccination may also be presented.   
 
The number (percentage) of subjects with adverse events will be summarized by MedDRA 
system organ class (SOC) and preferred term (PT).  Additional summaries will present the 
number (percentage) of subjects with adverse events by severity and by relationship to study 
drug; each subject will be counted once per preferred term at the greatest severity or most related 
state recorded for that term.   
 
Separate summaries of the number (percentage) of subjects with solicited adverse events will 
also be presented.  Solicited adverse events will also be summarized by severity and relationship 
to study drug; each subject will be counted once per preferred term at the greatest severity or 
most related state recorded for that term.   
 
In addition, dose-safety curves may be produced to examine the proportion of subjects who 
experience adverse events by treatment regimen. 
 
Serious adverse events will be recorded through the final study visit for all subjects.  Listings 
will be provided for subjects with serious adverse events. 
 
Listings will be provided for subjects who have discontinued prematurely due to an adverse 
event.   
 
The number (percentage) of subjects with post-vaccination clinical laboratory values or vital sign 
values recorded as newly abnormal following study vaccination and meeting toxicity mild 

 
 
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criteria (Grade 1) or above as specified in the Toxicity Table (Appendix E) will be tabulated at 
each post-vaccination time point and overall.  Clinical laboratory and vital sign abnormalities 
will also be reported as adverse events and will be included in the summary of adverse events. 
 
7.6.2 
Clinical Laboratory and Vital Sign Parameters 
For each clinical laboratory parameter and vital sign parameter prespecified in the protocol, 
summary statistics for continuous parameters will be presented by treatment regimen for all pre- 
and post-Study Drug assessments and for change from pre-Study Drug to post-Study Drug 
assessments. 
 
Statistical methods: Analysis of Safety 
Safety analyses will be performed using the Safety Population, as defined in Section 7.1. Count 
and percent summaries will be presented by treatment group for all subjects. 
Descriptive statistics (number of subjects, mean, standard deviation, percent coefficient of 
variation, median, minimum, and maximum) will be used to summarize all safety and laboratory 
data. 
 
7.7 
Sample Size Considerations 
 
The sample size for this Phase 2 study was selected based on requirement to consider 
noninferiority of the efficacy parameter, RVNA.  The power analysis was performed in SAS 9.2 
using the power procedure  for noninferiority testing under the assumption of the sample size of 
40 per group and likely margin corresponding to SYN023 being no less than 10% lower than 
RIG. Based on earlier studies, the mean RVNA for 0.3 mg/kg SYN023 of 20 with CV of 15-25% 
are reasonable.  For assumed underlying differences of 0 to1 IU/mL, there is over 80% to 
conclude non-inferiority of RVNA level at a specified time point. The sample size of 40 per 
treatment group should be sufficient to address the efficacy objectives of the study. 
 
The assumptions that a difference of 2 or less is considered unimportant (the approximate mean 
value for 0.3mg/kg SYN023 of 20 was used), with the range in mean difference from -1 to 1, 
standard deviation of 3 and power of 0.8, the required sample size of 29 is needed to declare that 
the new treatment (SYN023) is not more tolerably inferior to the previous treatment (RIG). Also, 
the power analysis was performed for the sample size of 40, standard deviation 3 and the mean 
difference of 2. This resulted in the power of 0.838. The above results from the sample size and 
power analysis showed that the sample size of 40 should be sufficiently powered for this study.  
 
Also, a power  analysis for non-inferiority of the AUCs was performed using “PowerTOST”, an 
R CRAN package run under Rstudio version 0.99.491. Under the assumption of a lower non-
inferiority bound of  0.9 (corresponding to SYN023 being no less than 10% lower than RIG), the 
selected sample size of 40 per group would provide over 80% power assuming a CV of 10-20%. 

 
 
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If no SAEs are observed among subjects in each dose group and the 40 subjects in the 3 dose 
groups combined, the one-sided exact upper 95% confidence bounds on the rate of SAE 
occurrence will be 45% and 18%, respectively. 
 
 
7.8 
Plan for Statistical Summaries and Analyses 
7.8.1 
Preliminary Data Reviews 
A  review of Rabies Virus Inhibitory Activity, anti-SYN023 antibodies, SYN023 
pharmacokinetic information and clinical safety data will be conducted following completion of 
Study Day 42.  This review may present individual and aggregate (mean or median [95% CI], as 
appropriate) and change from pre-study drug to each post administration time point by individual 
or in aggregate.  Study procedures and monitoring practices will not change following this 
preliminary review.  No decision cut points or stopping rules will be stipulated.  No hypothesis 
testing will be performed.  The purpose of this review is to obtain preliminary data for use in the 
decision-making process regarding Study Drug dose level.  Personnel at the research site and at 
the immunology laboratory will remain blinded to all study results and to treatment assignments 
until after the Study Day 112 data have been collected, reviewed and queries resolved.   
 
7.8.2 
Final Study Report 
The final study report will include all available safety data, immunogenicity data (including 
exploratory analyses), clinical assessments, and concomitant medications through the final study 
visit.  The database will be locked prior to preparation of the final study report when all of the 
above data have been entered, reviewed, and all queries related to the data have been addressed.   
 
Modifications or additions to the analyses described above will be included in the relevant 
statistical analysis plan(s).  Any decisions to deviate from the planned analyses described in the 
protocol and in the statistical analysis plan will be described in detail in the final study report. 
 
7.9 
Computer Methods 
Statistical analyses will be performed using SAS® version 9.2 or later under a Windows 
operating system. 
 
8 
DATA COLLECTION, MONITORING, AND RECORD RETENTION 
For the purpose of monitoring and auditing the study, source documentation will consist of 
existing medical records and/or study records developed and maintained by the investigator.  
Any source document templates provided by the sponsor or its designee will serve as 
supplements to the subject’s study record.  
 
Data recorded on source documents will be transcribed onto case report forms (CRFs) provided 
by the sponsor or entered using electronic case report forms (eCRFs) using an Electronic Data 

 
 
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Capture (EDC) system provided and approved by the sponsor.  Completed, original CRFs will be 
retrieved by the sponsor or its designee and a copy of each completed CRF will be retained at the 
clinical site as part of the study records.   
 
The study will be monitored regularly by the sponsor or its designee throughout the study period.  
For studies of unapproved investigational products, all study records (source documents, signed 
informed consent forms, copies of CRFs, IRB/IEC correspondence and approval letters, and 
study drug management records) will be kept secured for a minimum of 2 years following the 
marketing of the investigational product or for 2 years after the discontinuation of the IND.  The 
investigator will ensure that study records are not disposed of or removed from the clinical site 
without prior notification and approval from the sponsor or its designee. 
 
9 
HUMAN SUBJECTS 
9.1 
Ethics and Regulatory Considerations 
The study will be conducted according to the ethical principles set forth in the Declaration of 
Helsinki, ICH-GCP, Protection of Human Subjects (21 CFR 50), Institutional Review Boards 
(21 CFR 56), Obligations of Clinical Investigators (21 CFR 312), and local regulatory 
requirements.  
 
The protocol and informed consent form will be reviewed and approved by the IRB or IEC of 
each participating clinical site prior to any protocol-specified procedures being conducted.  The 
investigator will inform the IRB/IEC as to the progress of the study on a regular basis, or at 
minimum, once a year.  The sponsor will also have an independent IRB review and approval of 
the protocol and informed consent form and will keep the IRB informed of the progress of the 
study. 
 
Written informed consent will be obtained from each subject prior to any protocol-specified 
procedures being conducted.   
 
To maintain confidentiality, subject identification numbers will be used to identify the subject’s 
laboratory specimens, source documents, CRF, study reports, etc.  All study records will be 
maintained in a secured location.  Clinical information will not be released without written 
permission from the subject except as necessary for monitoring or auditing of the study by the 
sponsor or its designee or applicable regulatory authorities. 
 
After the study has been unblinded, the subject should be informed which treatment (Study 
Drug) the subject received.   
 
 

 
 
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9.2 
Institutional Review Board or Independent Ethics Committee 
All the documents the IRB/IEC may need to fulfill its responsibilities, such as the protocol, 
protocol amendments, information concerning subject recruitment, payment or compensation 
procedures, etc., will be submitted to the IRB/IEC by the investigator.  The IRB’s/IEC’s written, 
unconditional approval of the study protocol and the informed consent form will be in the 
possession of the investigator/clinical site staff prior to the conduct of any protocol-specified 
procedures.  
 
Modifications to the protocol may not be implemented without prior written IRB/IEC approval 
except when necessary to eliminate immediate hazards to the subjects or when the modification 
involves only logistical or administrative aspects of the study.  Such logistical or administrative 
modifications will be submitted to the IRB/IEC in writing by the investigator, and a copy of the 
correspondence to verify the submission will be maintained.   
 
The investigator must inform the IRB/IEC of modifications to the informed consent form or any 
other documents previously submitted for review/approval, of any new information that may 
adversely affect the safety of the subjects or the conduct of the study, provide an annual update 
and/or request for re-approval, and advise the IRB/IEC when the study has been completed.  
 
Any documents or forms to be provided to the subject (e.g., information cards, form letters from 
the investigator), and all forms of study advertising (flyers, brochures, print advertisements, radio 
or television scripts, etc.) must be approved by the sponsor or its designee prior to the clinical 
site submitting them to the IRB/IEC.  Approval from the IRB/IEC must be obtained prior to 
providing the documents or forms to the subject. 
 
9.3 
Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki and ICH-
GCP/21 CFR 50.25 should be implemented prior to any protocol-specified procedures being 
conducted.  Informed consent will be documented in writing on a consent form approved by the 
IRB/IEC. 
 
All relevant information should be provided in both oral and written form in a way that is 
understandable to the subject.  Ample time and opportunity must be given for the subject to 
inquire about details of the study.  The written consent document will embody the elements of 
informed consent as described in the Declaration of Helsinki and will also comply with local 
regulations.    
 
The investigator or the investigator’s qualified designee will explain the nature of the study and 
inform the subject that participation is voluntary and that the subject can leave the study at any 
time, without penalty or loss of benefits to which they are otherwise entitled.  The subject must 
be informed about the study’s purpose including why the subject was selected to participate, 
study goals, expected benefits and risks, potential risks, and that some potential risks are 
unforeseeable.  The subject must be provided with a description of the procedures and the 

 
 
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estimated duration of time required for participation in the study, as well as alternative 
interventions or courses of treatment, if applicable.   
 
The subject must receive an explanation as to whether any compensation and any medical 
treatments are available if injury occurs and, if so, what they are, where further information may 
be obtained, and who to contact in the event of a study-related injury.  The subject must be told 
who to contact for answers to any questions related to the study.  The extent of the 
confidentiality of subject records must be defined and the subject must be informed that 
applicable data protection legislation applies. 
 
The subject must be informed that the monitor(s), auditor(s), IRB/IEC members, and the 
applicable regulatory authorities will be granted direct access to the subject’s original study 
medical records for verification of protocol-specified procedures and/or data, without violating 
the confidentiality of the subject to the extent permitted by the applicable laws and regulations.  
The subject must be informed that his/her signature on the informed consent form indicates that 
he/she has decided to participate in the study, having read and discussed the information 
presented.  
 
Modifications made by the investigator to an informed consent form template provided to the 
investigator by the sponsor or its designee will be reviewed and approved by the sponsor or its 
designee prior to being submitted to the IRB/IEC.   
 
The original, signed informed consent form for each subject will be maintained by the 
investigator as part of the subject’s study records.  A copy of the signed informed consent form 
will be provided to each subject. 
 
10 
STUDY COMPLETION 
At the discretion of the sponsor, all materials and supplies provided to the investigator will be 
returned or disposed of in compliance with local regulatory requirements upon authorization 
from the sponsor, upon study completion.  The investigator or designated clinical site staff will 
notify the IRB/IEC when the study has been completed. 
 
11 
PUBLICATIONS 
The final study report will be made available to the principal investigator for purposes of 
publications.  The principal investigator and study staff must send all manuscripts, abstracts, and 
presentations using data from this study to the sponsor for review prior to their submission.  The 
sponsor reserves the right to delete any part or parts of such materials deemed to be confidential 
or proprietary. 
 

 
 
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12 
CHANGES IN THE PROTOCOL 
The protocol may not be modified without written approval from the sponsor.  All changes to the 
protocol must be submitted to the IRB/IEC and must be approved by the IRB/IEC prior to their 
implementation.   
 
12.1 
Changes to Version 2.0 from Version 1.0.   
 
Minor typographical, grammatical or administrative changes are not listed.  
 
Version 1.0 Chapter
Version 2.0 Chapter
Version 2.0 change 
Page
1.1 Background 
1.1 Background 
Discussion of the mortality of 
rabies vaccination alone 
compared to combined RIG and 
vaccination. Discussion of the 
temporal evolution of rabies 
virus neutralizing activity.
10 
1.4 Clinical 
Experience with 
SYN023 
1.5 Clinical 
Experience with 
SYN023 
RVNA data from SYN023-001 
presented in rationale for  
selection of 0.3 mg/kg as dose 
for current protocol
15 
3.1 Schedule of 
subject treatment 
and evaluation
3.1 Schedule of 
subject treatment 
and evaluation 
Table 3.1-1 Additional visit 
added on Study Day 1 for safety, 
PD and PK data point
15 
3.1 Schedule of 
subject treatment 
and evaluation
3.1 Schedule of 
subject treatment 
and evaluation 
Table 3.1-1 Anti-SYN023 
antibody data point added on 
Study Day 7
15 
3.1 Schedule of 
subject treatment 
and evaluation
3.1 Schedule of 
subject treatment 
and evaluation 
Table 3.1-1 CPK and troponin 
added to safety labs. 
15 
3.1 Schedule of 
subject treatment 
and evaluation
3.1 Schedule of 
subject treatment 
and evaluation 
Table 3.1-1 Urinalysis added 
Study Day 1 and 3 
15 
3.1 Schedule of 
subject treatment 
and evaluation
3.1 Schedule of 
subject treatment 
and evaluation 
Table 3.1-1 ECG added through 
Study Day 28 
15 
3.2.3 Inclusion 
Criteria 
3.2.3 Inclusion 
Criteria 
Pregnancy test increased to 
within 48 hours preceding 
receipt of the first dose
18 
3.2.5 Screening 
Clinical 
Assessments and 
Laboratory Tests
3.2.5 Screening 
Clinical 
Assessments and 
Laboratory Tests
Wording added that eligibility is 
determined by screening 
laboratories 
19 
3.3 Study 
3.3 Study 
4 sentinel subjects (1 for each 
20

 
 
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Randomization 
Randomization and 
Sentinel Subjects  
regimen) will be randomized and 
Study Day 14 safety data 
reviewed before enrollment of 
the remainder of the trial.  
3.5 Medicinal 
Product and Study 
Drug 
Administration
3.5 Medicinal 
Product and Study 
Drug 
Administration
Interval between Study Drug and 
vaccination lengthened to 75 
minutes 
22 
3.6.2 Immunology 
Laboratory 
Evaluations 
3.6.2 Immunology 
Laboratory 
Evaluations
Added Day 1 data point for PK.  
Added Day 7 data point for anti-
SYN023 antibodies
23 
3.6.3 Safety 
Evaluations 
3.6.3 Safety 
Evaluations
Added ECG, anaphylaxis and 
immune complex wording 
24 
3.6.3.1 Pre-Study 
Study Drug and 
Post Administration 
Monitoring of 
Subjects 
 3.6.3.1 Pre-Study 
Study Drug and 
Post-Study Drug 
Administration 
Clinical Monitoring 
of Subjects 
Added wording for clinical 
monitoring after all medicinal 
products are administered 
24 
3.6.3.1 Pre-Study 
Study Drug and 
Post Administration 
Monitoring of 
Subjects 
3.6.3.1 Pre-Study 
Study Drug and 
Post-Study Drug 
Administration 
Clinical Monitoring 
of Subjects 
Added drugs and listed 
equipment for management of 
acute allergic reactions 
24 
 
3.6.3.1 Pre-Study 
Study Drug and 
Post-Study Drug 
Administration 
Clinical Monitoring 
of Subjects 
Post SYN023 administration 
monitoring interval increased to 
240 minutes 
24 
 
3.6.3.2 New chapter 
Recognition of 
Anaphylaxis 
Added wording requiring plasma 
histamine, plasma tryptase and 
urinary N-methyl-histamine 
when the diagnosis of 
anaphylaxis is considered. 
25 
 
3.6.3.2 New chapter 
Recognition of 
Anaphylaxis
Wording added on recognition of 
anaphylaxis (Sampson) 
28 
 
3.6.3.3 New chapter 
Treatment of 
Anaphylaxis
Added chapter on treatment of 
anaphylaxis (Sampson)  
25 

 
 
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3.6.3.4 New chapter 
Recognition and 
evaluation of 
Immune Complex 
Illness 
Added chapter on recognition of 
immune complex induced illness
26 
3.6.4 Window 
Periods …
3.6.4 Window 
Periods …
ECG added  
28 
4.2 RIG(HyperRab 
ST®)
4.2 RIG 
((HyperRab ST®)
Wording added to permit supply 
by the sponsor
29 
5.15 Subject 
Temperature 
Monitoring.
5.15 Subject Daily 
Temperature 
Wording added to require 
temperature to be taken upon 
awakening.
42 
6.1 Safety Pausing 
Rules 
6.1 Safety Pausing 
Rules 
The following wording was 
added to the chapter; The FDA 
must be notified if the Study is 
paused for safety reasons.  The 
FDA must be notified if the 
Study is then resumed.  CPK 
was exempted from pausing 
rules since elevations are 
anticipated with IM RIG 
injections
 
42 
6.2 Safety Stopping 
Rules 
 
CPK was exempted from 
stopping rules since elevations 
are anticipated with IM RIG 
injections. FDA wording added.
42 
13 References
13 References
Added Karplod Reference
54
13 References 
13 References 
Added Sampson Reference for 
Anaphylaxis
54 
13 References 
13 References
Added Vodopija References
54

 
 
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REFERENCES 
 
Bahmanyar M, Fayaz A. Shokrollah N, et al. Postexposure treatment with the new human diploid 
cell rabies vaccine and antirabies serum. JAMA. 1976; 236: 2751 2754.  
 
Baltazard M, Bahmanyar M. Essai pratique du serum antirabique chez le mordus par loups 
enrages Bull WHO. 1955; 13:747-778. 
 
Fishbein DB. Human diploid cell rabies vaccine purified by zonal centrifugation: a controlled 
study of antibody response and side effects following primary and booster pre-exposure 
immunizations. Vaccine. 1989; 7: 437-442. 
 
Gompf,  FG. Rabies. Updated September 25, 2014. Available on line at: 
http://emedicine.medscape.com/article/220967-overview. 
 
Grandien M.  Evaluation of tests for rabies antibody and analysis of serum responses after 
administration of three different types of rabies vaccines J Clin Micro. 1977; 5: 263-267. 
 
Khawplod P, Wilde H, Chomchey P, et al. What is an acceptable delay in rabies immune 
globulin administration  when vaccine alone had been given previously? Vaccine.1996; 4: 389-
391. 
 
Manning SE, Rupprecht CE, Fishbein D, Hanlon CA, Lumlertdacha B, Guerra M, et al., National 
Center for Zoonotic, Vector-Borne and Enteric Diseases. Human Rabies Prevention – United 
States, 2008. Recommendations of the Advisory Committee on Immunization Practices. 
Published in Morbidity and Mortality Weekly Report. May 7, 2008. 57(RR-3):1-26, 28. 
Available on line at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr57e507a1.htm.  
 
Plotkin SA, Wiktor TJ, Koprowski EI et al Immunization schedules for the new human diploid 
cell vaccine against rabies. Am J Epidemiol. 1976: 103: 75-80. 
 
Sampson, HA, Muñoz-Furlong, BA, Ronna L,  et al. Second symposium on the definition and 
management of anaphylaxis: Summary report—Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium,  J Allergy Clin Immunol. 
2006;117:391-7. 
 
Vodopija I, Sureau P, Smerdel S. et al. Interaction of rabies vaccine with humans rabies 
immunoglobulin and reliability of a 2-1-1 schedule application for postexposure treatment. 
Vaccine. 1988; 6:283-286. 
 
Vodopija I, Sureau P, Smerdel S. et al. Comparative study of two human diploid rabies vaccines 
administered with antirabies globulin. Vaccine. 1988b; 6:489-490. 
 

 
 
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Salmon E, Mechanisms of immune-mediated tissue injury Type III hypersensitivity reactions. In: 
Lee Goldman,  Andrew Schaffer editors, Goldman’s Cecil Medicine  24th edition, Philadelphia, 
Elsiever 2012, pp:229-230. 
 
 
 

 
 
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APPENDIX A 
Detailed Description of Selected Study Visits 
 
Screening Visit (Up to 4 weeks prior to start of study medication, Day -28 to -1) 
 
Obtain informed consent 
 
Verify eligibility by review of inclusion/exclusion criteria 
 
Record medical history 
 
Conduct physical examination (including height and weight and BMI calculation) 
 
Perform ECG 
 
Collect urine sample for: 
- HCG (all females) 
- Urinalysis 
- Urine Toxicology 
 
Collect blood samples for: 
- Hepatitis B, Hepatitis C, HIV-1,2 
- PT and PTT 
- Serum chemistry: creatinine, ALT, AST, alkaline phosphatase and others if part of panel 
- Hematology: CBC including differential and platelets 
- Serum IgA 
Baseline Visit (Study Day 0) 
 
Verify eligibility by review of inclusion/exclusion criteria 
 
Conduct focused physical examination including weight 
 
Insure that results of Serum HCG are negative 
 
Record vital signs and oximetry 
 
Record interval history 
 
Record concurrent medications 
 
Collect urine sample for urinalysis 
 
Insure that blood samples collected for: 
- Serum chemistry: total bilirubin, BUN, CPK, troponin, creatinine, ALT, AST, alkaline 
phosphatase, sodium, potassium, chloride, bicarbonate calcium 

 
 
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- Hematology: CBC including differential and platelets 
- Clotting studies: PTT and prothrombin INR 
- Anti-SYN023 antibodies 
- SYN023 antibody levels 
- Rabies Virus Inhibitory Serum Activity 
 
Administer Study Drug (RIG or SYN023) on Right side of body 
 
Within approximately 75 minutes administer RVa or RVi on Left side of body  
 
Distribute diary and thermometer and instruct subject in their use 
 
Assess patient for AEs and SAEs 
 
Perform vital signs & oximetry every 30 minutes during the 240 minutes of observation prior 
to discharge 
 
 

 
 
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APPENDIX B 
SAE Reporting Scheme 
Synermore has designated Drug Safety Solutions to manage safety reporting for Protocol SYN-
002.  
Drug Safety Solutions, Inc. 
Raleigh, NC 27613 
www.drugsafetysolutionsusa.com 
Contact information: 
Kristen Eagle 
Phone:  
+1 (704)488-6031 
Fax:   
+1 (919) 844-6948  
Email:  
keagle@drugsafety.biz 
 
Backup:  
Katherine Smith, MD 
Phone:  
+1 (919) 264-5626  
Fax:   
+1 (919) 844-6948  
Email:   
ksmith@drugsafety.biz 
 
 
 
SAEs should be reported to: 
saereports@drugsafety.biz

 
 
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APPENDIX C 
Sponsor’s Representative 
 
ERIC TSAO 
Chief Executive Officer 
Synermore Biologics Co., Ltd 
6F-6, No. 5, Aly. 22, Ln. 513, Ruiguang Rd.,  
Neihu Dist., Taipei 11492, Taiwan 
Tel: +886 2 2659 0988 
Fax +886 2 2659 0950 

 
 
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APPENDIX D 
Protocol Facility and Contact List 
 
Role in Study 
Name 
Contact Information 
Clinical Study Manager 
Jorge Mejia-Galvis 
inVentiv Health Clinical Research Services 
LLC 
1951 NW 7th Avenue, Suite 450 
Miami, FL 33136, USA 
Tel.: 1-305-547-5800
Responsible Physician 
David Wyatt, M.D. 
Vice President, Medical Affairs 
Miami 
Principal Investigator 
inVentiv Health Clinical Research Services 
LLC 
1951 NW 7th Avenue, Suite 450 
Miami, FL 33136, USA 
Tel.: 1-305-547-5800 
Medical Monitor 
(Emergency Contact) 
J. Bruce McClain, M.D. 
11673 Garnet Road 
Lovettsville, VA 20180 
(Mobile) 202-236-6975 
Study Monitoring 
MJ Research Inc.  
 
1815 Edgewood  
St. Bruno (Quebec) J3V 4P1 
Canada  
Tel.:  450-461-6245 
InVentiv Clinical 
Research Facility 
 
inVentiv Health Clinical 
Research Services LLC (« 
inVentiv ») 
1951 NW 7th Avenue, Suite 450 
Miami, FL 33136, USA 
Tel.: 1-305-547-5800 
Biomedical 
Laboratory Facilities 
(clinical safety 
laboratory tests) 
LabCorp 
 
 
 
 
 
LabCorp 
4200 N. 29th Avenue 
Hollywood, FL 33020-1017 
Tel.: 1-800-877-7831 
 
 

 
 
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Clinical  
Pharmacology & 
Regulatory Affairs 
Mario Tanguay, B. 
Pharm., Ph.D., Vice-
President, Clinical 
Pharmacology 
Clinical Pharmacology and Regulatory 
Affairs, inVentiv Health Clinique Inc. 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Clinical  
Pharmacology & 
Regulatory Affairs 
Stéphane Lamouche,Ph.D.
Director, Clinical 
Pharmacology & 
Regulatory Affairs 
inVentiv Health Clinique inc. 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Clinical 
Pharmacology & 
Regulatory Affairs 
Pierre-Olivier Tremblay, M.Sc.
Director, Pharmacometrics 
inVentiv Health Clinique inc. 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Rabies Virus 
Neutralizing 
Activity (RVNA) 
Susan Moore 
Rabies Laboratory, Mosier Hall,  
Kansas State University, 
1800 Denison Avenue,  
Manhattan KS 66506-5600 
Bioanalytical Facility 
 
Christopher Beaver, Ph.D. 
Senior Director, Bioanalysis 
inVentiv Health Clinical Bioanalytical 
Facility 
301D College Road East 
Princeton, NJ 08540 
Tel: 609-951-0005 
 
 
 

 
 
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APPENDIX E 
Toxicity Table 
2. 
Note: From final US FDA guidance: Toxicity Grading Scale for Healthy Adult and Adolescent Subjects Enrolled in Preventive Drug 
Clinical Trials (September 2007); laboratory values are in conventional and SI units.  The laboratory values provided in the tables serve as 
guidelines and are dependent upon institutional normal parameters.  Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
 
Local Site of Infusion 
Symptoms
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Very Severe (Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of  
non-narcotic pain reliever 
> 24 hours or interferes 
with activity
Any use of narcotic pain 
reliever or prevents 
daily activity 
ER visit or hospitalization 
Tenderness 
Mild discomfort to 
touch
Discomfort with 
movement
Significant discomfort 
at rest
ER visit or hospitalization 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
>10 cm 
Necrosis or exfoliative 
dermatitis
Induration/Swelling ** 
2.5 - 5 cm and 
does not interfere 
with activity
5.1 - 10 cm or interferes 
with activity 
>10 cm or prevents 
daily activity 
Necrosis 
3. 
* In addition to grading the local reaction at the greatest single diameter, the measurement should be recorded as a continuous variable. 
4. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  
 
Vital Signs*
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Very Severe (Grade 4)
Fever** 
38.0 – 38.4C 
100.4 – 101.1F 
38.5 - 38.9C 
101.2 - 102.0F 
39.0 - 40C 
102.1 - 104F 
>40C 
>104F 
Tachycardia – beats per 
minute 
101 – 115 
116 – 130 
>130 
ER visit or hospitalization for 
arrhythmia 
Bradycardia – beats per 
minute
50 – 54 
45 –  49 
<45 
ER visit or hospitalization for 
arrhythmia
Hypertension (systolic) – 
mm Hg
141 – 150 
151 – 155 
>155 
ER visit or hospitalization for 
malignant hypertension
Hypertension (diastolic) – 
mm Hg
91 – 95 
96 – 100 
>100 
ER visit or hospitalization for 
malignant hypertension
Hypotension (systolic) – 
mm Hg 
85 – 89 
80 – 84 
<80 
ER visit or hospitalization for 
hypotensive shock 
Respiratory rate – breaths 
per minute 
17 – 20 
21 – 25 
25 
Intubation 
5. 
* Subject should be at rest for all vital sign measurements.  ** Oral temperature; no recent hot or cold beverages or smoking.  
 
Systemic (General)
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3) 
Very Severe (Grade 4)
Nausea/vomiting 
No interference 
with activity or  
1 - 2 episodes/24 
hours
Some interference with 
activity or  
>2 episodes/24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or hospitalization for 
hypotensive shock 
Diarrhea 
2 - 3 loose stools 
or < 400 grams/ 
24 hours 
4 - 5 stools or 400 - 800 
grams/24 hours 
6 or more watery stools 
or > 800 grams/24 hours 
or requires outpatient 
IV hydration
ER visit or hospitalization for 
hypotensive shock 
Headache 
No interference 
with activity 
Repeated use of non-
narcotic pain reliever > 24 
hours or some interference 
with activity 
Significant; any use of 
narcotic pain reliever or 
prevents daily activity  
ER visit or hospitalization 
Fatigue 
No interference 
with activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or hospitalization 
Myalgia 
No interference 
with activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or hospitalization 

 
 
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Infusion reaction 
Requires no 
intervention and 
transient in 
duration
Requires slowing of 
infusion or non-
prescription drug treatment
Requires prescription 
drug reatment presence 
of respiratory symtoms 
ER visit or hospitalization 
Illness or clinical adverse 
event (as defined 
according to applicable 
regulations)
No interference 
with activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or hospitalization 
 
 
Serum
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Very Severe (Grade 4)**
Sodium – hyponatremia
mEq/L or mmol/L:
 
132 – 134 
 
130 – 131 
 
125 – 129 
 
125 
Sodium – hypernatremia
mEq/L or mmol/L:
 
144 – 145 
 
146 – 147 
 
148 – 150 
 
150 
Potassium – hyperkalemia
mEq/L or mmol/L:
 
5.1 – 5.2 
 
5.3 – 5.4 
 
5.5 – 5.6 
 
5.6 
Potassium – hypokalemia
mEq/L or mmol/L:
 
3.5 – 3.6 
 
3.3 – 3.4 
 
3.1 – 3.2 
 
3.1 
Glucose – hypoglycemia 
mg/dL:
mmol/L:
 
65 – 69 
3.6 – 3.8
 
55 – 64 
3.0 – 3.5 
 
45 – 54 
2.5 – 2.9
 
<45 
<2.5
Glucose – hyperglycemia
Fasting -  mg/dL:
mmol/L:
Random – mg/dL:
mmol/L:
 
100 – 110 
5.5 – 6.0 
110 - 125 
6.1 – 6.8 
 
111 – 125 
6.1 – 6.8 
126 - 200 
6.9 – 11.0 
 
>125 
6.8 
>200 
11.0
Insulin requirement or 
hyperosmolar coma 
 
Blood urea nitrogen 
(BUN) – mg/dL:
mmol/L:
 
23 – 26 
8.3 – 9.5
 
27 – 31 
9.6 – 11.2
 
>31 
>11.2
Requires dialysis 
Creatinine – elevated
mg/dL:
umol/L:
 
1.5 – 1.7 
121 – 145
 
1.8 – 2.0 
146 – 170
 
2.1 – 2.5 
171 – 208
 
>2.5 or requires dialysis 
>208 or requires dialysis
Calcium – hypocalcemia
mg/dL:
mmol/L:
 
8.0 – 8.4 
2.00 – 2.10 
 
7.5 – 7.9 
1.87 – 1.99
 
7.0 – 7.4 
1.75 – 1.86
 
<7.0 
<1.75
Calcium – hypercalcemia
mg/dL:
mmol/L:
 
10.5 – 11.0 
2.63 – 2.76 
 
11.1 – 11.5 
2.77 – 2.88
 
11.6 – 12.0 
2.89 – 3.00
 
>12.0 
>3.00
Magnesium – hypomagnesemia 
mg/dL:
mmol/L:
 
1.3 – 1.5 
0.52 – 0.62 
 
1.1 – 1.2 
0.43 – 0.51
 
0.9 – 1.0 
0.37 – 0.42
 
<0.9 
<0.37
Phosphorus – hypophosphatemia
mg/dL:
mmol/L:
 
2.3 – 2.5 
0.73 – 0.80 
 
2.0 – 2.2 
0.63 – 0.72
 
1.6 – 1.9 
0.51 – 0.62
 
<1.6 
<0.51
CPK – elevated
mg/dL or ukat/L:
 
1.25 – 1.5 x ULN***
 
1.6 – 3.0 x ULN
 
3.1 – 10 x ULN
 
>10 x ULN
Albumin – hypoalbuminemia
g/dL:
g/L:
 
2.8 – 3.1 
28 – 31 
 
2.5 – 2.7 
25 – 27
 
<2.5 
25
 
---- 
----
Total protein – hypoproteinemia
g/dL:
g/L:
 
5.5 – 6.0 
55 – 60 
 
5.0 – 5.4 
50 – 54 
 
<5.0 
50
 
---- 
---- 
Alkaline phosphatase 
(ALP) – increased
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
>10 x ULN 
Liver Function Tests (LFT): 
AST, ALT – increased
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
>10 x ULN 
Bilirubin (with any increase 
in LFT) - increased
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
>1.75 x ULN 
Bilirubin (with normal LFT) 
- increased
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 – x ULN 
>3.0 x ULN 

 
 
Page 64 of 64 
SYN023 
Protocol SYN-023-002  
21 June 2016 
CONFIDENTIAL 
Final  Version 2.0 
 
Cholesterol – increased
mg/dL:
mmol/L:
 
201 - 210 
6.0 – 6.3
 
211 – 225 
6.4 – 6.7 
 
>226 
6.7
 
---- 
----
Pancreatic enzymes: 
amylase, lipase  – increased
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
>5.0 x ULN 
6. 
**  The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory abnormalities 
as Very Severe (Grade 4).  For example, a low sodium value that falls within a grade 3 parameter (125-129 mEq/L) should be recorded as a 
Grade 4 hyponatremia event if the subject had a new seizure associated with the low sodium value. 
7. 
*** ULN (upper limit of normal) dependent on normal reference ranges per institutional parameters.  
 
Hematology
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Very Severe (Grade 4)
Hemoglobin (Female) – 
g/dL:
g/L:
 
11.0 – 12.0 
110 – 120
 
9.5 – 10.9 
95 – 109
 
8.0 – 9.4 
80 – 94
 
<8.0 
<80
Hemoglobin (Male) –  
g/dL:
g/L:
 
12.5 – 13.5 
125 – 135
 
10.5 – 12.4 
105 - 124
 
8.5 – 10.4 
85 – 104
 
<8.5 
<85
WBC – increased
cells/mm3:
cells x 109/L: 
 
10,800 – 15,000 
10.8 – 15.0 
 
15,001 – 20,000 
15.1 – 20.0
 
20,001 – 25,000 
20.1 – 25.0
 
>25,000 
>25.0
WBC – decreased
 cells/mm3:
cells x 109/L:
 
2,500 – 3,500 
2.5 – 3.5
 
1,500 – 2,499 
1.5 – 2.4
 
1,000 – 1,499 
1.0 – 1.4
 
<1,000 
<1.0
Lymphocytes – decreased 
cells/mm3:
cells x 109/L:
 
750 – 1,000 
0.8 – 1.0
 
500 – 749 
0.5 – 0.7
 
250 – 499 
0.3 – 0.4
 
<250 
<0.3
Neutrophils – decreased 
cells/mm3:
cells x 109/L:
 
1,500 – 2,000 
1.5 – 2.0
 
1,000 – 1,499 
1.0 – 1.4
 
500 – 999 
0.5 – 0.9
 
<500 
<0.5
Eosinophils – increased 
cells/mm3:
cells x 109/L:
 
650 – 1,500 
0.7 – 1.4 
 
1,501 – 5,000 
1.5 – 5.0 
 
5,000 
>5.0
Hypereosinophilic 
Platelets – decreased
cells/mm3:
cells x 109/L:
 
125,000 – 140,000
125 – 140
 
100,000 – 124,000 
100 – 124
 
25,000 – 99,000 
25 – 99
 
<25,000 
<25
International normalized 
ratio (INR) – increased
>1.0 – 1.10 x 
ULN**
1.11 – 1.20 x ULN 
1.21 – 1.25 x ULN 
1.25 x ULN 
Partial thromboplastin 
time (PTT) – increased 
>1.0 – 1.2 x ULN 
1.21 – 1.4 x ULN 
1.41 – 1.5 x ULN 
>1.5 x ULN 
Fibrinogen – increased
mg/dL:
g/L:
 
400 – 500 
4.00 – 5.00 
 
501 – 600 
5.01 – 6.00 
 
>600 
6.00
 
---- 
---- 
Fibrinogen – decreased
mg/dL:
g/L:
 
150 - 200 
1.50 – 2.00 
 
125 – 149 
1.25 – 1.49 
 
100 - 124 
1.00 – 1.24 
1.0 or associated with gross 
bleeding or disseminated 
intravascular coagulation 
(DIC)
8. 
**  “ULN” is the upper limit of the normal range.   
 
Urine 
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Very Severe (Grade 4)
Protein
Trace 
1+ 
2+ 
Hospitalization or dialysis 
Glucose
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia
Blood 
(microscopic) – red 
blood cells per high 
power field 
(rbc/hpf)
1 – 10 
11 – 50 
>50 and/or gross blood
Hospitalization or packed red 
blood cells (PRBC) 
transfusion