A Phase 2b Randomized Blinded Study to Evaluate SYN023 Compared to Human Rabies Immune Globulin in Post Exposure Prophylaxis of Rabies in Adults With Different Rabies Exposure Risks
Phase: PHASE2
Conditions: Rabies
Sponsor: Synermore Biologics Co., Ltd.

 
 
 
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Protocol SYN-023-004  
 
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A Phase 2b Randomized Blinded Study to Evaluate SYN023 Compared to Human 
Rabies Immune Globulin in Post Exposure Prophylaxis of Rabies in Adults with 
Different Rabies Exposure Risks  
 
 
Investigational Product:  
 
SYN023 
 
Protocol Number:  
 
 
SYN023-004  
 
 
US FDA IND Number: 
 
 
BB-IND-121522 
  
 
Sponsor: 
Synermore Biologics Co., Ltd. 
6F-6, No 5, Aly 22, Ln 513, Ruiguang Rd. 
Neihu Dist., Taipei City 11492   
Taiwan 
Phone: 011.886.202.2659.0988 
Fax: 
011.866.202.2659.0950 
 
 
 
 
Amendments Incorporated: 
 
 
Version and Date: 
 
 
Version 6.0 (09/22/2020)  
Version Superseded   
 
 
Version 4.0 (08/15/2019) 
 
 
 
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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 TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS .......................................................................................... 8 
STUDY ABSTRACT ...................................................................................................... 11 
1 
INTRODUCTION............................................................................................... 24 
1.1 
Background ............................................................................................................. 24 
1.2 
Description of SYN023 ........................................................................................... 25 
1.3 
Nonclinical Experience with SYN023 .................................................................... 25 
1.4 
Clinical Experience with SYN023 .......................................................................... 29 
1.5 
Clinical Experience with Products Related to SYN023 .......................................... 30 
1.6 
Rationales for Study ................................................................................................ 31 
2 
STUDY OBJECTIVES AND DESIGN ............................................................. 36 
2.1 
Objectives ................................................................................................................ 36 
2.2 
Design ...................................................................................................................... 36 
2.2.1 
Low Risk Group (LRG) ............................................................................ 37 
2.2.2 
Initial Enrollment in the LRG (20 Subjects) ............................................. 37 
2.2.3 
Advancement from Initial Enrollment LRG to General 
Enrollment LRG........................................................................................ 38 
2.2.4 
General Enrollment LRG .......................................................................... 38 
2.2.5 
Advancement from LRG General Enrollment to the Normal 
Risk Group (NRG) .................................................................................... 38 
2.2.6 
The Normal Risk Group (NRG) ............................................................... 38 
2.2.7 
Enrollment of the NRG ............................................................................. 38 
2.3 
Study Trial Size ....................................................................................................... 39 
2.4 
Study Duration and Follow-up ................................................................................ 40 
2.5 
Study Populations .................................................................................................... 40 
2.5.1 
Failure to Meet Inclusion/exclusion Criteria at Initial Screening ............. 40 
2.5.2 
As-Treated Population .............................................................................. 40 
2.5.3 
LRG Per-Protocol Population ................................................................... 40 
2.5.4 
NRG Per-Protocol Population................................................................... 40 
2.6 
Randomization ........................................................................................................ 41 
2.6.1 
LRG Initial Enrollment Randomization.................................................... 41 
2.6.2 
LRG General Enrollment and NRG Randomization ................................ 41 
2.7 
Non-Replacement of Randomized Patients ............................................................. 41 
2.8 
Adjustments to Randomization ............................................................................... 41 
3 
STUDY PROCEDURES .................................................................................... 41 
3.1 
Schedule of Subject Evaluations ............................................................................. 41 
3.2 
Subject Selection ..................................................................................................... 43 
3.2.1 
Recruitment and Informed Consent .......................................................... 43 

 
 
 
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3.2.2 
Screening................................................................................................... 44 
3.2.3 
LRG Inclusion Criteria ............................................................................. 44 
3.2.4 
NRG Inclusion Criteria ............................................................................. 45 
3.2.5 
Exclusion Criteria LRG and NRG ............................................................ 45 
 
Major Protocol Deviations and Eligibility for the Per-protocol 
Population ................................................................................................. 46 
3.2.6 
46 
3.2.6.1 
Pregnancy During Study .......................................................... 47 
3.2.7 
Screening Clinical Assessments and Laboratory Tests ............................ 47 
3.2.7.1 
Window Period for Screening Laboratory Tests ...................... 48 
3.2.8 
Per-protocol Adjudication Board (exclusion from the per-
protocol population) .................................................................................. 48 
3.3 
Study Randomization .............................................................................................. 48 
3.4 
Blinding ................................................................................................................... 49 
3.4.1 
Blinding at the Study Level ...................................................................... 49 
3.4.2 
Blinding at the Site Level ......................................................................... 49 
3.4.3 
Individual Unblinding for Clinical Emergencies ...................................... 50 
3.5 
Clinical Evaluation, Photography, Decontamination and Treatment of 
Wounds .................................................................................................................... 50 
3.6 
Decontamination of Mucous Membranes ............................................................... 51 
3.7 
Study Drug Infiltration for Bite and Non-bite Exposures ....................................... 51 
3.7.1 
Human Rabies Immune Globulin (HyperRab®  S/D) ................................ 52 
3.7.2 
SYN023..................................................................................................... 52 
3.8 
Rabies Vaccine (RabAvert®  or Rabipur®) Administration ...................................... 53 
3.9 
Study Efficacy Evaluations ..................................................................................... 53 
3.9.1 
Clinical Efficacy Evaluations ................................................................... 53 
3.9.2 
Pharmacodynamic Efficacy Evaluations .................................................. 54 
3.9.2.1 
The Window Interval for Collection of Efficacy 
Evaluation Specimens .............................................................. 54 
3.9.3 
Efficacy: Confirmation of Anti-rabies Activity in the Initial 
Enrollment LRG........................................................................................ 54 
3.9.4 
Modified WHO Rabies Risk Exposure Categories ................................... 54 
3.9.5 
WHO Category III Rabies Risk Substrata ................................................ 55 
3.10 Immunology Laboratory Evaluations ...................................................................... 56 
3.11 Virology Laboratory Evaluations ............................................................................ 56 
3.12 Safety Evaluations ................................................................................................... 56 
3.12.1 
Adverse Event Reporting Intervals ........................................................... 56 
3.12.2 
Pre-Study Drug and Post-Study Drug Monitoring of Subjects ................. 57 
3.12.3 
Clinical Assessments and Laboratory Tests ............................................. 57 
3.12.4 
Concomitant Medications and Prohibited Medications ............................ 58 
3.12.5 
Subject Follow-up and Contact ................................................................. 58 
3.12.6 
Loss to Follow-up ..................................................................................... 59 
3.13 Pharmacokinetic Evaluations LRG and NRG ......................................................... 59 

 
 
 
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3.14 Preservation of Clinical and Veterinary Materials .................................................. 59 
4 
STUDY DRUGS .................................................................................................. 59 
4.1 
SYN023 ................................................................................................................... 59 
4.1.1 
Receipt and Storage .................................................................................. 60 
4.1.2 
SYN023 Preparation ................................................................................. 60 
4.1.3 
Disposal of Unused Supplies .................................................................... 60 
4.2 
HRIG (HyperRab® S/D) .......................................................................................... 60 
4.2.1 
Receipt and Storage .................................................................................. 60 
4.2.2 
HRIG Preparations .................................................................................... 61 
4.2.3 
Disposal of Unused Supplies .................................................................... 61 
4.3 
Study Rabies Vaccine U.S. (RabAvert®) ................................................................ 61 
4.3.1 
Receipt and Storage .................................................................................. 61 
4.3.2 
Rabies Vaccine (RabAvert®) Preparation ................................................. 61 
4.3.3 
Disposal of Unused Supplies .................................................................... 62 
4.4 
Study Rabies Vaccine Philippines (Rabipur®) ....................................................... 62 
4.4.1 
Receipt and Storage .................................................................................. 62 
4.4.2 
Rabies Vaccine (Rabipur®) Preparation.................................................... 62 
4.4.3 
Disposal of Unused Supplies .................................................................... 63 
4.5 
Accountability ......................................................................................................... 63 
5 
SAFETY ............................................................................................................... 63 
5.1 
Responsibilities for Ensuring the Safety of Trial Subjects ..................................... 63 
5.1.1 
Principal Investigator ................................................................................ 63 
5.1.2 
Study Sponsor ........................................................................................... 64 
5.1.3 
Medical Monitor ....................................................................................... 64 
5.1.4 
Global Medical Monitor ........................................................................... 64 
5.1.5 
Data and Safety Monitoring Committee (DSMB) .................................... 64 
5.1.5.1 
DSMB Confirmation of Rabies Cases in the Trial .................. 65 
5.1.5.2 
DSMB Evaluation of Safety and Pharmacodynamic 
Activity in the Initial Enrollment LRG .................................... 65 
5.1.5.3 
DSMB Review of Safety and Pharmacodynamic 
Activity in the Initial and General Enrollment LRG ................ 65 
 
The RVNA values are in the protective range in ≥ 
75% of SYN023 recipients on Study Day 99 (Section 
3.9.2). ....................................................................................... 66 
5.1.5.4 
DSMB Review of Safety in the NRG ...................................... 66 
 
The DSMB will assess the safety (while enrollment 
continues) after 80 subjects have completed Study 
Day 99.  If there are no adverse events or patterns of 
concern it will issue permission for the trial to 
continue. ................................................................................... 66 
5.1.5.5 
DSMB Management of Safety Issues in the Trial ................... 66 
5.1.6 
Institutional Review Boards and Ethics Committees................................ 67 

 
 
 
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5.1.7 
National Regulatory Authority ................................................................. 67 
5.2 
Safety Surveillance During the Study ..................................................................... 67 
5.3 
Definition of Adverse Event ................................................................................... 67 
5.4 
Assessing Severity ................................................................................................... 68 
5.5 
Assessing Causal Relationship (Relatedness) ......................................................... 69 
5.6 
Definition of Adverse Reaction ............................................................................... 70 
5.7 
Solicited Adverse Events ........................................................................................ 71 
5.8 
Assessing “Seriousness” and Serious Adverse Events ........................................... 71 
5.9 
Assessing Expectedness .......................................................................................... 72 
5.10 Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) ............ 72 
5.11 Reporting of Serious Adverse Events ..................................................................... 72 
5.12 Immediately Reportable Events .............................................................................. 74 
5.13 Adverse Event Treatment, Follow-up, and Outcome .............................................. 74 
5.14 Pregnancy Safety Reporting .................................................................................... 75 
5.15 Immunological Adverse Events .............................................................................. 75 
5.16 Recognition of Anaphylaxis .................................................................................... 75 
5.17 Treatment of Anaphylaxis ....................................................................................... 76 
5.18 Recognition and Evaluation of Immune Complex Illness ...................................... 77 
6 
PAUSING AND STOPPING RULES ............................................................... 77 
6.1 
DSMB Efficacy Pausing Rules ............................................................................... 77 
6.1.1 
Confirmation of Initial LRG Pharmacodynamic activity ......................... 77 
6.1.2 
Confirmation of Rabies in Trial Participants ............................................ 77 
6.2 
Safety Pausing Rules ............................................................................................... 78 
6.3 
Safety Stopping Rules ............................................................................................. 78 
7 
STATISTICAL CONSIDERATIONS .............................................................. 79 
7.1 
Subject Populations ................................................................................................. 79 
7.2 
Demographics and Protocol Compliance ................................................................ 81 
7.3 
Primary Objective: Efficacy Analyses .................................................................... 81 
7.4 
Secondary Objectives: Clinical and Pharmacodynamic Efficacy. .......................... 83 
7.5 
Secondary Objective Pharmacokinetic Analysis ..................................................... 83 
7.6 
Secondary Objective: Immunogenicity Anti-SYN023 Antibodies ......................... 83 
7.7 
Secondary Objective Safety Analyses ..................................................................... 83 
7.7.1 
Adverse Events ......................................................................................... 84 
7.7.2 
Clinical Laboratory and Vital Sign Parameters ........................................ 85 
7.8 
Sample Size Considerations Primary Objective: Composite Endpoint 
Element .................................................................................................................... 85 
7.8.1 
Superiority of Geometric Mean of RVNA Study Day 8........................... 86 
7.8.2 
Non-inferiority of Geometric Serum RVNA on Study Day 99 ................ 86 
7.8.3 
Non-inferiority of Percentage of Subjects with Serum RVNA ≥ 
0.5 IU/mL on Study Day 99 ...................................................................... 88 
7.8.4 
Superiority of  Secondary endpoint AUEC1-15 ....................................... 89 
7.8.5 
Absence of Rabies: ................................................................................... 89 

 
 
 
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7.9 
Plan for Statistical Summaries and Analyses .......................................................... 89 
7.9.1 
Preliminary Data Reviews ........................................................................ 89 
7.9.2 
Final Study Report .................................................................................... 90 
7.10 Computer Methods .................................................................................................. 90 
8 
DATA COLLECTION, MONITORING, AND RECORD 
RETENTION....................................................................................................... 90 
9 
HUMAN SUBJECTS .......................................................................................... 91 
9.1 
Ethics and Regulatory Considerations .................................................................... 91 
9.2 
Institutional Review Board or Independent Ethics Committee ............................... 92 
9.3 
Informed Consent .................................................................................................... 92 
9.4 
Payments and  Reimbursement of Human Research Subjects ................................ 93 
10 
STUDY COMPLETION .................................................................................... 94 
11 
PUBLICATIONS ................................................................................................ 94 
12 
CHANGES IN THE CURRENT VERSION OF THE PROTOCOL ............ 94 
13 
REFERENCES .................................................................................................... 97 
APPENDIX A 
Protocol Facilities and Contact List .................................................... 103 
APPENDIX B 
Toxicity Table ........................................................................................ 105 
APPENDIX C 
Phlebotomy Volume by Visit................................................................ 108 
APPENDIX D 
Listing of Procedures by Study Visit ................................................... 109 
 

 
 
 
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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 
AUC1-last 
area under the curve time 0 Study Day 1 to last time 
point 
AUC1-inf, 
area under the curve time 0 Study Day 1 to infinity 
AUEC1-8 
area under the efficacy curve time 0 Study Day1 
through Study Day 8 
AUEC1-15 
area under the efficacy curve time 0 Study Day1 
through Study Day 15 
HCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
BP 
blood pressure 
BSR cells 
a hamster cell line 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CDC 
Centers for Disease Control 
Cmax,  
maximum concentration 
Clp 
plasma clearance 
CFR 
code of federal regulations 
cm 
Centimeter 
Cr 
Creatinine 
CRF 
case report form 
CNS 
central nervous system 
CPK 
creatinine phosphokinase 
CV 
coefficient of variation 
DSMB 
data and safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay  
ERIG 
equine rabies immune globulin 
FAT 
fluorescent antibody test 
FDA 
U.S. Food and Drug Administration 

 
 
 
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GMC 
geometric mean concentration 
HIV 
human immunodeficiency virus 
HRIG 
human rabies immune globulin 
ICI 
immune complex illness 
IgG 
immunoglobulin G 
IUD 
intrauterine device 
IEC 
independent ethics committee 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgG1κ 
immunoglobulin G type 1 kappa  
IM 
Intramuscular 
IRB 
institutional review board 
IU 
international units 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
kg 
Kilogram 
λz 
terminal elimination rate constant 
LD50 
lethal dose 50% 
LLN 
lower limit of normal 
LRG 
low risk group 
MNT 
mouse neutralization test 
MedDRA 
medical dictionary for regulatory activities 
mL 
Milliliter 
Mab 
monoclonal antibody 
NRG 
normal risk group 
PCR 
polymerase chain reaction 
PD 
Pharmacodynamic 
PEF 
peak expiratory flow 
PEP 
post exposure prophylaxis 
PK 
Pharmacokinetics 
PEP 
post-exposure prophylaxis 
PT  
preferred term 
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 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse event 

 
 
 
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Tmax 
time till maximum concentration 
t1/2 
half-life 
ULN 
upper limit of normal 
Vd 
volume of distribution 
WHO 
World Health Organization 
 
 
 

 
 
 
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STUDY ABSTRACT 
List of changes to Version 6.0 are in Section 12 
 
TITLE: 
 
A Phase 2b Randomized Blinded Study to Evaluate SYN023 Compared to Human Rabies 
Immune Globulin in Post Exposure Prophylaxis of Rabies in Adults with Different Rabies 
Exposure Risks 
 
RATIONALES: 
 
Rationale for SYN023 development 
Effective regimens of RIG and anti-rabies vaccination exist in the US and other developed 
countries with close to 100% effectiveness.  The available immunoglobulin preparations are 
produced through vaccination of humans or animals followed by a multi-step plasma collection 
and purification process that takes months to release product.  This long production chain is 
vulnerable to interruption and has resulted in unavailability of the product resulting in failure to 
provide protection for rabies.  The global use of these PEP agents is constrained by their 
unavailability that is as high as 10% in some surveys. (Bharti et al. 2016, Jentes et al.2013, Wilde 
et al. 2013, c-Equine rabies immunoglobulin soon to be available 2016)  Shortages and 
unavailability are a risk for global PEP activities. The major clinical risks from HRIG 
administration are anaphylaxis at approximately 1/20,000 (Sandler et al.1995). The major risks 
from ERIG are immune complex disease at about 0.7% and anaphylaxis at a much lower rate 
(Wilde et al. 1989).  The known adverse reactions to RIG are not the major risks for animal 
products rather it is their unavailability.  When there is no ERIG, rabies death is the major risk.  
Thus the major reason for anti-rabies Mab development is to provide a robust supply chain to 
avoid deaths from unavailability.  
 
The availability of an alternate effective, well characterized humanized IgG therapy 
manufactured through a well-defined industrial process will ensure the availability of anti-rabies 
PEP and should be an objective of global anti-rabies efforts. This trial is proposed to further the 
licensure of SYN023 to provide an effective PEP alternative available to those exposed persons 
who need such a product.  
 
Rationale for HRIG as a control group 
A placebo controlled rabies trial is unethical thus HRIG is selected as the control group. Rabies 
immune globulin from equine and human sources (HRIG) have been evaluated in many trials 
and HRIG is the standard of care in the United States (Manning 2008).   
 
Rationale for 5 dose (Essen) dose regimen rather than the 4 dose regimen 
The sponsor has selected the 5 dose Essen regimen or rabies vaccination: Days, 0, 3, 7, 14 and 28 
(Study Days 1, 4, 8, 15, 29). This is the regimen in the current version of the package insert of 

 
 
 
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the rabies vaccine selected for this trial. The sponsor is aware that the WHO and the American 
Committee on Immunization Practices have changed their recommendations to a 4 dose regimen: 
Days 0, 3, 7 and 14 (WHO Background Paper 2017, Rupprecht et al. 2010). A recent survey has 
summarized the heterogeneity of pre-exposure prophylaxis (PEP) recommendations (Buchy 
2017). The 5 dose regimen remains the standard in rabies vaccine product information.  All of 
the regions where SYN023 will be studied in its development currently include or have included 
the 5 dose regimen in the recent past (Buchy 2017, Republic of the Philippines 2018, WHO 
Background Paper 2017). Synermore is confident that the 5 dose regimen is clinically and 
ethically acceptable for use in a clinical study in all jurisdictions.  Since analysis of multiple 
vaccine regimens is not an objective of the protocol the 5 dose regimen is selected to reduce 
analytic difficulties when data is combined from different studies for biological licensing 
submissions.   
  
Rationale for the composite efficacy endpoint 
The primary objective is a composite endpoint with four elements to reflect the 
pharmacodynamics of administered SYN023/HRIG, the immune response to rabies vaccine and 
the occurrence of rabies, all important features of rabies prophylaxis.   
 
The first composite element is superiority of the geometric mean RVNA concentration in 
SYN023 recipients on Study Day 8.  RVNA was selected because it is a generally accepted 
correlate for rabies vaccine protection.  Animal and human studies suggest that tissue levels of 
RVNA may correlate with protection by neutralizing the rabies virus before the virus is taken up 
into peripheral nerves from where it gains fatal access to the central nervous system (Watson et 
al. 1981, Schumacher et al. 1989, Shankar et al. 1991).  The reason for HRIG injection in 
addition to vaccination is to provide immediate rabies neutralizing antibodies to prevent the entry 
of rabies virus into nervous tissue before rabies vaccination has elicited neutralizing antibodies 
through the natural immune response.  This practice in historical studies seems to have reduced 
infection from rabies compared to rabies exposed individuals receiving only vaccination. If it is 
possible to demonstrate quicker and higher concentrations in the blood of RVNA from SYN023, 
then this may be evidence of greater potency and perhaps effectiveness. It is logical that serum 
levels represent passive diffusion along a concentration gradient from sites of local infiltration 
where the local concentration is higher than serum concentration.  The pharmacodynamic 
variable Synermore selected to assess the prompt availability of RVNA for serum RVNA 
concentration (Synermore’s correlate of effectiveness) on Study Day 8 after which vaccine 
induced antibodies will have begun to predominate as a contributor to serum RVNA.  Synermore 
will demonstrate superiority of the GMC with an 80% power of observing a 10% margin of 
superiority with a p value ≤ 0.025 (Section 7.8.1). 
 
The second element of the endpoint is noninferiority of the Study Day 99 GMC of RVNA in 
SYN023 recipients compared to Study Day 99 GMC of RVNA in the HRIG recipients.  It is 
important that any immunoglobulin product administered be compatible with rabies vaccination 
and thus not significantly inhibit the immune response to rabies vaccination. When should this 
comparison of immunogenicity be performed and secondly what margin of non-inferiority 

 
 
 
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should be employed?  It is Synermore’s position that assessment of rabies vaccine 
immunogenicity should be performed on or around Study Day 99.  This interval is over four 
times the half-lives of administered human IgG.  By Study Day 99 anti-rabies antibodies 
including SYN023 that were administered for prophylaxis will have dissipated.  Thus Study Day 
99 RVNA values will reflect the long term production of natural rabies antibodies from 
vaccination.  Synermore defines non-inferiority of a rabies vaccine response with a 20% margin 
of non-inferiority and equal number of SYN023 and HRIG subjects in HRIG (Section 7.8.2). 
The alpha value is taken to be ≤ 0.025. 
 
The third element is the percentage of PEP recipients that have a serum RVNA concentration 
≥0.5 IU/mL on Study Day 99. This is the RVNA concentration that is generally recognized to 
reflect protection from rabies when subjects are vaccinated.  Achievement of RVNA ≥0.5 IU/mL 
should indicate that that the subject’s vaccination has elicited a protective immune response 
despite the geometric mean concentration, thus any differences are not clinically important.  
Synermore defines non-inferiority of the percentage of SYN023 subjects with serum RVNA 
concentration ≥0.5 IU/mL with a 20% margin of non-inferiority and equal number of SYN023 
and HRIG subjects in HRIG (7.8.3). The alpha value is taken to be ≤ 0.025. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The fourth element of the endpoint is the absence of probable or confirmed cases of rabies in the 
SYN032 recipients (Section 3.9.1). There is no need to specify “suspected” cases of rabies since 
entry into the protocol requires exposure to a possibly rabid animal and this is the factor that 
makes a case “probable” as opposed to “suspected.” A possibly rabid animal has a “risk of 
rabies” according to national and local rabies policies and agreement with the research site.  It is 
likely that there will no cases of rabies in the per protocol population of either treatment arm 
therefore a non-inferiority test could not be done.  Synermore estimates the failure rate of 
properly administered PEP in adults to be between 1 in 1,000 and 1 in 10,000 (Hemachudha, 
1999, Hampson 2008, Quiambao, 2008, Quiambao 2009 Shantavasinkul et al. 2010, Wilde et al. 
2007).  A single case of rabies in a subject properly treated with PEP meeting the per-protocol 
conditions in a 160 (or 184) sample of adults would be an occurrence rate of 0.6% and would be 
evidence for a lack of effectiveness (7.8.4).   
 
Rationale for stratification 
Bites above the level of the shoulder in the head or neck will be stratified in a 1:1 ratio by 
treatment arm so that there are approximately equal numbers in each treatment arm since bites in 
the head or neck seem to have a much higher chance of rabies transmission than bites of the 
trunk or extremity (Sitthi-Amorn et al. 1987, Cleveland et al. 2002, Fe’vre et al. 2005, Tenzin et 
al. 2011). 
 
Rationale for extra-United States majority enrollment.  
Most of the treatment allocations are to geographical areas of high rabies transmission to 
evaluate protection from rabies. Since this product is intended as a global product the study will 
occur in more than one country to examine exposure to different strains. 
 

 
 
 
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Rationale for per-protocol exclusion after randomization 
Subjects who are randomized may be excluded from the per protocol populations after 
randomization if important factors that affect rabies risk or efficacy endpoint elements are 
discovered. PEP must not be delayed but since protocol entry criteria for patients who fail to 
have confirmation of inclusion/exclusion criteria such as previous rabies vaccination may not be 
known at the time of consent and PEP there must be some mechanism for later exclusion.  All 
excluded subjects will be analyzed but not as part of the “per-protocol” population  
 
 In Synermore’s experience about 2% to 5% of subjects may have evidence of unknown 
or unrecalled rabies vaccination. Their RVNA response may be much quicker and higher 
than in naïve patients.  Since the RVNA is a crucial efficacy element these subjects with 
a RVNA ≥ 0.1 IU that is taken to be evidence of previous vaccination must be analyzed 
differently.    
 Subjects will be excluded for conditions discovered after randomization that impair 
protection such as immunodeficiency.   
 Subjects will be excluded if excessive treatment delay (>54 hours) is discovered.   
 Subjects will be excluded if they receive or have received protocol prohibited treatments 
such as RIG that will confound analysis.   
 Subjects will be excluded if all of the bite wounds are discovered to have not been 
properly treated or injected.  
 Subjects will be excluded if bites are determined to be due to non-protocol listed animals  
 Subjects will be excluded if they leave the trial or their status is unknown.  
 
Rationale for bite, broken skin lick and broken skin scratch exposure injuries eligibility for trial 
Individuals with WHO Category III rabies exposures with some exceptions are eligible for the 
trial since they are considered WHO Category 3 exposures and RIG is indicated for these 
exposures.   WHO Category 3 exposures include single or multiple transdermal bites or scratches 
or licks on broken skin, mucous membrane saliva contamination and unprotected bat exposures.  
Depending on the protocol defined risk substratum all observed bites, broken skin scratches and 
broken skin licks unprotected bat contacts and saliva contamination of mouth nose and eyes are 
eligible for the trial.  
 
Rationale for bite-to-treatment interval 
The bite-to-treatment interval for the administration of RIG is recommended to be as soon as 
possible up to 7 days by the WHO (WHO 2013).  This judgment reflects the emergence of 
naturally produced antibodies at about 7 days.  A number of surveys report that rabies cases were 
rare when treatment was instituted within 2 to 3 days (Si et al.  2008, Quiambao et al. 2009).  
Animal studies suggest that rabies virus may enter nerves within hours (Watson et al. 1981).  
Rabies virus may gain access to the brain within approximately 30 hours from a jaw injection 
(Shankar et al. 1991). Anti-rabies Mabs can interrupt this process (Schumacher et al. 1989). It is 
difficult to pinpoint the exact interval from studies reporting days since the counting of days may 
use different conventions.  The interval chosen for this protocol is 48 hours plus 6 hours (54 

 
 
 
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hours) that would permit PEP to start on the third day after the bite but more likely 48 hours 
from the bite assuming that most bites and their PEP will occur in the daytime.    
 
Rationale for blinding 
The pharmacy will be unblinded in this study because of the need to draw up the dose based on 
patient weight.  Since weights will be different the different volumes will not disclose identity 
and it will be necessary to visually blind the syringes with tubes because of slight differences in 
the appearance of the Study Drugs.  Nevertheless it will be difficult to have absolute blinding 
with HRIG.  Synermore judges that since the elements of the endpoint are objective the 
importance of blinding weaknesses in this study is secondary to adequate objective controls. 
 
Rationale for NRG follow-up period 
When the exposure time is known the incubation period of most cases occurs between 46-189 
days (Noah et al.1998, Quiambao et al. 2009, Ren et al. 2015,)  Some rabies incubation periods 
are more than a year (Boland et al. 2014).  A six month follow-up will capture most cases but 
follow up for a year should capture almost all cases of rabies.  
 
Rationale for interval for avoidance of pregnancy 
SYN023 and HRIG are both immunoglobulins.  SYN023 is not detectable in the blood by Study 
Day 99. Study Day 121 will be over 5 half-lives from administration and SYN023 should be 
eliminated from the circulation thus prohibition of pregnancy for the rest of the trial cannot be 
based on SYN023 exposure. 
 
Rationale for route of administration 
Immune globulins are administered by direct injection into the wound or by subcutaneous or 
intramuscular injection when this is not possible. Direct injection into the wound has been 
associated with good outcomes whereas injection at remote sites has been associated with failure 
of PEP (Wilde et al. 1996, Wilde et al. 1992, Shantavsinkul et al. 2010, Hemachudha et al. 1999, 
Bharti et al. 2016) 
 
Rationale for SYN023 dose level 
The dose level was determined by pharmacokinetic studies that demonstrated generally accepted 
as adequate levels of RVNA persisting for at least a month and from compatibility studies with 
rabies vaccines that demonstrated RVNA levels ≥ 0.5 IU/mL in rabies vaccine recipients 
receiving 0.3 mg/kg of SYN023 after Study Day 15 and from in vitro neutralization studies of 
multiple strains of rabies virus.   
 
Rationale for photographic documentation of bite wounds 
Simple uncalibrated photographs of wounds have a utility in presenting the extent number and 
severity of a bite wound. They will be useful during analysis with discussing individual cases 
and understanding safety information. They must not delay the start of PEP and thus may be 
recorded either before or after treatment.  Interval photographs may record progress and healing. 
They will need to avoid recording the facial characteristics and a means must be provided for 

 
 
 
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pixilation to avoid identification of the subject.   They need to be stored as a source document in 
a secure manner at the research site with encryption and an access roster. They will not be 
required for non-bite exposures. Specific consent for photography shall be obtained from the 
subject. 
   
OBJECTIVES: 
 
Primary Objective 
The primary objective is a composite endpoint with four elements: 
 To demonstrate that the geometric mean RVNA concentration for SYN023 recipients is 
superior to the geometric mean RVNA concentration for HRIG recipients on Study Day 8 
AND  
 To demonstrate that the Study Day 99 geometric mean RVNA concentration for SYN023 
recipients is not inferior to the geometric mean RVNA concentration for HRIG recipients 
AND 
 To demonstrate that the percentage of subjects with RVNA concentration ≥0.5 IU/mL on 
Study Day 99 in SYN023 recipients is not inferior to the percentage of recipients with 
RVNA concentration ≥0.5 IU/mL for HRIG 
AND 
 There are no probable or confirmed cases of rabies in SYN023 recipients. 
 
Secondary Objective(s) 
 To demonstrate that the geometric mean RVNA concentration for SYN023 is superior to 
the geometric mean RVNA concentration for HRIG on Study Day 4 
 To demonstrate that the geometric mean RVNA AUEC1-15 for SYN023 is superior to the 
geometric mean RVNA AUEC1-15 for HRIG 
 To describe the ratio of the geometric mean concentrations of RVNA at each time point 
in SYN023 recipients divided by the geometric mean concentrations of RVNA in HRIG 
recipients for LRG and NRG in the per-protocol and as-treated populations. 
 To describe the percentage of RVNA concentration ≥0.5 IU/mL at each time point for 
SYN023 and HRIG recipients for LRG and NRG in the per-protocol and as-treated 
populations.  
 To describe the pharmacokinetics of SYN023 using non-compartmental analysis. Vd, 
Cmax, Tmax, AUC1-t, AUC1-inf, t½, Cl, and λz will be calculated when possible in the LRG 
and NRG protocol and as treated populations. 
 To evaluate presence and effects of anti-SYN023 antibodies (anti-CTB011, anti-CTB012)  
 To evaluate the safety of SYN023 compared to HyperRab® S/D  
 To describe any effect of increasing BMI on SYN023 and RVNA concentrations. 
 
DESIGN 
This is a Phase 2b, double blinded, randomized study of SYN023 compared to HyperRab® S/D 
(a licensed HRIG) for PEP of patients who have been confirmed to have met all 
inclusion/exclusion criteria for their treatment group. The desired indication is the prevention of 

 
 
 
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rabies as part of PEP. The trial will be conducted in least two countries where rabies occurs. The 
trial will enroll sequentially two different risk substrata of WHO Category 3 rabies exposure.   
 
Low Risk Group (LRG) 
The Low Risk Group (LRG) is composed of subjects who meet the modified WHO Category 3  
protocol exposure criteria (Table 2.2-1 below and Sections 3.9.4 and 3.9.5). Inclusion is limited 
to bites to the foot, ankle, leg or trunk and licks to broken skin, scratches with, or to broken skin, 
unprotected bat exposure or mucous membrane contamination by saliva or neural tissue.  These 
exposures represent a lower rabies risk exposure within WHO Categories 3.  Bites to the head, 
neck or genitalia are excluded from LRG Initial Enrollment and LRG General Enrollment 
(Section 2.2.2 to Section 2.2.4). The purpose of the LRG is to obtain early safety, 
pharmacodynamic and pharmacokinetic information from field sites. Since it does not have the 
same rabies risk as the NRG it, will be analyzed separately for clinical rabies.    
 
Table 2.2-1 Exposure Characteristics of the Low Risk Group and Normal Risk 
Group   
 
Exposure Type 
LRG 
NRG 
Head and neck bite 
- 
+ 
Genitalia bite 
- 
+ 
Arms bite 
- 
+ 
Hands bite 
- 
+ 
Trunk bite 
+ 
+ 
Legs bite 
+ 
+ 
Ankles bite 
+ 
+ 
Foot bite 
+ 
+ 
Non-bite lick  
+ 
+ 
Non-bite scratch 
+ 
+ 
Non-bite bat contact 
+ 
+ 
Non-bite mucous membrane  
+ 
+ 
    
Initial Enrollment in the LRG (20 Subjects) 
Safety and RVNA data through Study Day 29 from the initial 20 subjects of the LRG will be 
reviewed by the DSMB to confirm safety and the achievement of adequate RVNA levels ≥ 0.5 
IU/mL on Study Day 15 and 29 from standard, wound management, Study Drug administration 
and rabies vaccination before LRG general enrollment is permitted.  Subjects excluded for cause 
by the Per-protocol Adjudication Board (Section 3.2.8) will not be included in the RVNA per-
protocol analysis but will be included in as-treated population.  The initial 20 subjects in the 
LRG will be randomized on a 3:1 (SYN023 to HRIG) ratio.  The size of the initial LRG 

 
 
 
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enrollment is arbitrary.  The initial LRG enrollment is not part of the sample size calculations for 
the primary objective.  
 
Advancement from Initial Enrollment LRG to General Enrollment LRG 
The DSMB will permit enrollment of the General LRG Enrollment group if safety from the as-
treated population and RVNA pharmacodynamic data from the per protocol population Study 
Days 8-29 from the initial LRG enrollment are found to be satisfactory by the DSMB (Section 
5.1.5.2). 
 
General Enrollment LRG 
The LRG general enrollment of an additional 60 subjects will consist of low risk WHO Category 
3 exposures (Table 2.2-1, Section 3.9.4 and 3.9.5). Subjects General Enrollment LRG will be 
allocated with a 1:1 randomization to either SYN023 or HRIG treatment arms.   Bites to the head, 
neck or genitalia are not included in the LRG.  
 
Advancement from LRG General Enrollment to the Normal Risk Group (NRG) 
If Study Day 99 efficacy (RVNA) and safety LRG data from the initial and general enrollment 
have been judged to be adequate by the DSMB and there are no cases of rabies in SYN023 
recipients by Study Day 183 then randomization into the NRG will be permitted (Section 
5.1.5.3).  It is presumed that a case of clinical rabies in the study population would become 
known to the DSMB promptly.  Clinical rabies follow-up of the LRG will be made available to 
the DSMB through 6+ months on all patients for consideration of NRG commencement.  The 12 
months of LRG follow-up will not have ended when NRG enrollment starts.  
  
Normal Risk Group (NRG) 
The NRG will consist of all WHO Category 3 exposure (Table 2.2-1, Sections 3.9.4 and 3.9.5).  
The NRG includes all rabies risks. It is powered to evaluate the primary and some secondary 
study objectives and to contribute to the pharmacokinetic and pharmacokinetic description of 
SYN023.  
 
Enrollment of the NRG 
Subjects will be allocated with a 1:1 randomization to either SYN023 or HRIG treatment arms.   
Within the NRG group bites to the head, neck or genitalia that have the highest rabies risk will 
be stratified for each treatment arm in a 1:1 ratio. The DSMB will review the progress of 
pharmacodynamic and safety data during the NRG study period to avoid unnecessary risk or 
expense (Section 5.1.5.4). 
 
Study Trial Size 
Data from an initial subgroup of 20 subjects will be evaluated by the DSMB to ensure 
pharmacodynamic activity before the remainder of the LRG is enrolled. The size of this group 
was determined by non-statistical reasons (Table 2.3-1). 
 

 
 
 
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Safety and pharmacodynamic data from the entire LRG will be reviewed by the DSMB to ensure 
safety and pharmacodynamic adequacy.  The size of the LRG is 80 subjects. Up to 45 LRG 
subjects will have received SYN023.  This number was judged adequate to give a preliminary 
assessment of Study Drug performance in the LRG. 
 
Three hundred and twenty patients are required in the per-protocol population to satisfy the 
efficacy elements of the AUEC-1-15 secondary endpoint. Synermore anticipates approximately 
15% (48 patients) of loss to follow-up and exclusions resulting in a total NRG size of 368.  Since 
PEP should not be delayed and some inclusion/exclusion criteria may not be known at the time 
of randomization some subjects may be excluded (but not replaced) from the per-protocol 
population by the Per-Protocol Adjudication Board if they are later discovered to have met an 
exclusion criterion.   
  
Randomization will be adjusted by the randomization center such that patients are 
proportionately distributed between the trial sites and patients with wounds of the head, neck or 
genitalia are stratified approximately equally into the treatment groups.   
 
 
Table 2.3-1  Enrollment by Risk Group and Treatment 
 
Group 
Enrollment 
Dosage 
Rabies Vaccination 
Number of 
subjects 
LRG 
initial 
HRIG 20 IU/kg  
Day 1,4,8,15,29 
5 
LRG 
initial 
SYN023  
0.3 mg/kg 
Day 1,4,8,15,29 
15 
LRG 
general 
HRIG 20 IU/kg  
Day 1,4,8,15,29 
30 
LRG 
general 
SYN023  
0.3 mg/kg 
Day 1,4,8,15,29 
30 
NRG 
general 
HRIG 20 IU/kg  
Day 1,4,8,15,29 
184 
NRG 
general 
SYN023  
0.3 mg/kg 
Day 1,4,8,15,29 
184 
Total required for initial LRG enrollment 
20 
Total required for general LRG enrollment 
60 
Total required for NRG efficacy element 
368 
Total maximum enrollment 
448 
 
 
Study Duration 
Subjects will be followed for 365 days post receipt of Study Drug unless withdrawn from the 
trial.  It is important to have follow-up information on all study enrollees for the full duration of 
the study. Every effort should be made to remain in contact with study subjects in at least six-

 
 
 
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week intervals to establish if the subject is in good health and to inquire about planned 
relocations. If health problems have occurred a verbal or written account of the duration and 
character of the difficulties should be obtained.  This is specially important in the last six months 
of the study when clinic visits are less frequent.  
 
Study Populations 
 
Failure to meet inclusion/exclusion criteria at initial screening 
Screening includes informed consent, satisfaction of inclusion criteria and an initial survey of 
exclusion criteria.  Rabies exposed subjects that are known to fail inclusion criteria at initial 
screening or any immediately evaluable exclusion criteria will not be randomized into the study. 
They will be treated outside of the study protocol with the national standard of care for PEP. The 
minimum PEP standard will include ERIG or HRIG and rabies vaccination according to the 
national recommendations. Not all exclusion criteria need to be known at the time of 
randomization but those that are known will determine enrollment. 
 
As-Treated Population 
All subjects who are randomized and receive Study Drug are included in the “as-treated” 
population. 
 
LRG Per-Protocol Population 
Since PEP of rabies is urgent and should not be delayed, randomization and prophylaxis will 
begin after a screening event that includes informed consent and survey of inclusion criteria 
(including urine pregnancy test results) before some exclusion criteria have been confirmed.  
WHO Category 3 exposure victims that meet all initially knowable inclusion/exclusion criteria 
(Section 3.2.3 – 3.2.5) will be randomized receive wound treatment, receive Study Drug and 
begin a regimen of rabies vaccination.    
 
NRG Per-Protocol Population 
Since PEP of rabies is urgent and should not be delayed, randomization and prophylaxis will 
begin after a screening event that includes informed consent and survey of inclusion criteria 
(including urine pregnancy test) before some exclusion criteria have been confirmed.  WHO 
Category 3 exposure victims that meet all initially knowable inclusion/exclusion criteria will be 
randomized receive Study Drug and begin a regimen of rabies vaccination 
 
Randomization 
LRG Initial Enrollment 
Subjects in the initial enrollment group will be randomized on a 3:1 basis to treatment with 
SYN023 or HRIG.  Eligibility for the LRG subjects is described in Section 2.2.1.  The group as 
described in Table 2.3.1 is randomized in a 3:1 ratio.   Subjects in the initial LRG may be 
excluded from the LRG per-protocol population but they will not be replaced. 
 
LRG General Enrollment and NRG  

 
 
 
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Subjects in the general enrollment of LRG and NRG will be randomized on a 1:1 basis within 
each group to treatment with SYN023 or HRIG.  Subjects will be allocated to treatment sites to 
approximate the ratio in Table 2.3-1. Within NRG enrollment subjects with head or neck bites or 
bites to genitalia will be stratified on a 1:1 basis into SYN023 or HRIG treatment groups.    
 
Study sites wishing to randomize a subject will contact the study randomization center either 
telephonically or by electronic means.  The study center will determine the randomization 
allocation and return the randomization assignment in written communication to the study site.  
 
Non-replacement of Randomized LRG and NRG Patients 
Subjects will not be replaced after randomization. They may be excluded from the per-protocol 
population 
 
Adjustments to Randomization 
Allocation of randomization among sites will be adjusted to accommodate stratification of head, 
neck or genitalia bites or site enrollment imbalances. 
 
Protocol Deviations and Eligibility for the Per-protocol Population 
Continuation in the per-protocol population depends on the absence of uncorrectable major 
protocol deviations. Major deviations are those that would degrade the fidelity of the data from 
the protocol.  Protocol deviations requiring removal from the per-protocol population include but 
are not limited to those listed below.  
 
 Defective informed consent  
 Received the incorrect Study Drug 
 Received the incorrect dose (± 20%) of Study Drug 
 Failed to complete the scheduled rabies vaccinations through Study Day 29 
 Are discovered to lack adequate prophylactic treatment of all exposure sites  
 Are discovered to be injured by animal other than those listed 
 Are discovered to have an interval > 54 hours from rabies exposure to the start of 
prophylaxis 
 Are discovered to have RVNA ≥ 0.1 IU in serum obtained at Study Day 1 
 Receives prohibited treatment during the trial 
 Are found not to have a modified WHO Category 3 exposure (Table 2.2-1, Section 3.9.4)  
 Are discovered to have or have developed HIV infection or other immunodeficiency state. 
 Second high risk animal bite or contact requiring PEP 
 Are discovered to have or have developed HIV infection or other immunodeficiency state. 
 Second high risk animal bite or contact requiring PEP 
 
Subjects who are discovered to not have satisfied any criteria for the per-protocol population 
may be excluded from that population by the Per Protocol Adjudication Board. Any exclusion of 

 
 
 
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randomized subjects from the per-protocol population after randomization must be made by the 
Per Protocol Adjudication Board (Section 3.2.8). 
 
ANALYSIS OF EFFICACY  
The absence of a confirmed or probable case of rabies in the per-protocol population is part of 
the composite endpoint (3.9.1).  Subject will be periodically evaluated for the clinical signs and 
symptoms of human rabies. If these develop they will be referred for medical evaluation and 
laboratory or anatomic confirmation. All clinical rabies diagnostic tests may be performed 
locally at a qualified laboratory.  All rabies cases will be reviewed by the DSMB. 
 
The primary pharmacodynamic efficacy parameter is a composite endpoint with the following 
elements elements (see Section 2.1):  
 the superiority of RVNA GMC RVNA on Study Day 8 in SYN-23 recipients compared. 
This represents early anti-rabies activity 
 the noninferiority of Study Day 99 GMC RVNA in SYN023 recipients vs HRIG 
recipients. This represents the immune response to rabies vaccination. 
 the noninferiority of the Study Day 99 percentage of SYN023 recipients with RVNA ≥ 
0.5 IU/mL compared to HRIG recipients. 
 
The criteria for a probable or definite (confirmed) rabies case in Sections 3.9.1 and 7.8.4. 
The criteria for superiority for Study Day 8 GMC RVNA are described in Section 7.3 and 7.8.1 
The criteria for non-inferiority of the Study Day 99 GMC RVNA and percentage of the group 
with RVNA ≥ 0.5 IU/mL are described in Section 7.3, 7.8.2 and 7.8.3. 
 
Analyses of efficacy will be performed on the per-protocol and as-treated populations for each 
risk group. 
 
All pharmacokinetic analyses of serum SYN023 concentrations will be done on the per-protocol 
and as treated populations.  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. Vd, Cmax, Tmax, AUC0-t, AUC0-inf, t½, Cl, and λz will 
be calculated when possible.  Effect of BMI on pharmacodynamic and pharmacokinetic 
parameters will be performed. 
 
ANALYSIS OF ANTI-DRUG ANTIBODY 
All analyses of anti-drug antibody (anti-SYN023) will be based on per-protocol and as-treated 
subjects for each risk group who received at least one dose of Study Drug.  The presence and 
effect of anti-SYN023 antibodies (anti-CTB011, anti-CTB012) will be evaluated.  
Immunogenicity will be summarized for all time points as collected and as available.  No 
imputation for missing immunology data will be performed.  Data will be transformed as 
appropriate prior to analysis. The development of anti-SYN023 antibodies will be analyzed as a 
categorical variable by treatment assignment, with descriptive statistics.  Any effect of anti-
SYN023 antibodies on pharmacokinetics, pharmacodynamics or safety will be described. 

 
 
 
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ANALYSIS OF SAFETY 
Safety analyses will be performed using the as-treated population for each risk group as defined 
in Section 7.1.  Summaries will be presented by treatment group for all subjects in the safety 
population.  The safety profile of Study Drug will be described by treatment group.  The primary 
variable for evaluation of the safety profile will be the number and percentage of adverse events 
(AEs) recorded at all available post-Study Drug administration time points.   
 
The number (percentage) of subjects with AEs will be summarized for each treatment arm 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 PT at the greatest severity or most related state 
recorded for that term.   
 
Serious adverse events (SAEs) will be recorded through the final study visit for all subjects.  
SAE listings will be provided for subjects by treatment arm. 
 
Listings will be provided for subjects who have discontinued prematurely due to an AE.   
 
The number (percentage) of subjects with post-Study Drug administration clinical laboratory 
values or vital sign values recorded as newly abnormal or increased by a toxicity grade following 
Study Drug administration and meeting toxicity mild criteria (Grade 1) or above as specified in 
the Toxicity Table  will be tabulated at each post- Study Drug administration time point and 
overall.  Clinical laboratory and vital sign abnormalities will also be reported as AEs and will be 
included in the summary of AEs. 
 
A sample size of 184 subjects per treatment group will also permit an initial estimate of general 
safety and tolerability.  An approximation to the upper 95% confidence bound on the true rate of 
occurrence for a SYN023 associated AE not encountered in 160 (160 calculated minimum 
sample) subjects in the per-protocol receiving SYN023 is 2.2%.  
 
 

 
 
 
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1 
INTRODUCTION 
 
1.1 
Background 
Rabies is an acute lethal viral disease transmitted from animals to humans. Rabies is present in 
more than 150 countries and territories and on every continent except Antarctica. All mammals 
are believed to be susceptible to infection with the rabies 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 bites or scratches 
(WHO 2017). 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, PEP 
against rabies infection is of critical importance.  Rabies vaccination alone is used for pre-
exposure prophylaxis (Immunization Practices Advisory Committee 1980).  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 rabies vaccine have 
adequate rabies neutralizing activity (Grandien  et al.1977, Vodopija et al.1988a)   
 
The rabies mortality from bites to the head by the same rabid wolf in Iran in 1955 was 3/5 (60%) 
in subjects receiving rabies vaccine alone.  The mortality fell to 1/12 (8%) when both rabies 
vaccination and rabies antisera were administered (Baltazard et al.1955).  A study by the same 
group 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 et al.1976). Delays of up to 4 days 
in the initiation of rabies immune globulin after anti-rabies vaccination have demonstrated no 
inhibition of anti-rabies activity in blood (Khawplod et al.1996). There is some inhibition of the 
immune response to rabies vaccination by rabies immune globulin itself that has been recognized 
since early experience (Loofbourow et al. 1971, Hattwick et al.1974, Vodopija et al. 1988).   The 
inhibition of immune response by RIG varied in a range generally accepted as adequate.  There 
has not been a single case of rabies in an individual receiving proper PEP in the United States 
since 1980.  The combination of rabies vaccine with rabies immune globulin (RIG) has 
continued to be used and remains the standard of care despite inhibition of rabies vaccine 
immune response (Manning et al. 2008, Kedrab, 2017).   
 
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 
rabies 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 

 
 
 
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rabies immune globulin must be evaluated to ensure no significant inhibition (Vodopija et 
al.1988b). 
 
Three anti-rabies immunoglobulin formulations prepared from hyperimmunized human donors 
have been approved by the FDA: HyperRab® S/D (Grifols Therapeutics) and Imogam® Rabies-
HT (Sanofi Pasteur) and Kedrab® (Kamada Ltd.).  Since all HRIG preparations are considered 
equivalent HyperRab® S/D will be used as the HRIG in this trial.  
 
1.2 
Description of SYN023 
SYN023 is an equal mass mixture of CTB011 and CTB012, two monoclonal antibodies that 
exhibit a wide spectrum of activity against various wild-type rabies strains in vitro. CTB012 
possesses a slightly broader spectrum of activity than CTB011.  Both monoclonal antibodies 
bind to non-overlapping epitopes thus single point mutations should not escape binding by at 
least one Mab.  The combined mixture SYN023 demonstrated medium to high neutralizing 
activity against most of the strains evaluated. These results were verified from two different 
laboratories. 
 
1.3 
Nonclinical Experience with SYN023 
Nonclinical pharmacology studies included Mab binding studies, neutralizing potency studies of 
these Mabs by rapid fluorescent foci inhibition test (RFFIT) and mouse neutralization test 
(MNT), determination of the breadth of neutralization against a broad panel of street rabies virus, 
a study of the interference with vaccination in non-challenged mice and hamsters and PEP 
performance in Syrian hamster and Beagle dog rabies virus challenge models. 
The preclinical pharmacology studies performed to date with the SYN023 Mab mixture 
(humanized Mabs CTB011 and CTB012) have examined the binding of antibodies CTB011 and 
CTB012 to non-overlapping determinants on the rabies virus glycoprotein antigen, and have 
identified amino acid residues critical for specific binding of both antibodies. 
In vitro rabies virus inhibition by CTB011 and CTB012 exhibited a wide spectrum of activity 
against various wild-type rabies strains.  CTB012 has a slightly broader spectrum of activity. The 
combined CRB011 and CTB012 product elicited medium to high neutralizing activity against 
most of the strains evaluated. 
 
Rabies vaccine inhibition in the hamster 
Studies in hamsters were performed to determine whether the SYN023 component antibodies 
would interfere with the immune response to rabies vaccine in non-challenged Syrian hamsters. 
CTB011 treatment had no adverse impact on active immunization produced by the rabies 
vaccine, and hamsters maintained high serum antibody levels until the end of the study.  CTB012 

 
 
 
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produced higher serum RVNA concentrations following IM dosing. CTB012 treatment did not 
adversely impact the active immune response to rabies vaccine seen at later time points. The 
magnitude of the response was comparable to that produced by HRIG + rabies vaccine.   
Inhibitory mean antibody titers were maintained until the end of the study in all CTB012-treated 
groups, and these were comparable to the levels observed with HRIG + rabies vaccine.  
In the SYN023-dosed hamsters, there were clear dose-dependent differences in the RVNA 
titers/profiles from 0.003 to 1 mg/kg SYN023.  Ultimately, this study established that the RVNA 
response to a moderate dose of SYN023 might be capable of supplying sufficient immune 
protection to bridge animals/patients to the point of active immunity.  Importantly, early 
treatment with either CTB011 or CTB012 or their combination (SYN023) did not appear to 
adversely impact the eventual immune response to rabies vaccine treatment.   
Studies in rabies vaccine-immunized hamsters demonstrated that neither SYN023 nor HRIG 
adversely impacted the ability of the rabies vaccine (US approved) to induce RVNA 
concentrations generally accepted as adequate (≥0.5 IU/mL) in this hamster model.  Comparison 
of the RVNA mean titers of each group by day indicates some inhibition of RVNA response, 
since the mean titers of the hamsters administered rabies vaccine alone or rabies vaccine and 
HRIG were higher at each time point than the titers of the hamsters administered SYN023 with 
rabies vaccine.  SYN023 administration induced a high RVNA at Day 3, when the antibody 
response to vaccination is generally very low or undetectable.  The RVNA inducing potency of 
the SYN023 Mab mixture is higher than the HRIG induced RVNA potency. Despite the higher 
potency of the SYN023 antibody mixture, the hamsters in that group were able to produce 
RVNA above the concentrations generally accepted as adequate (≥0.5 IU/mL) at all remaining 
time points. 
Rabies challenge studies in Syrian hamsters 
Three PEP studies were performed with the CTB011/CTB012 mixture in a Syrian hamster model 
of rabies infection. In the first study, three different doses of rabies virus were used for challenge.  
Results showed that when Syrian hamsters were challenged with the standard infection dose of 
50 LD50, the incubation latent period of the rabies virus was 7-8 days and PEP of hamsters with 
rabies vaccine at all doses of the Mab mixture resulted in 100% survival (10/10).  
Challenge with 200 LD50 of rabies virus resulted in an incubation period of the rabies virus of 6-
7 days and PEP with Mab mixture (1000 and 5000 IU/kg) plus rabies vaccine resulted in a 
survival rate of 7/8 and 8/8, respectively, which was higher than the survival rate for HRIG plus 
rabies vaccine (50%). Challenge with the ultra-high infection dose (400 LD50) resulted in a latent 
rabies virus period of 5-6 days and there was no survival when hamsters were treated with HRIG 
plus rabies vaccine. Treatment of hamsters with 1000 and 5000 IU/kg of the Mab mixture 
resulted in a survival rate of approximately 40% (3/8). Overall, results showed that the Mab 
mixture provided a level of protection against rabies comparable with that of HRIG plus rabies 
vaccine at the standard virus infection dose (50 LD50) and protection that was superior to HRIG 

 
 
 
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plus rabies vaccine with the high and ultra-high infection doses. These data support 
administration of the CTB011/CTB012 Mab mixture with rabies vaccine to provide protection 
from rabies virus infection. 
In this experiment the SYN023 Mab mixture provided dose-dependent increases in protection 
and survival following rabies virus challenge 
A second dose response study was performed using a narrower dose range of SYN023 Mab 
mixture (i.e., 0.03, 0.1, 0.3, and 1 mg/kg).  Findings were similar to those of the first study, and 
again demonstrated dose-dependent increases in protection and survival with SYN023 Mab 
mixture plus rabies vaccine.  These results further confirmed that antibodies CTB011 and 
CTB012 were protective and did not interfere significantly with the immune response to rabies 
vaccine in the hamster model.   
A third study in hamsters also suggests that PEP treatment with SYN023 in tandem with rabies 
vaccine provides dose-dependent protection against lethal challenge with rabies virus in Syrian 
hamsters. At the end of the study RVNA levels were generally elevated in surviving SYN023-
treated hamsters with highest RVNA titers observed at the lower doses of SYN023 plus rabies 
vaccine.  
 
Rabies challenge studies in Beagle dogs 
 
In the first Beagle PEP experiment SYN023 was tested at doses ranging from 0.03 up to 1 mg/kg 
in different groups of 4 animals each.  SYN023 provided higher survival against rabies virus 
challenge compared to the positive control of HRIG 20 IU/kg + rabies vaccine. SYN023 at both 
0.1 and 1.0 mg/kg, administered with rabies vaccine, provided complete (100%) protection 
against virus challenge, with all dogs surviving until the end of the study. A single dog in the 4 
dog group dosed with 0.3 mg/kg SYN023 died on Day 12 post-challenge. In the low-dose 0.03 
mg/kg group SYN023 group, two dogs died for 50% mortality. The mortality in the HRIG group 
was 75%.  Mortality in the negative control (saline-treated) group was 100%.  SYN023 exhibited 
a dose response of increased survival.  All SYN023 doses had increased survival compared to the 
HRIG group.   
 
In the second Beagle PEP study, SYN023 was tested with rabies vaccine at doses ranging from 
0.03 up to 1 mg/kg in groups of 8 Beagle dogs. In the positive control group of HRIG 20 IU/kg 
administered with rabies vaccine all 8 animals survived through Day 28.  All animal receiving 
SYN023 at any dose plus rabies vaccine survived.  There were three negative controls in this 
study: saline alone, rabies vaccine alone, and SYN023 alone without rabies vaccine.  In the 
saline group 7/8 animal had developed rabies by the end of the study at day 28.  In the rabies 
vaccine alone group 2/8 animal had developed rabies by the end of the study.  In the SYN023 
alone group none of the animals had developed rabies.  There was no dose response in this study 
since survival was 100% in any animal receiving SYN023 plus rabies vaccine. 
 

 
 
 
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In the third Beagle PEP experiment a highly virulent New York City street rabies virus strain 
was used as the challenge in groups of 6 Beagle dogs.  None (0/6) of the animal receiving rabies 
vaccine alone survived.   All animals (6/6) receiving 0.3 mg/kg SYN023 plus rabies vaccine 
survived. 
 
Toxicology 
 
Tissue Binding 
No specific binding of CTB011 or CTB012 Mabs alone or in combination to normal, frozen 
human tissues in situ human tissues was identified compared to results obtained with control 
groups.  CTB011 and CTB012 Mabs could specifically bind with rabies virus infected BSR cells, 
whereas no specific binding was observed to normal human tissues for SYN023, CTB011, or 
CTB012. Mabs CTB011, CTB012, and SYN023 did not reveal any notable cytotoxicity at 
concentrations up to 40 μg/mL in either normal or rabies-infected BSR cells, nor did any of the 
single Mabs or the SYN023 Mab mixture produce any observable ADCC activity at 
concentrations up to 40 μg/mL in either normal or infected cells. Both Mabs as well as the 
SYN023 antibody mixture all produced dose-dependent CDC activity in rabies infected, but not 
normal BSR cells, suggesting that these antibodies can target cells infected with rabies virus and 
can destroy them via a CDC-dependent mechanism.   
 
A Pilot Repeat-dose Intramuscular Toxicity Study in Rats 
A pilot repeat-dose intramuscular study was performed with SYN023 in male and female 
Sprague-Dawley rats. Rats were dosed IM once weekly for two consecutive weeks (total twice) 
on Days 1 and 8 with either saline or SYN023 at doses of 1, 3, or 10 mg/kg.  No mortality or 
morbidity was observed in any animals throughout the study.  There were no apparent 
abnormalities in clinical observations, body weights, food consumption, clinical pathology, and 
organ weight and organ weight ratios noted in animals treated with 1, 3, and 10 mg/kg of 
SYN023 as compared to the concurrent control group. No abnormal macroscopic findings were 
noted in any animals on Day 15.  SYN023 was found to be non-toxic at these doses tested in rats. 
 
Repeat-dose Intramuscular Toxicity and Toxicokinetic Study of SYN023 in Rats 
A second repeat-dose (3-dose) intramuscular toxicity and toxicokinetic study was also performed 
in Sprague-Dawley rats.   Groups of rats were treated once weekly for three consecutive weeks 
with vehicle (0.9% saline) or SYN023 at 1, 3 or 10 mg/kg and were observed for either 3 days or 
6 weeks following their final dose.   
There were no deaths or morbidity noted in any animals treated with 1, 3, and 10 mg/kg of 
SYN023 throughout the study. No toxicologically significant changes in clinical observations, 
body weights, body temperature, food consumption, clinical pathology, ophthalmic exams, 
urinalysis, T-Lymphocyte subsets, and organ weight or organ weight ratios were noted in 
SYN023-treated rats as compared to the control group. There were no apparent abnormal 
changes noted at injection sites, and there were no SYN023-related changes in macroscopic or 
microscopic findings in rats dosed once weekly for three weeks with SYN023 at doses up to 10 

 
 
 
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mg/kg/day or in rats maintained for a further 6-week recovery period. Following repeated IM 
dosing of male and female rats with SYN023 for three consecutive weeks (three doses) at 1, 3 or 
10 mg/kg, the no observed adverse event level (NOAEL) was considered to be equal to or 
greater than 10 mg/kg for both females and male Sprague Dawley rats.  
During the study, totals of 3/18, 4/18, and 4/18 animals exhibited antibodies against CTB011, 
and 3/18, 4/18, and 4/18 demonstrated antibodies against CTB012 in Groups 6-8 at 1, 3, and 
10 mg/kg, respectively. Neutralizing activity of anti-CTB011 and anti-CTB012 antibodies was 
observed in these animals.  
Conclusions from nonclinical studies  
In vitro rabies neutralization studies and in vivo pharmacokinetic and immunization dose 
response studies demonstrate that SYN023 components have anti-rabies activity and while there 
may be some effect on RVNA concentrations post-immunization the doses studied (0.003 to 1.0 
mg/kg) do not seem to interfere with the development of RVNA concentrations generally 
accepted as adequate (≥ 0.5 IU/mL).  Rabies challenge studies in hamsters and Beagle dogs 
indicate that SYN023 exhibits either a complete or dose dependent protective effect on the 
development of rabies compared to HRIG and rabies vaccine-only controls at clinically relevant 
dosages (0.03 to 1.0 mg/kg).  SYN023 administered to rats at repeated doses of 10mg/kg, a dose 
that exceeds those found to have activity in animals suggest that SYN023 is non-toxic in the 
species tested. 
 
1.4 
Clinical Experience with SYN023 
A total of 209 individuals have been enrolled in SYN023 studies.  Of the 209 enrollees 127 have 
received SYN023.  Doses up to 2 mg/kg were evaluated and found to have an acceptable safety 
profile.  One hundred seventeen have received the 0.3 mg/kg dose by intramuscular or 
subcutaneous injection.   
SYN023 administered alone to human volunteers at the 0.3 mg/kg dose by intramuscular or 
subcutaneous routes exceeded the ≥ 0.5 IU/mL blood inhibitory threshold RVNA levels 
promptly usually within 1 day.   Supra-inhibitory levels at the 0.3 mg/kg dose are then 
maintained for 35 to 42 days.   
SYN023 was co-administered with both US licensed rabies vaccines, Rabavert® and Imovax®. 
SYN023 achieved inhibitory blood levels faster compared to HRIG during the critical first week 
of a PEP regimen.  Since the local tissue levels from direct injection of antibodies into the rabies 
wound are likely more important than blood levels in rabies prevention, the significance of these 
rapidly achieved blood levels is not known.  Synermore speculates that rapid blood 
concentrations from antibodies injected into tissues imply more rapid diffusion through tissues 
and such tissue diffusion might be an important property.  The RVNA concentrations in the 
SYN023 cohort were also higher than HRIG in the first week although again the significance of 
supra-inhibitory RVNA activity is unknown.   

 
 
 
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Many anti-rabies antibodies seem to possess some ability to lower the immune response to rabies 
vaccination (Loofbourow 1971, Lang 1998a, Lang 1998 b). HRIG still permits effective rabies 
vaccination because any lowering of RVNA is still in the adequate range.  The higher RVNA 
concentrations from SYN023 measured early in PEP is followed by a lower but still supra-
inhibitory RVNA value starting at Day 14 after SYN023 and HRIG injection.  SYN023 seems to 
inhibit the apparent immunogenicity of the rabies vaccine more than HRIG as measured by blood 
RVNA concentrations.  Since both SYN023 and HRIG given with rabies vaccine induced 
adequate RVNA activity in recipients the significance of this difference is unknown.   Both 
HRIG and SYN023 seem to be compatible with both licensed rabies vaccines in a PEP regimen. 
Antibodies to SYN023 components: anti-CTB011and anti-CTB012 antibodies were surveyed. 
Surprisingly about 20% of subjects with no history of exposure to CTB011 had anti-CTB011 
prior to administration.  Only about 3% of individuals had antibodies to CTB012 pre-exposure.  
When analyzed by the presence or absence of anti-CTB011 antibodies no difference in 
pharmacokinetics, RVNA value or AEs could be discerned.  The anti-CTB011antibodies do not 
seem to have a pharmacokinetic, pharmacodynamic or safety effect and have an unknown 
significance. 
SYN023 had an acceptable safety profile with no deaths, related serious adverse events or 
systemic injection reactions.  The most common related adverse event was headache followed by 
local injection site manifestations. 
Conclusions from human studies 
SYN023 seems to provide very early serum levels of RVNA from both IM and subcutaneous 
administration while permitting the development of rabies vaccine induced RVNA 
concentrations generally accepted as adequate (≥0.5 IU/mL). Pre-existing anti-CTB011 
antibodies encountered in about 20% of recipients do not seem to affect the serum RVNA 
activity, the pharmacokinetics or the AE profile. The safety profile is acceptable.   
 
1.5 
Clinical Experience with Products Related to SYN023 
An anti-rabies Mab SII RMAB was licensed during 2017 in India for use in PEP.  The product 
was licensed based on achievement of noninferiority of RVNA values from a 3.3. IU/kg SII 
RMAB dose recipients that were not inferior to those observed in 20 IU/kg HRIG dose recipients 
on Study Day 14. There were 200 participants in the trial.  The rabies vaccine regimen was the 
standard 5 dose IM regimen. Clinical rabies was not an endpoint in the 84 day trial but was not 
mentioned in the paper (Gogtay 2018). The 84 day follow-up was long enough to have observed 
some rabies cases.  This study indicates that some regulatory authorities believe that RVNA 
values are a surrogate of PEP protection from rabies. At the time of this protocol no information 
is available on the Indian government’s pharmacovigilance site or in clinical reports regarding 
clinical success or failure of SII RMAB. 
 

 
 
 
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1.6 
Rationales for Study 
 
Rationale for SYN023 development 
Effective regimens of RIG and anti-rabies vaccination exist in the US and other developed 
countries with close to 100% effectiveness.  The available immunoglobulin preparations are 
produced through vaccination of humans or animals followed by a multi-step plasma collection 
and purification process that takes months to release product.  This long production chain is 
vulnerable to interruption and has resulted in unavailability of the product resulting in failure to 
provide protection for rabies.  The global use of these PEP agents is constrained by their 
unavailability that is as high as 10% in some surveys. (Bharti et al. 2016, Jentes et al.2013, Wilde 
et al. 2013, c-Equine rabies immunoglobulin soon to be available 2016)  Shortages and 
unavailability are a risk for global PEP activities. The major clinical risks from HRIG 
administration are anaphylaxis at approximately 1/20,000 (Sandler et al.1995). The major risks 
from ERIG are immune complex disease at about 0.7% and anaphylaxis at a much lower rate 
(Wilde et al. 1989).  The known adverse reactions to RIG are not the major risks for animal 
products rather it is their unavailability.  When there is no ERIG, rabies death is the major risk.  
Thus the major reason for anti-rabies Mab development is to provide a robust supply chain to 
avoid deaths from unavailability.  
 
The availability of an alternate effective, well characterized humanized IgG therapy 
manufactured through a well-defined industrial process will ensure the availability of anti-rabies 
PEP and should be an objective of global anti-rabies efforts. This trial is proposed to further the 
licensure of SYN023 to provide an effective PEP alternative available to those exposed persons 
who need such a product.  
 
Rationale for HRIG as a control group 
A placebo controlled rabies trial is unethical thus HRIG is selected as the control group. Rabies 
immune globulin from equine and human sources (HRIG) have been evaluated in many trials 
and HRIG is the standard of care in the United States (Manning 2008).   
 
Rationale for 5 dose (Essen) dose regimen rather than the 4 dose regimen 
The sponsor has selected the 5 dose Essen regimen or rabies vaccination: Days, 0, 3, 7, 14 and 28 
(Study Days 1, 4, 8, 15, 29). This is the regimen in the current version of the package insert of 
the rabies vaccine selected for this trial. The sponsor is aware that the WHO and the American 
Committee on Immunization Practices have changed their recommendations to a 4 dose regimen: 
Days 0, 3, 7 and 14 (WHO Background Paper 2017, Rupprecht et al. 2010). A recent survey has 
summarized the heterogeneity of pre-exposure prophylaxis (PEP) recommendations (Buchy 
2017). The 5 dose regimen remains the standard in rabies vaccine product information.  All of 
the regions where SYN023 will be studied in its development currently include or have included 
the 5 dose regimen in the recent past (Buchy 2017, Republic of the Philippines 2018, WHO 
Background Paper 2017). Synermore is confident that the 5 dose regimen is clinically and 
ethically acceptable for use in a clinical study in all jurisdictions.  Since analysis of multiple 
vaccine regimens is not an objective of the protocol the 5 dose regimen is selected to reduce 

 
 
 
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analytic difficulties when data is combined from different studies for biological licensing 
submissions.   
  
Rationale for the composite efficacy endpoint 
The primary objective is a composite endpoint with four elements to reflect the 
pharmacodynamics of administered SYN023/HRIG, the immune response to rabies vaccine and 
the occurrence of rabies, all important features of rabies prophylaxis.   
 
The first composite element is superiority of the geometric mean RVNA concentration in 
SYN023 recipients on Study Day 8.  RVNA was selected because it is a generally accepted 
correlate for rabies vaccine protection.  Animal and human studies suggest that tissue levels of 
RVNA may correlate with protection by neutralizing the rabies virus before the virus is taken up 
into peripheral nerves from where it gains fatal access to the central nervous system (Watson et 
al. 1981, Schumacher et al. 1989, Shankar et al. 1991).  The reason for HRIG injection in 
addition to vaccination is to provide immediate rabies neutralizing antibodies to prevent the entry 
of rabies virus into nervous tissue before rabies vaccination has elicited neutralizing antibodies 
through the natural immune response.  This practice in historical studies seems to have reduced 
infection from rabies compared to rabies exposed individuals receiving only vaccination. If it is 
possible to demonstrate quicker and higher concentrations in the blood of RVNA from SYN023, 
then this may be evidence of greater potency and perhaps effectiveness. It is logical that serum 
levels represent passive diffusion along a concentration gradient from sites of local infiltration 
where the local concentration is higher than serum concentration.  The pharmacodynamic 
variable Synermore selected to assess the prompt availability of RVNA for serum RVNA 
concentration (Synermore’s correlate of effectiveness) on Study Day 8 after which vaccine 
induced antibodies will have begun to predominate as a contributor to serum RVNA.  Synermore 
will demonstrate superiority of the GMC with an 80% power of observing a 10% margin of 
superiority with a p value ≤ 0.025 (Section 7.8.1). 
 
The second element of the endpoint is noninferiority of the Study Day 99 GMC of RVNA in 
SYN023 recipients compared to Study Day 99 GMC of RVNA in the HRIG recipients.  It is 
important that any immunoglobulin product administered be compatible with rabies vaccination 
and thus not significantly inhibit the immune response to rabies vaccination. When should this 
comparison of immunogenicity be performed and secondly what margin of non-inferiority 
should be employed?  It is Synermore’s position that assessment of rabies vaccine 
immunogenicity should be performed on or around Study Day 99.  This interval is over four 
times the half-lives of administered human IgG.  By Study Day 99 anti-rabies antibodies 
including SYN023 that were administered for prophylaxis will have dissipated.  Thus Study Day 
99 RVNA values will reflect the long term production of natural rabies antibodies from 
vaccination.  Synermore defines non-inferiority of a rabies vaccine response with a 20% margin 
of non-inferiority and equal number of SYN023 and HRIG subjects in HRIG (Section 7.8.2). 
The alpha value is taken to be ≤ 0.025. 
 

 
 
 
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The third element is the percentage of PEP recipients that have a serum RVNA concentration 
≥0.5 IU/mL on Study Day 99. This is the RVNA concentration that is generally recognized to 
reflect protection from rabies when subjects are vaccinated.  Achievement of RVNA ≥0.5 IU/mL 
should indicate that that the subject’s vaccination has elicited a protective immune response 
despite the geometric mean concentration, thus any differences are not clinically important.  
Synermore defines non-inferiority of the percentage of SYN023 subjects with serum RVNA 
concentration ≥0.5 IU/mL. with a 20% margin of non-inferiority and equal number of SYN023 
and HRIG subjects in HRIG (7.8.3). The alpha value is taken to be ≤ 0.025. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The fourth element of the endpoint is the absence of probable or confirmed cases of rabies in the 
SYN023 recipients (Section 3.9.1). There is no need to specify “suspected” cases of rabies since 
entry into the protocol requires exposure to a possibly rabid animal and this is the factor that 
makes a case “probable” as opposed to “suspected.” A possibly rabid animal has a “risk of 
rabies” according to national and local rabies policies and agreement with the research site.  It is 
likely that there will no cases of rabies in the per protocol population of either treatment arm 
therefore a non-inferiority test could not be done.  Synermore estimates the failure rate of 
properly administered PEP in adults to be between 1 in 1,000 and 1 in 10,000 (Hemachudha, 
1999, Hampson 2008, Quiambao, 2008, Quiambao 2009 Shantavasinkul et al. 2010, Wilde et al. 
2007).  A single case of rabies in a subject properly treated with PEP meeting the per-protocol 
conditions in a 160 (or 184) sample of adults would be an occurrence rate of 0.6% and would be 
evidence for a lack of effectiveness (7.8.4).   
 
Rationale for stratification 
Bites above the level of the shoulder in the head or neck will be stratified in a 1:1 ratio by 
treatment arm so that there are approximately equal numbers in each treatment arm since bites in 
the head or neck seem to have a much higher chance of rabies transmission than bites of the 
trunk or extremity (Sitthi-Amorn et al. 1987, Cleveland et al. 2002, Fe’vre et al. 2005, Tenzin et 
al. 2011). 
 
Rationale for extra-United States majority enrollment.  
Most of the treatment allocations are to geographical areas of high rabies transmission to 
evaluate protection from rabies. Since this product is intended as a global product the study will 
occur in more than one country to examine exposure to different strains. 
 
Rationale for per-protocol exclusion after randomization 
Subjects who are randomized may be excluded from the per protocol populations after 
randomization if important factors that affect rabies risk or efficacy endpoint elements are 
discovered. PEP must not be delayed but since protocol entry criteria for patients who fail to 
have confirmation of inclusion/exclusion criteria such as previous rabies vaccination may not be 
known at the time of consent and PEP there must be some mechanism for later exclusion.  All 
excluded subjects will be analyzed but not as part of the “per-protocol” population  
 

 
 
 
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 In Synermore’s experience about 2% to 5% of subjects may have evidence of unknown 
or unrecalled rabies vaccination. Their RVNA response may be much quicker and higher 
than in naïve patients.  Since the RVNA is a crucial efficacy element these subjects with 
a RVNA ≥ 0.1 IU that is taken to be evidence of previous vaccination must be analyzed 
differently.    
 Subjects will be excluded for conditions discovered after randomization that impair 
protection such as immunodeficiency.   
 Subjects will be excluded if excessive treatment delay (>54 hours) is discovered.   
 Subjects will be excluded if they receive or have received protocol prohibited treatments 
such as RIG that will confound analysis.   
 Subjects will be excluded if all of the bite wounds are discovered to have not been 
properly treated or injected.  
 Subjects will be excluded if bites are determined to be due to non-protocol listed animals  
 Subjects will be excluded if they leave the trial or their status is unknown.  
 
Rationale for bite, broken skin lick and broken skin scratch exposure injuries eligibility for trial 
Individuals with WHO Category III rabies exposures with some exceptions are eligible for the 
trial since they are considered WHO Category 3 exposures and RIG is indicated for these 
exposures.   WHO Category 3 exposures include single or multiple transdermal bites or scratches 
or licks on broken skin, mucous membrane saliva contamination and unprotected bat exposures.  
Depending on the protocol defined risk substratum all observed bites, broken skin scratches and 
broken skin licks unprotected bat contacts and saliva contamination of mouth nose and eyes are 
eligible for the trial.  
 
Rationale for bite-to-treatment interval 
The bite-to-treatment interval for the administration of RIG is recommended to be as soon as 
possible up to 7 days by the WHO (WHO 2013).  This judgment reflects the emergence of 
naturally produced antibodies at about 7 days.  A number of surveys report that rabies cases were 
rare when treatment was instituted within 2 to 3 days (Si et al.  2008, Quiambao et al. 2009).  
Animal studies suggest that rabies virus may enter nerves within hours (Watson et al. 1981).  
Rabies virus may gain access to the brain within approximately 30 hours from a jaw injection 
(Shankar et al. 1991). Anti-rabies Mabs can interrupt this process (Schumacher et al. 1989). It is 
difficult to pinpoint the exact interval from studies reporting days since the counting of days may 
use different conventions.  The interval chosen for this protocol is 48 hours plus 6 hours (54 
hours) that would permit PEP to start on the third day after the bite but more likely 48 hours 
from the bite assuming that most bites and their PEP will occur in the daytime.    
 
Rationale for blinding 
The pharmacy will be unblinded in this study because of the need to draw up the dose based on 
patient weight.  Since weights will be different the different volumes will not disclose identity 
and it will be necessary to visually blind the syringes with tubes because of slight differences in 
the appearance of the Study Drugs.  Nevertheless it will be difficult to have absolute blinding 

 
 
 
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with HRIG.  Synermore judges that since the elements of the endpoint are objective the 
importance of blinding weaknesses in this study is secondary to adequate objective controls. 
 
Rationale for NRG follow-up period 
When the exposure time is known the incubation period of most cases occurs between 46-189 
days (Noah et al.1998, Quiambao et al. 2009, Ren et al. 2015,)  Some rabies incubation periods 
are more than a year (Boland et al. 2014).  A six month follow-up will capture most cases but 
follow up for a year should capture almost all cases of rabies.  
 
Rationale for interval for avoidance of pregnancy 
SYN023 and HRIG are both immunoglobulins.  SYN023 is not detectable in the blood by Study 
Day 99. Study Day 121 will be over 5 half-lives from administration and SYN023 should be 
eliminated from the circulation thus prohibition of pregnancy for the rest of the trial cannot be 
based on SYN023 exposure. 
 
Rationale for route of administration 
Immune globulins are administered by direct injection into the wound or by subcutaneous or 
intramuscular injection when this is not possible. Direct injection into the wound has been 
associated with good outcomes whereas injection at remote sites has been associated with failure 
of PEP (Wilde et al. 1996, Wilde et al. 1992, Shantavsinkul et al. 2010, Hemachudha et al. 1999, 
Bharti et al. 2016) 
 
Rationale for SYN023 dose level 
The dose level was determined by pharmacokinetic studies that demonstrated generally accepted 
as adequate levels of RVNA persisting for at least a month and from compatibility studies with 
rabies vaccines that demonstrated RVNA levels ≥ 0.5 IU/mL in rabies vaccine recipients 
receiving 0.3 mg/kg of SYN023 after Study Day 15 and from in vitro neutralization studies of 
multiple strains of rabies virus.   
 
Rationale for photographic documentation of bite wounds 
Simple uncalibrated photographs of wounds have a utility in presenting the extent number and 
severity of a bite wound. They will be useful during analysis with discussing individual cases 
and understanding safety information. They must not delay the start of PEP and thus may be 
recorded either before or after treatment.  Interval photographs may record progress and healing. 
They will need to avoid recording the facial characteristics and a means must be provided for 
pixilation to avoid identification of the subject.   They need to be stored as a source document in 
a secure manner at the research site with encryption and an access roster. They will not be 
required for non-bite exposures. Specific consent for photography shall be obtained from the 
subject. 
 
 

 
 
 
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2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Objectives 
 
Primary Objective 
The primary objective is a composite endpoint with four elements: 
 To demonstrate that the geometric mean RVNA concentration for SYN023 recipients is 
superior to the geometric mean RVNA concentration for HRIG recipients on Study Day 8 
AND  
 To demonstrate that the Study Day 99 geometric mean RVNA concentration for SYN023 
recipients is not inferior to the geometric mean RVNA concentration for HRIG recipients 
AND 
 To demonstrate that the percentage of subjects with RVNA concentration ≥0.5 IU/mL on 
Study Day 99 in SYN023 recipients is not inferior to the percentage of recipients with 
RVNA concentration ≥0.5 IU/mL for HRIG 
AND 
 There are no probable or confirmed cases of rabies in SYN023 recipients. 
 
Secondary Objective(s) 
 To demonstrate that the geometric mean RVNA concentration for SYN023 is superior to 
the geometric mean RVNA concentration for HRIG on Study Day 4 
 To demonstrate that the geometric mean RVNA AUEC1-15 for SYN023 is superior to the 
geometric mean RVNA AUEC1-15 for HRIG 
 To describe the ratio of the geometric mean concentrations of RVNA at each time point 
in SYN023 recipients divided by the geometric mean concentrations of RVNA in HRIG 
recipients for LRG and NRG in the per-protocol and as-treated populations. 
 To describe the percentage of RVNA concentration ≥0.5 IU/mL at each time point for 
SYN023 and HRIG recipients for LRG and NRG in the per-protocol and as-treated 
populations.  
 To describe the pharmacokinetics of SYN023 using non-compartmental analysis. Vd, 
Cmax, Tmax, AUC1-t, AUC1-inf, t½, Cl, and λz will be calculated when possible in the LRG 
and NRG protocol and as treated populations. 
 To evaluate presence and effects of anti-SYN023 antibodies (anti-CTB011, anti-CTB012)  
 To evaluate the safety of SYN023 compared to HyperRab®  S/D  
 To describe any effect of increasing BMI on SYN023 and RVNA concentrations. 
 
2.2 
Design 
This is a Phase 2b, double blinded, randomized study of SYN023 compared to HyperRab® S/D 
(a licensed HRIG) for PEP of patients who have been confirmed to have met all 
inclusion/exclusion criteria for their treatment group. The desired indication is the prevention of 
rabies as part of PEP. The trial will be conducted in least two countries where rabies occurs. The 
trial will enroll sequentially two different risk substrata of WHO Category 3 rabies exposure.   

 
 
 
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2.2.1 
Low Risk Group (LRG) 
The Low Risk Group (LRG) is composed of subjects who meet the modified WHO Category 3  
protocol exposure criteria (Table 2.2-1 below and Sections 3.9.4 and 3.9.5). Inclusion is limited 
to bites to the foot, ankle, leg or trunk and licks to broken skin, scratches with, or to broken skin, 
unprotected bat exposure or mucous membrane contamination by saliva or neural tissue.  These 
exposures represent a lower rabies risk exposure within WHO Categories 3.  Bites to the head, 
neck or genitalia are excluded from LRG Initial Enrollment and LRG General Enrollment 
(Section 2.2.2 to Section 2.2.4). The purpose of the LRG is to obtain early safety, 
pharmacodynamic and pharmacokinetic information from field sites. Since it does not have the 
same rabies risk as the NRG it, will be analyzed separately for clinical rabies.    
 
Table 2.2-1 Exposure Characteristics of the Low Risk Group and Normal Risk 
Group   
 
Exposure Type 
LRG 
NRG 
Head and neck bite 
- 
+ 
Genitalia bite 
- 
+ 
Arms bite 
- 
+ 
Hands bite 
- 
+ 
Trunk bite 
+ 
+ 
Legs bite 
+ 
+ 
Ankles bite 
+ 
+ 
Foot bite 
+ 
+ 
Non-bite lick  
+ 
+ 
Non-bite scratch 
+ 
+ 
Non-bite bat contact 
+ 
+ 
Non-bite mucous membrane  
+ 
+ 
    
2.2.2 
Initial Enrollment in the LRG (20 Subjects) 
Safety and RVNA data through Study Day 29 from the initial 20 subjects of the LRG will be 
reviewed by the DSMB to confirm safety and the achievement of adequate RVNA levels ≥ 0.5 
IU/mL on Study Day 15 and 29 from standard, wound management, Study Drug administration 
and rabies vaccination before LRG general enrollment is permitted.  Subjects excluded for cause 
by the Per-protocol Adjudication Board (Section 3.2.8) will not be included in the RVNA per-
protocol analysis but will be included in as-treated population.  The initial 20 subjects in the 
LRG will be randomized on a 3:1 (SYN023 to HRIG) ratio.  The size of the initial LRG 
enrollment is arbitrary.  The initial LRG enrollment is not part of the sample size calculations for 
the primary objective.  

 
 
 
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2.2.3 
Advancement from Initial Enrollment LRG to General Enrollment LRG  
The DSMB will permit enrollment of the General LRG Enrollment group if safety from the as-
treated population and RVNA pharmacodynamic data from the per protocol population Study 
Days 8-29 from the initial LRG enrollment are found to be satisfactory by the DSMB (Section 
5.1.5.2). 
 
2.2.4 
General Enrollment LRG 
The LRG general enrollment of an additional 60 subjects will consist of low risk WHO Category 
3 exposures (Table 2.2-1, Section 3.9.4 and 3.9.5). Subjects General Enrollment LRG will be 
allocated with a 1:1 randomization to either SYN023 or HRIG treatment arms.   Bites to the head, 
neck or genitalia are not included in the LRG.  
 
2.2.5 
Advancement from LRG General Enrollment to the Normal Risk Group 
(NRG) 
If Study Day 99 efficacy (RVNA) and safety LRG data from the initial and general enrollment 
have been judged to be adequate by the DSMB and there are no cases of rabies in SYN023 
recipients by Study Day 183 then randomization into the NRG will be permitted (Section 
5.1.5.3).  It is presumed that a case of clinical rabies in the study population would become 
known to the DSMB promptly.  Clinical rabies follow-up of the LRG will be made available to 
the DSMB through 6+ months on all patients for consideration of NRG commencement.  The 12 
months of LRG follow-up will not have ended when NRG enrollment starts.  
 
2.2.6 
The Normal Risk Group (NRG) 
The NRG will consist of all WHO Category 3 exposure (Table 2.2-1, Sections 3.9.4 and 3.9.5).  
The NRG includes all rabies risks. It is powered to evaluate the primary and some secondary 
study objectives and to contribute to the pharmacokinetic and pharmacokinetic description of 
SYN023.  
 
2.2.7 
Enrollment of the NRG 
Subjects will be allocated with a 1:1 randomization to either SYN023 or HRIG treatment arms.   
Within the NRG group bites to the head, neck or genitalia that have the highest rabies risk will 
be stratified for each treatment arm in a 1:1 ratio. The DSMB will review the progress of 
pharmacodynamic and safety data during the NRG study period to avoid unnecessary risk or 
expense (Section 5.1.5.4). 
 
 

 
 
 
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2.3 
Study Trial Size 
Data from an initial subgroup of 20 subjects will be evaluated by the DSMB to ensure 
pharmacodynamic activity before the remainder of the LRG is enrolled. The size of this group 
was determined by non-statistical reasons (Table 2.3-1). 
 
Safety and pharmacodynamic data from the entire LRG will be reviewed by the DSMB to ensure 
safety and pharmacodynamic adequacy.  The size of the LRG is 80 subjects. Up to 45 LRG 
subjects will have received SYN023.  This number was judged adequate to give a preliminary 
assessment of Study Drug performance in the LRG. 
 
Three hundred and twenty patients are required in the per-protocol population to satisfy the 
efficacy elements of the AUEC-1-15 secondary endpoint. Synermore anticipates approximately 
15% (48 patients) of loss to follow-up and exclusions resulting in a total NRG size of 368.  Since 
PEP should not be delayed and some inclusion/exclusion criteria may not be known at the time 
of randomization some subjects may be excluded (but not replaced) from the per-protocol 
population by the Per-Protocol Adjudication Board if they are later discovered to have met an 
exclusion criterion.   
  
Randomization will be adjusted by the randomization center such that patients are 
proportionately distributed between the trial sites and patients with wounds of the head, neck or 
genitalia are stratified approximately equally into the treatment groups.   
 
Table 2.3-1 Enrollment by Risk Group and Treatment 
Group 
Enrollment 
Treatment 
Rabies Vaccination 
Number of 
subjects 
LRG 
initial 
HRIG 20 IU/kg  
Day 1,4,8,15,29 
5 
LRG 
initial 
SYN023  
0.3 mg/kg 
Day 1,4,8,15,29 
15 
LRG 
general 
HRIG 20 IU/kg  
Day 1,4,8,15,29 
30 
LRG 
general 
SYN023  
0.3 mg/kg 
Day 1,4,8,15,29 
30 
NRG 
general 
HRIG 20 IU/kg  
Day 1,4,8,15,29 
184 
NRG 
general 
SYN023  
0.3 mg/kg 
Day 1,4,8,15,29 
184 
Total required for initial LRG enrollment 
20 
Total required for general LRG enrollment 
60 
Total required for NRG enrollment 
368 
Total maximum enrollment 
448 
 
 

 
 
 
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2.4 
Study Duration and Follow-up 
Subjects will be followed for 365 days post receipt of Study Drug unless withdrawn from the 
trial.  It is important to have follow-up information on all study enrollees for the full duration of 
the study. Every effort should be made to remain in contact with study subjects in at least six-
week intervals to establish if the subject is in good health and to inquire about planned 
relocations. If health problems have occurred a verbal or written account of the duration and 
character of the difficulties should be obtained.  This is specially important in the last six months 
of the study when clinic visits are less frequent.  
 
2.5 
Study Populations 
2.5.1 
Failure to Meet Inclusion/exclusion Criteria at Initial Screening 
Screening includes informed consent, satisfaction of inclusion criteria and an initial survey of 
exclusion criteria.  Rabies exposed subjects that are known to fail inclusion criteria at initial 
screening or any immediately evaluable exclusion criteria will not be randomized into the study. 
They will be treated outside of the study protocol with the national standard of care for PEP. The 
minimum PEP standard will include ERIG or HRIG and rabies vaccination according to the 
national recommendations. Not all exclusion criteria need to be known at the time of 
randomization but those that are known will determine enrollment. 
 
2.5.2 
As-Treated Population 
All subjects who are randomized and receive Study Drug are included in the “as-treated” 
population. 
 
2.5.3 
LRG Per-Protocol Population 
Since PEP of rabies is urgent and should not be delayed, randomization and prophylaxis will 
begin after a screening event that includes informed consent and survey of inclusion criteria 
(including urine pregnancy test results) before some exclusion criteria have been confirmed.  
WHO Category 3 exposure victims that meet all initially knowable inclusion/exclusion criteria 
(Section 3.2.3 – 3.2.5) will be randomized receive wound treatment, receive Study Drug and 
begin a regimen of rabies vaccination.    
 
2.5.4 
NRG Per-Protocol Population 
Since PEP of rabies is urgent and should not be delayed, randomization and prophylaxis will 
begin after a screening event that includes informed consent and survey of inclusion criteria 
(including urine pregnancy test) before some exclusion criteria have been confirmed.  WHO 
Category 3 exposure victims that meet all initially knowable inclusion/exclusion criteria will be 
randomized receive Study Drug and begin a regimen of rabies vaccination.   
 

 
 
 
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2.6 
Randomization 
2.6.1 
LRG Initial Enrollment Randomization 
Subjects in the initial enrollment group will be randomized on a 3:1 basis to treatment with 
SYN023 or HRIG.  Eligibility for the LRG subjects is described in Section 2.2.1.  The group as 
described in Table 2.3.1 is randomized in a 3:1 ratio.   Subjects in the initial LRG may be 
excluded from LRG the per-protocol population but they will not be replaced. 
 
2.6.2 
LRG General Enrollment and NRG Randomization 
Subjects in the general enrollment of LRG and NRG will be randomized on a 1:1 basis within 
each group to treatment with SYN023 or HRIG.  Subjects will be allocated to treatment sites to 
approximate the ratio in Table 2.3-1. Within NRG enrollment subjects with head or neck bites or 
bites to genitalia will be stratified on a 1:1 basis into SYN023 or HRIG treatment groups.    
 
Study sites wishing to randomize a subject will contact the study randomization center either 
telephonically or by electronic means.  The study center will determine the randomization 
allocation and return the randomization assignment in written communication to the study site.  
 
2.7 
Non-Replacement of Randomized Patients 
Subjects will not be replaced after randomization. They may be excluded from the per-protocol 
population 
 
2.8 
Adjustments to Randomization 
Allocation of randomization among sites will be adjusted to accommodate stratification of head, 
neck or genitalia bites or site enrollment imbalances. 
  
 
3 
STUDY PROCEDURES 
3.1 
Schedule of Subject Evaluations 
A Summary Schedule of Evaluations depicting all visit-specific procedures is provided in Table 
3-1.  A more detailed description of the tasks and evaluations by Study Day is supplied in the 
Appendix.  A table of phlebotomy volumes by visit may be found in Appendix C.  
 

 
 
 
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Table 3-1 
Summary Schedule of Subject Evaluations LRG Group 
Study Visit Day  
1 
4 
8 
15 
29 
43 
71 
99 
127 
155 
183 
274 
365 
Visit window (days) 
0 
0 
0 
0 
2 
4 
7 
7 
7 
7 
14 
14 
14 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria verification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine HCG (all females) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C a 
4 
 
 
 
 
 
 
 
 
 
 
 
 
HIV a 
5 
 
 
 
 
 
 
 
 
 
 
 
5 
CBC, platelets a 
2 
2 
 
2 
 
2 
 
 
 
 
 
 
 
Urinalysis a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry a, c 
4 
4 
 
4 
 
4 
 
 
 
 
 
 
 
PT(INR), PTT a 
2 
 
 
 
 
2 
 
 
 
 
 
 
 
Bite wound washing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Interval history 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Focused physical examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Wound photographs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Wound 
Injection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rabies Vaccination 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Serum RVNA 
10a 
10b 
10b 
10b 
10b 
10 
10 
10 
10 
10 
10 
10 
10 
Confirmation visit 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Anti-SYN023 serum assay  
5a 
 
 
5 
5 
 
 
5 
 
 
 
 
 
SYN023 concentration  
5a  
5b 
5b  
5b 
5b 
5  
 
5 
 
 
 
 
 
Adverse events (incl. con. 
Meds.) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Solicited adverse events 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Serious adverse events (incl. 
con. Meds.) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Site of injection examination 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Per visit phlebotomy volume 
37 
21 
15 
26 
20 
23 
10 
20 
10 
10 
10 
10 
15 
Cumulative phlebotomy 
volume 
37 
58 
73 
99 
119 
142 
152 
172 
182 
192 
202 
212 
227 
a. 
Study Day 1 samples must be obtained before Study Drug administration 
b. Samples must be obtained before vaccination. 
c. 
Serum chemistries are total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, potassium, 
chloride, bicarbonate, calcium. 
d. Numbers in lab specimen rows indicate approximate blood volume in mL. 
 

 
 
 
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Table 3-2 
Summary Schedule of Subject Evaluations NRG Group 
Study Visit Day  
1 
4 
8 
15 
29 
43 
71 
99 
127 
155 
183 
274 
365 
Visit window (days) 
0 
0 
0 
0 
2 
4 
7 
7 
7 
7 
14 
14 
14 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria verification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine HCG (all females) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C a 
4 
 
 
 
 
 
 
 
 
 
 
 
 
HIV a 
5 
 
 
 
 
 
 
 
 
 
 
 
5 
CBC, platelets a 
2 
2 
 
2 
 
2 
 
 
 
 
 
 
 
Urinalysis a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry a, c 
4 
4 
 
4 
 
4 
 
 
 
 
 
 
 
PT(INR), PTT a 
2 
 
 
 
 
2 
 
 
 
 
 
 
 
Bite wound washing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Interval history 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Focused physical examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Wound photographs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Wound 
Injection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rabies Vaccination 
X 
X  
X 
X 
X  
 
 
 
 
 
 
 
 
Serum RVNA a 
10a 
10b 
10b 
10 b 
10 b 
10 
10 
10 
10 
10 
10 
10 
10 
Confirmation visit 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Anti-SYN023 serum assay  
5a 
 
 
5b 
 
 
 
5 
 
 
 
 
 
SYN023 concentration  
5a  
5b 
5b 
5 b 
 
 
 
5 
 
 
 
 
 
Adverse events (incl. con. 
Meds.) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Solicited adverse events 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Serious adverse events (incl. 
con. Meds.) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Site of injection examination 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Per visit phlebotomy volume 
37 
21 
15 
26 
10 
18 
10 
20 
10 
10 
10 
10 
15 
Cumulative phlebotomy 
volume 
37 
58 
73 
99 
109 
127 
137 
157 
167 
177 
187 
197 
212 
 
a. 
Study Day 1 samples must be obtained before Study Drug administration 
b. Samples must be obtained before vaccination. 
c. 
Serum chemistries are total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, potassium, 
chloride, bicarbonate, calcium. 
d. Numbers in lab specimen rows indicate approximate blood volume in mL. May differ from actual. 
 
 
3.2 
Subject Selection 
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 

 
 
 
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form approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
and signed and dated by the subjects at the time of consent.  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 subjects on the day of study entry. 
 
3.2.2 
Screening 
After informed consent is obtained, a unique screening number will be assigned to each subject 
for identification purposes, and 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.  Screening log will record name, birth date, sex, 
ethnicity and race. 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. 
  
Eligibility for entry into the study will be based on the inclusion and exclusion criteria described 
below.  Results of the urine pregnancy test must be known before enrollment. The investigator 
must document confirmation of eligibility prior to randomization 
 
3.2.3 
LRG Inclusion Criteria  
Subjects must meet all of the following criteria at the time of subject ID assignment: 
1. History of dog, cat, mongoose, fox, ferret, skunk, bat or raccoon bite to trunk, leg, ankle or 
foot, or lick or scratch with, or of broken skin or mucous membrane saliva or neural tissue 
contamination, unprotected physical bat contact, scratch or saliva contamination of the head 
or neck without broken skin all ≤ 54 hours (Section 3.9.4 and 3.9.5) 
2. Has completed the written informed consent process and signed informed consent document 
3. Males and females 
4. Is age 18 years on Study Day 1 
5. Agrees to stay in contact with the study site for the duration of the study, provide updated 
contact information as necessary, and has no current plans to move from the study area for 
the duration of the study 
6. Lives within 2 hour journey by available transportation to study center 
7. For female subjects:  agrees to avoid pregnancy from Study Day 1 through Study Day 121.  
Women physically capable of pregnancy (not sterilized and still menstruating or within 1 
year of the last menses if menopausal) in sexual relationships with men must use an 
acceptable method of avoiding pregnancy during this period.  Acceptable methods of 
avoiding pregnancy include a sterile sexual partner, sexual abstinence (not engaging in 
sexual intercourse), hormonal contraceptives (oral, injection, transdermal patch, or implant), 
vaginal ring, intrauterine device (IUD), or the combination of a condom or diaphragm with 
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3.2.4 
NRG Inclusion Criteria  
Subjects must meet all of the following criteria at the time of subject ID assignment: 
1. History of dog, cat, mongoose, fox, ferret, skunk, bat or raccoon bite to any body part, lick or 
scratch with, or of broken skin, mucous membrane saliva or neural tissue contamination, or 
unprotected physical bat contact all ≤ 54 hours from PEP (Section 3.9.4 and 3.9.5) 
2. Has completed the written informed consent process and signed informed consent document. 
3. Males and females 
4. Is age 18 years on Study Day 1 
5. Agrees to stay in contact with the study site for the duration of the study, provide updated 
contact information as necessary, and has no current plans to move from the study area for 
the duration of the study 
6. Lives within 2 hour journey by available transportation to study center 
7. For female subjects:  agrees to avoid pregnancy from agrees to avoid pregnancy from Study 
Day 1 through Study Day 121.  Women physically capable of pregnancy (not sterilized and 
still menstruating or within 1 year of the last menses if menopausal) in sexual relationships 
with men must use an acceptable method of avoiding pregnancy during this period.  
Acceptable methods of avoiding pregnancy include a sterile sexual partner, sexual abstinence 
(not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal 
patch, or implant), vaginal ring, intrauterine device (IUD), or the combination of a condom or 
diaphragm with spermicide 
 
3.2.5 
Exclusion Criteria LRG and NRG  
Subjects must have had none of the following at the time of subject ID assignment: 
1. Clinical evidence of rabies infection 
2. Category 3 exposure  > 54 hours before Study Drug receipt 
3. History or serological evidence of previous rabies vaccination  
4. Previous receipt of equine or human rabies globulin 
5. History of hypersensitivity reaction to equine or human immunoglobulin. 
6. Received immunoglobulin or blood products within 42 days before Study Day 1 
7. Received any investigational drug therapy or investigational vaccine within 60 days 
before Study Day 1  
8. Planned participation in any other investigational study during the study period. 
9. Receiving systemic immunosuppressant medication such as systemic corticosteroids but 
not limited to systemic corticosteroids 
10. History or laboratory evidence of any past, present, or possible immunodeficiency state 
including but not limited to any laboratory indication of HIV infection 
11. Previous medical history that may compromise the safety of the subject in the study 
according to the opinion of the principal investigator 
12. History or evidence on physical examination of any systemic disease or any acute or 
chronic illness that, in the opinion of the investigator, may interfere with the evaluation of 
the safety or activity of SYN023 
13. Pregnancy (results of the urine pregnancy test MUST be known before enrollment) 

 
 
 
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3.2.6 
Major Protocol Deviations and Eligibility for the Per-protocol 
Population  
Continuation in the per-protocol population depends on the absence of uncorrectable major 
protocol deviations. Major deviations are those that would degrade the fidelity of the data from 
the protocol.  Protocol deviations requiring removal from the per-protocol population include but 
are not limited to those listed below.  
 
 Defective informed consent  
 Received the incorrect Study Drug 
 Received the incorrect dose (± 20%) of Study Drug 
 Failed to complete the scheduled rabies vaccinations through Study Day 29 
 Are discovered to lack adequate prophylactic treatment of all exposure sites  
 Are discovered to be injured by animal other than those listed 
 Are discovered to have an interval > 54 hours from rabies exposure to the start of 
prophylaxis 
 Are discovered to have RVNA ≥ 0.1 IU in serum obtained at Study Day 1 
 Receives prohibited treatment during the trial 
 Are found not to have a modified WHO Category 3 exposure (Table 2.2-1, Section 3.9.4)  
 Are discovered to have or have developed HIV infection or other immunodeficiency state. 
 Second high risk animal bite or contact requiring PEP 
 
Subjects who are discovered to not have satisfied any criteria for the per-protocol population 
may be excluded from that population (Section 3.2.8). These deviations may become known at 
different intervals from randomization.  Likely intervals for discovery of these deviations are 
listed in Table 3.2.6-1 based on the occurrence of site review, monitoring visits and vaccination 
schedules. 
 
Table 3.2.6-1 Intervals for Per-protocol Exclusions (approximate) 
Major Protocol Deviation 
Rationale 
Likely 
Interval 
Days 
Defective consent 
Data without effective consent 
cannot be used 
43 
Diagnosis of HIV after enrollment 
New HIV may affect PEP response 
365 
Received incorrect study drug 
Mixes SYN023 and HIRG results 
43 
Incorrect dose (± 20%) of Study Drug 
Arbitrary but reasonable dose 
margin. Used for biosimilars.  
43 
> 54 hr from rabies exposure to the Study Drug 
Early PEP initiation is important 
Should be discovered early from 
wound state and investigation 
15 
Failed to complete all rabies vaccinations 
Important feature of PEP. Should 
be known by Study Day 29 
29 

 
 
 
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Failure to treat all exposure sites  
Documented cause of treatment 
failure. Should be discovered early 
from wound state and investigation 
15 
Exposure from animal not in inclusion criteria 
Some not animals don’t transmit 
rabies. Should be discovered early 
from wound state and investigation 
15 
Serum RVNA ≥ 0.1 IU at Study Day 1 
Indicates previous Rabies 
vaccination. Results from central 
reference laboratory needs 
shipment, processing and return of 
results 
43 
Receives prohibited treatment during the trial 
Has potential to increase or 
decrease vaccine protection.  Will 
turn up in monitoring visit 
365 
Are found not to have a modified WHO 
Category 3 exposure (Table 2.2-1, Section 
3.9.4)  
Different rabies risks.  Should turn 
up in local investigation or 
monitoring 
15 
Second high risk animal bite or contact 
requiring PEP 
Subjects should have same rabies 
risk. Should turn up in monitoring.  
365 
 
 
3.2.6.1 Pregnancy During Study 
Results of the urine pregnancy test MUST be known before enrollment.  Subjects who have a 
positive pregnancy test on Study Day 1 should not be enrolled since this is an exclusion criteria.  
If a subject becomes pregnant during the study, she will continue in the study. She will not be 
withdrawn from the per-protocol population by the Per Protocol Adjudication Board unless she 
declines phlebotomy.  If she wishes to withdraw study consent she should be asked to complete 
follow-up visits without phlebotomy.  Follow-up should continue for pregnancy outcome 
including premature terminations, and data are to be included in the safety reports.  
 
3.2.7 
Screening Clinical Assessments and Laboratory Tests 
Subjects will provide a detailed medical history and will undergo a physical examination.  
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. Subjects who are discovered to have newly diagnosed HIV will 
undergo formal counseling and referral. 
 
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.   
 

 
 
 
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Screening laboratory tests will be collected on Study Day 1.  Results from these laboratory tests 
will serve as study-entry baseline values.  Findings that might later make the subject ineligible 
such HIV status will be discussed with the subject and the subject will be referred for follow-up 
care with their healthcare provider if necessary.  Urine Pregnancy test results MUST be known 
before randomization. 
 
The study has inclusion and exclusion criteria that are required for entry on the study. Those that 
are knowable on Study Day 1 prior to study entry will determine eligibility for randomization.  
Since the results of all of the screening assessments may not be known at the time of 
randomization subjects may be found to be ineligible for the per protocol population after 
randomization. For example an individual may be found to have serological evidence of previous 
rabies immunization when the RVNA results are returned. This subject may continue on the trial 
but will be excluded from the per protocol population.  
 
3.2.7.1 Window Period for Screening Laboratory Tests 
There is no window for screening laboratory evaluations.  These must be collected on Study Day 
1.  Because of the necessity for prompt anti-rabies care the results may be known and eligibility 
confirmed after study entry and randomization.  This means that some subjects may be found to 
be ineligible for the study or the per protocol population after randomization. 
 
3.2.8 
Per-protocol Adjudication Board (exclusion from the per-protocol 
population) 
Since all inclusion/exclusion criteria are not able to be known at the time of study randomization 
the per-protocol status of some randomized subjects may need to be changed based on review of 
blinded screening information that becomes available at a later time. The Sponsor will create the 
Per-protocol Adjudication Board whose duty will be to review screening data, management 
information and initial determination of eligibility for the per-protocol population. The Per-
protocol Adjudication Board will review blinded data and will not be able to unblind subjects or 
data.  Based on inclusion/exclusion criteria, the protocol deviation and the impact of the 
deviation on protocol data, the Per-protocol Adjudication Board may exclude randomized 
subjects from the per-protocol population.  Its judgments will be forwarded to the DSMB and the 
study enrollment center for the adjustment of randomization to maintain stratification and 
distribution of cases at the different sites.  The subjects excluded from the per-protocol 
population will continue on the study in the “as-treated” population unless they withdraw 
consent. The Sponsor will maintain a roster of its actions and the reasoning behind them. 
 
3.3 
Study Randomization  
Subjects will be randomized to the study by and IVRS/IWRS. The procedure for randomization 
will require CRO contract before completion. Since a CRO has not been contracted this 
information is not yet available for this version.   

 
 
 
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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 1. 
 
3.4 
Blinding 
3.4.1 
Blinding at the Study Level 
The LRG and the NRG are both blinded until Study Day 365. If the last subject in LRG reaches 
Study Day 365 even if the NRG is still in progress, then the LRG group may be unblinded. The 
LRG may be unblinded to the extent recommended or required by the DSMB for analysis of 
safety or efficacy data for Study Day 99 DSMB review. The NRG group will remain blinded 
until Study Day 365.  The DSMB will conduct unblinded analyses before Study day 365 as 
specified by the protocol and inform the sponsor of the overall results of those analyses.  The 
purpose of these analyses is to permit advancement of the study risk groups and to inform the 
sponsor so that product development decisions can be made.  Since investigational agent will 
have been administered to the NRG, blinded specimens for analysis collected and individual 
treatment assignments still unknown to the sponsor for the NRG, this should not affect the 
conduct of the trial during the observation period required for clinical rabies surveillance. 
 
The NRG is powered for the efficacy outcomes of the study. The smaller LRG’s purpose is 
primarily pharmacodynamic and pharmacokinetic. The LRG will remain blinded for safety and 
clinical efficacy through Study Day 365.  The sponsor will know without blinding that there are 
no rabies cases but the rabies risk in the LRG is much lower than from the NRG so the clinical 
efficacy results from the LRG do not mean the same thing.  The DSMB must give permission for 
advancement to the NRG. The combined LRG and NRG study will take years to complete 
without information for Synermore. The sponsor will be able to infer meager pharmacodynamic 
characteristics from the progress of the blinded study. The LRG pharmacodynamic and 
pharmacokinetic data will help in planning and maintaining support for SYN023 development.  
Once this cohort has final data there is no reason to continue to blind the LRG study cohort since 
its efficacy results are objective, separately analyzed and cannot affect the efficacy conclusions 
from the NRG.     
 
3.4.2 
Blinding at the Site Level 
The site’s investigational pharmacist or product manager (or designee) will need to be unblinded 
in order to manage Study Drug inventory and prepare doses.  Other unblinded persons on the 
study are the unblinded study monitor that will need to audit Study Drug stocks 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 investigational pharmacist or product manager must be a designated study team member 
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responsibilities associated with the conduct of the study during the entire study period.  
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.     
 
Labels accompanying the syringes of prepared Study Drug will not indicate which Study Drug is 
in the syringe but will only contain the study identification and subject ID number.  Identical 
syringes and needles will be used for preparation and administration of each Study Drug.   
 
3.4.3 
Individual 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 to 
the investigational pharmacist or product  manager for urgent unblinding of a subject’s treatment.  
The request must include the subject ID number, the date, a brief justification of the clinical 
requirement to the Study Drug 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 investigational pharmacist or product manager 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 
Clinical Evaluation, Photography, Decontamination and Treatment of 
Wounds 
The correct management of rabies bite wounds in animals has as much influence on the 
development of rabies as vaccination and wound immunoglobulins (Dean et al. 1963).  
Regardless of the risk for rabies, the optimal medical treatment of animal bite wounds includes 
the evaluation and treatment of serious nerve, tendon and vascular lacerations.  Avoidance of 
infection through wound debridement and irrigation will yield the best possible cosmetic results. 
Care should be taken not to damage skin or tissues (Manning et al. 2008).  Immediate gentle 
irrigation with at least 200 mL of sterile water or normal saline with either commercially 
available wound cleansing solutions, mild soap or povidone-iodine (10%) diluted to 1-2% 
concentration in water.  Gentle cleaning of the wound with gauze may be required.   Irrigation 
should involve gentle cleaning with irrigation fluid expressed through 20 to 21 gauge plastic 
catheter tip from a 30 to 50 mL syringe.  The tip of the catheter should be held approximately 2 
cm from the wound surface. (Gouin et al. 2001, Singer et al. 2008).  Eye protection and splash 
guards should be employed for protection of medical staff.    Puncture wounds should be gently 
cleaned with cotton swabs and irrigation solution.  Wound cleansing is especially important in 
rabies prevention because wound cleansing alone without other PEP markedly reduces the 
likelihood of rabies in animal studies (Kaplan et al. 1962, Dean et al. 1963).  

 
 
 
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Local anesthetics may be employed to assist in wound management. 
Complete primary wound closure should be avoided with delayed closure employed when 
necessary.  Partial closure may be individualized on the basis of wound size and location of the 
wound(s), and time interval since the bite with delayed closure at a later time.   Suturing should 
be avoided when possible. When wounds require some closure (such as suturing) this should 
occur only after administration of Study Drug.  
Decisions regarding the use of antibiotic prophylaxis and management of infection (both local 
and systemic) should be individualized based on the wound and the biting animal. 
If the subject has received the primary tetanus immunization series and has not received a tetanus 
booster within 10 years (or five years for severely contaminated bite wound) a tetanus vaccine 
booster immunization should be given. Tetanus immunization should be begun if the subject has 
not received a primary tetanus vaccination series. 
Uncalibrated photographs of all wounds should be recorded if possible within 48 hours of PEP 
start.  The photograph should record the date and the subject number but no other personal 
identification.  The photos with facial characteristics should be pixilated before permanent 
storage to avoid identification. All photos will be stored in a locked secure location at the 
research site and if stored electronically should be encrypted and access limited by an access 
roster. The photographs are for medical use only and may not be used commercially.  
 
3.6 
Decontamination of Mucous Membranes 
Mucous membranes of the eyes nose and mouth may be decontaminated by copious irrigation 
with potable water or sterile saline.  
 
3.7 
Study Drug Infiltration for Bite and Non-bite Exposures 
After decontamination and before wound dressing the wound surface itself should be injected 
with the calculated dose of Study Drug through a 25 gauge needle or similar of approximately 
2.5 to 3 cm in length.  Study drug should be injected through the skin subcutaneously as if local 
anesthesia were being administered creating a wheal of fluid within a centimeter of the wound 
margin.  After creation of the first wheal the needle should be withdrawn with the tip remaining 
in the injection hole and the needle redirected to accomplish infiltration of a different axis.  If the 
wound involves muscle tissue, injection of the muscle should be performed. If the wound surface 
has been thoroughly injected and there is remaining Study Drug it should be injected 
subcutaneously as close to the wound as anatomically possible.   
 
Care should be taken to avoid intravenous or intra-arterial injection by aspiration and looking for 
blood return before infiltration.  Remove the needle and re-insert it in a new location and repeat 
the aspiration step before administering. All bite injuries and breaks in the skin related to bites 
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compartments should be done with a volume appropriate to the anatomic volume to avoid 
compartment syndrome.  Study drug should be administered within 45 minutes of when the dose 
is constituted.  Study drug volume may be expanded with dilution of normal saline if the extent 
of the wound area to be injected is large and may require extra injection volume. All Study Drug 
must be injected.  Subjects must be observed for at least 60 minutes after the end of Study Drug 
administration. 
 
For the non-bite exposures the calculated doses of Study drug should be administered 
intramuscularly as above without regard to proximity to exposure. 
 
3.7.1 
Human Rabies Immune Globulin (HyperRab® S/D)   
There are two dosage forms of HRIG that may be used in the study a presently available 150 
IU/mL preparation and a newly available 300 IU/mL preparation.  All stocks of 150 IU/mL 
HRIG (HyperRab) should be used at a study site before the study site can switch to the 300 
IU/mL preparation.  Once a study site has switched to the 300 IU/mL preparation it cannot again 
use the 150 IU/mL.   
 
The dose of HRIG (HyperRab) 20 IU/kg should be calculated based on body weight. The dose 
for the 150 IU/mL potency preparation is 0.133 mL/kg. The dose for the 300 IU/mL potency is 
0.0665 mL/kg.    
 
The calculated dose should be administered into the wound whether in subcutaneous tissue or 
muscle. For example, a 70 kg person receiving the 150 IU/mL potency has a calculated dose of 
9.31 mL. The entire calculated dose must be given.  If the fluid volume of the injection needs to 
be increased to enable all sites to be injected the pharmacy may dilute the calculated dose with 
saline when the syringe is prepared. Doses up to 3 mL may be given in at a single injection site 
(Hopkins et al. 2013).  
 
Care must be taken NOT to administer a rabies vaccine near the Study Drug administration site.  
 
3.7.2 
SYN023 
After thorough wound sanitation, injections of the entire calculated dose of SYN023 should be 
administered into and around all the bite wounds on Study Day 1. The dose of SYN023 should 
be calculated based on body weight: 0.3 mg/kg.  For example, a 70 kg person has a calculated 
dose of 21 mg.  The entire calculated dose should be given. Doses up to 3 mL may be given at a 
single injection site. Care must be taken NOT to administer a rabies vaccine near the Study Drug 
administration site.   
 

 
 
 
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3.8 
Rabies Vaccine (RabAvert® or Rabipur®) Administration 
Rabies Vaccine (RabAvert® or Rabipur®) must be administered in a different area from the Study 
Drug infiltration to reduce interference. The 1 mL dose of the chicken fibroblast rabies vaccine 
should be administered in deltoid muscle. If not possible, then vaccination may be administered 
in the vastus lateralis (thigh) or rectus femoris (thigh). Five doses of the rabies vaccine should be 
administered on Study Days 1, 4, 8, 15 and 29. The rabies vaccine should be administered as 
soon as possible after dose constitution. Rabies vaccination should be administered within 75 
minutes after Study Drug. 
 
 
 
3.9 
Study Efficacy Evaluations 
3.9.1 
Clinical Efficacy Evaluations  
The absence of a confirmed or probable case of rabies in the per-protocol population is part of 
the composite endpoint.  Subject will be periodically evaluated for the clinical signs and 
symptoms of human rabies. If these develop they will be referred for medical evaluation and 
laboratory or anatomic confirmation. All clinical rabies diagnostic tests may be performed 
locally at a qualified laboratory. All rabies cases will be reviewed by the DSMB. 
 
Human Rabies Clinical Case Definition:  
A person presenting with an acute neurological syndrome (encephalitis) dominated by 
forms of hyperactivity (furious rabies) or paralytic syndromes (dumb rabies) progressing 
towards coma and death, usually by respiratory failure, within 7-10 days after the first 
symptom if no intensive care is instituted.   
 
A subject who is alive and not hospitalized is presumed not to have rabies.  Contact with 
a non-hospitalized subject on any date is evidence that rabies has not occurred on that 
date. If a subject is discharged from hospital rabies has not occurred. 
 
Case Classification Human Rabies  
 Suspected: A case that is compatible with the clinical case definition 
 Probable: A suspected case (above) plus history of contact with a suspected rabid animal.  
 Confirmed: A suspected case that is laboratory-confirmed.  
 
Rabies Laboratory Diagnosis Confirmation Criteria 
One or more of the following:  
 Rabies viral isolation from clinical specimens 
 RVNA in the CSF 
 Detection of rabies viral RNA by RT/PCR in clinical specimens, saliva,  
 Detection of rabies by FAT on skin biopsy such as from neck (ante mortem).  
 Detection of rabies by FAT preferably brain tissue (collected post mortem).   

 
 
 
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 Detection of rabies by FAT after inoculation of brain tissue, saliva or CSF in cell culture, 
or after intracerebral inoculation in mice or in suckling mice.  
 Detection of viral nucleic acids by PCR on tissue collected before or after death in a 
clinical specimen (brain tissue or skin, cornea, urine, saliva or other).  
 
3.9.2 
Pharmacodynamic Efficacy Evaluations  
The serum RVNA ≥ 0.5 IU/mL for the 365 day trial duration is the pharmacodynamic efficacy 
parameter. These specimens will be collected and forwarded to the study laboratory at the 
University of Kansas. These measurements will be used to calculate both superiority for Study 
Day 8 GMC RVNA and non-inferiority for Study Day 99 GMC RVNA and % population 
RVNA ≥ 0.5 IU/mL. A missing RVNA datapoint or RVNA data point less than 0.5 IU/mL 
preceded and followed by RVNA concentrations ≥ 0.5 IU/mL will be considered to be in the 
protective range. 
 
3.9.2.1 The Window Interval for Collection of Efficacy Evaluation Specimens 
The time window for collection of efficacy evaluation specimens is listed in Table 3-1 and 3-2. 
 
3.9.3 
Efficacy: Confirmation of Anti-rabies Activity in the Initial Enrollment 
LRG 
This study includes the first administration of SYN023 in the setting of animal exposures.   All 
subjects should have a WHO Category 3 rabies exposure (Section 3.9.4). The first twenty 
subjects in the LRG (the Initial Randomization) will have serum RVNA concentrations (Section 
3.9.5) reviewed through Study Day 29. The DSMB will ensure that RVNA concentrations are 
≥0.5 IU/mL on the Study Day 15 visit in all subjects before the remainder of the site’s subjects 
are enrolled. Enrollment will be paused at the site until this review is completed.   
 
3.9.4 
Modified WHO Rabies Risk Exposure Categories 
In countries or areas enzootic for rabies, exposure to suspected or confirmed rabid (domestic or 
wild) animals is categorized as follows (WHO 2013): 
 
Category I: touching or feeding animals, licks on intact skin, contact of intact skin with 
secretions or excretions of a rabid animal or human. These are not regarded as exposures, and no 
PEP is required. 
 
Category II: nibbling of uncovered skin, minor scratches or abrasions without bleeding. Vaccine 
should be administered as soon as possible. 
 
Category III: single or multiple transdermal bites OR scratches to broken skin OR licks 

 
 
 
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on broken skin OR contamination of mucous membrane with saliva or neural tissue from licks or 
exposure to bats. Vaccine and rabies immune globulin should be administered as soon as 
possible.   
 
For this protocol “exposure to bats” means a subject with unprotected (e.g. without gloves or 
other similar barriers) physical contact with a bat.  Mucous membrane contamination means the 
transfer of saliva or neural tissue from the suspect animal into the eyes, nose or mouth of the 
victim.  
 
3.9.5 
WHO Category III Rabies Risk Substrata   
Within the WHO Category III four additional risk sub-strata based on the probability of rabies 
development by bitten or exposed body part have been described (Sitthi-Amorn et al.  1987, 
Cleveland et.al. 2003, Fe’vre et al., 2005, Knobel et al. 2005, Tenzin et al. 2011). These sub-
strata are listed in Table 3.9-1.  These Category III substrata also serve as the basis for selection 
of an initial cohort.  Bites to the head, neck, arms, hands and genitalia are considered the highest 
risk from empirical and enervation density estimates. These highest risk espouses are excluded 
from the LRG.  The LRG is enrolled into the trial to confirm pharmacokinetics and 
pharmacodynamics in a field setting by DSMB before enrollment of the NRG.  This is the basis 
for restriction of enrollment by bite or exposure location for the LRG Initial Enrollment (Section 
2.6.1) and also the basis for stratification by bite or exposure location in the NRG (Section 2.6.2) 
randomization.   
 
Table 3.9-1 Relative Probability of Rabies by Bite Location 
Bite Location 
Risk Estimate 
1= highest 
Probability 
(mode) 
Maximum/ 
minimum 
Head and neck  
1 
0.45 
0.6/ 0.3 
Genitalia 
1 
n/a 
n/a 
Arms 
2 
0.28 
0.4/ 0.15 
Hands 
2 
n/a 
n/a 
Trunk 
3 
0.05 
0.1/ 0.0 
Legs  
3 
0.05 
0.1/ 0.0 
Ankles 
3 
n/a 
n/a 
Foot 
3 
n/a 
n/a 
Non-bite lick  
4 
n/a 
n/a 
Non-bite scratch 
4 
n/a 
n/a 
Non-bite bat physical 
contact 
5 
n/a 
n/a 
Non-bite Mucous 
membrane contamination 
with saliva or neural tissue  
5 
n/a 
n/a 
n/a: not available 
 

 
 
 
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For this protocol bites to the foot and ankle are considered to be in the same risk stratum as bites 
to the leg. The absolute risk is unknown for the following categories of exposure but they are 
held to be lower than the bite risk to the lower extremity: 
 non-bite exposure of broken skin to licks by suspect animal  
 non-bite exposure by scratch to broken skin or that breaks the skin by suspect animal 
 non-bite mucous membrane contact with saliva or neural tissue from a suspect animal  
 non-bite unprotected physical bat exposure. 
 
3.10 
Immunology Laboratory Evaluations  
A summary of immunological laboratory evaluations is presented in Table 3.10-1.  
 
Table 3.10-1 Summary of Immunology Laboratory Evaluations 
 
Sample 
Type 
Assay 
Purpose of Assay 
 
Serum 
SYN023 concentration (CTB011 and 
CTB012) 
Pharmacokinetics 
Serum 
Rabies virus neutralizing activity 
(RVNA) by RFFIT 
Rabies neutralizing antibody 
concentration from Study Drug and 
vaccination, surrogate of protection  
Serum 
Anti-SYN023 antibodies (CTB011 and 
CTB012) 
Effect on safety and efficacy analysis 
 
3.11 
Virology Laboratory Evaluations  
Biting animal specimens when available from brain, skin or blood will be evaluated locally for 
rabies diagnosis. 
 
3.12 
Safety Evaluations 
3.12.1 Adverse Event Reporting Intervals 
The collection periods for adverse events are: 
Unsolicited adverse events: Through Study Day 43 
Solicited adverse events: 
Through Study Day 8 
Serious adverse events: 
Entire study period (i.e., 365 days) 
For this study, solicited adverse events to be collected are listed in section 5.7 Solicited Adverse 
Events. 
 

 
 
 
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3.12.2 Pre-Study Drug and Post-Study Drug Monitoring of Subjects 
Hypersensitivity reactions are a potential adverse effect both Study Drugs administered in this 
protocol. Allergic reactions to vaccination are also 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 Study Drug and 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 
antiarrhythmics and pressors.  Appropriate equipment includes devices for blood pressure 
monitoring, oximetry, maintenance of airway and intratracheal intubation and, removal of 
secretions and cardiac defibrillation. 
 
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 60 minutes after receiving 
rabies vaccination that is administered after Study Drug.  Vital signs and oximetry will be 
repeated every 30 minutes during and at the end of the monitoring period before subjects leave 
the clinic.   
 
Electrocardiograms are performed as a baseline to monitor subject safety (Table 3-1 and 3-2).  
Laboratory evaluations for subject safety are clinical chemistry evaluations, CBC, platelet counts 
and differential counts, PT (INR) and PTT and urinalyses. Please refer to Table 3-1 and 3-2 for a 
list of laboratory tests for monitoring of safety.  Window intervals for specimen collection are 
also listed in Table 3-1 and 3-2.  
 
3.12.3 Clinical Assessments and Laboratory Tests 
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. 
 
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 B for toxicity grading scales) from pre-vaccination 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 

 
 
 
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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.   
 
3.12.4 Concomitant Medications and Prohibited Medications 
The collection of information on concomitant medications used by subjects following Study 
Drug administration will coincide with the collection period of adverse events.  The collection 
period for concomitant medications associated with the treatment of adverse events will be 42 
days following the last Study Drug.  The collection period for concomitant medications 
associated with the treatment of serious adverse events (SAE) will be Study Days 1-365. The 
collection period for prohibited medications will be Study Days 1-365.   
 
Concomitant medication includes prescription and non-prescription drugs or other treatments, 
and any vaccines other than rabies or tetanus vaccines specified by the protocol.  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. 
 
Prohibited medications include any vaccination or immunoglobulin directed against rabies.  
Systemic corticosteroids or other immunosuppressants administered within 29 days of first rabies 
vaccination are prohibited.  
 
3.12.5 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 clinic, medical records will, to the extent possible, be obtained by the 
investigator.   
 
During each clinic visit, subjects 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) 

 
 
 
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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. 
 
3.12.6 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 365 
visit date, then a determination of “lost to follow-up” can be made. 
 
3.13 
Pharmacokinetic Evaluations LRG and NRG 
Pharmacokinetic evaluations (Sections 2.1 “secondary objectives” and Table 3-1) on samples 
obtained on all subjects will be performed on SYN023 recipients in the LRG and compared to 
pharmacodynamic activity over time. 
 
Pharmacokinetic evaluations (Sections 2.1 “secondary objectives” and Table 3-2) will be 
obtained at selected time points from all NRG subjects but will be performed only on SYN023 
recipients and compared to pharmacodynamic activity. 
 
3.14 
Preservation of Clinical and Veterinary Materials 
On some cases there may be diagnostic clinical and veterinary materials available.  Every effort 
should be made to preserve these materials for review by investigators at the end of the trial.  
 
 
4 
STUDY DRUGS 
There are three substances administered as part of this study.  There are two Study Drugs 
SYN023 and HRIG ( HyperRab® S/D Grifols) and rabies vaccines RabAvert® or Rabipur® that 
are used in rabies PEP.   SYN023 is investigational agent that has been administered previously 
to human subjects and tolerated in a Phase 1 and Phase 2 trials.  HyperRab® S/D is an HRIG that 
is licensed in the US and commercially available for PEP. RabAvert® is a rabies vaccine licensed 
in the US. Rabipur® is the same GSK rabies vaccine licensed in the Philippines. 
 
4.1 
SYN023 
SYN023 will be supplied by Synermore Biologics. 

 
 
 
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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. 
 
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 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 
HRIG (HyperRab® S/D) 
HRIG (HyperRab® S/D, Grifols Therapeutics) will be supplied by 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.  HRIG 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. HRIG liquid will be 
stored at 2-8° C in a secured location. HRIG 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. 
 

 
 
 
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4.2.2 
HRIG Preparations 
There are two HRIG preparations that may be used in this trial (Section 3.7): the 150IU/mL 
preparation is packaged in 2 mL and 10 mL single dose vials. HRIG 300IU/mL is packaged in 1 
and 5 mL single dose vials.  After cleaning of the vial top with an alcohol swab, the proper dose 
of HRIG is withdrawn slowly from the vial with a 21 gauge needle to avoid foaming. Study drug 
should be inspected for particulate matter and discarded if present. If more than one vial of 
HRIG is required the dose may be accumulated from a second vial. HRIG must be allowed to sit 
at room-temperature for at least 15 minutes before intramuscular administration to allow the 
HRIG to warm before administration. A constituted HRIG 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. 
 
4.2.3 
Disposal of Unused Supplies 
Upon completion of the study, the sponsor must provide authorization for any unused HRIG 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 
Study Rabies Vaccine U.S. (RabAvert®)  
RabAvert® will be supplied by the sponsor. 
 
4.3.1 
Receipt and Storage 
Upon receipt of Study Drug supplies, the Study Drug manager must immediately inspect all vials 
of Study Drug for damage.  The RabAvert® 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 vaccine 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 
Rabies Vaccine (RabAvert®) Preparation 
 
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.  
 

 
 
 
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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. A constituted dose of rabies vaccine 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.  
 
4.3.3 
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. 
 
4.4 
Study Rabies Vaccine Philippines (Rabipur®) 
Study Drug will be supplied by the sponsor 
 
4.4.1 
Receipt and Storage 
Upon receipt of Study Drug supplies, the Study Drug manager must immediately inspect all vials 
of vaccine for damage.  The Rabipur® 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 vaccine 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 
Rabies Vaccine (Rabipur®) Preparation 
 
Rabipur® 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 

 
 
 
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syringe. Remove the reconstitution needle and discard. Attach a sterile needle of your choice that 
is suitable for intramuscular injection of the subject. A constituted dose of rabies vaccine 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 will provide for disposal of unused supplies 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 
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 SYN023 sponsor, Synermore, the institution 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 an active control, or the 
investigational product.  

 
 
 
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5.1.2 
Study Sponsor 
The sponsor (Synermore) also has an institutional responsibility to ensure subject safety.  This 
responsibility is vested in two medical monitors (one local medical monitor and one global 
medical monitor) and a DSMB. 
 
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, like the principal investigator, is blinded for a blinded study.  
 
5.1.4 
Global Medical Monitor 
The purpose of the global medical monitor is to permit SUSAR (suspected unexpected serious 
adverse reaction, see Section 5.10) reporting to regulatory agencies (that generally do not permit 
placebo or control “suspect drugs” in their safety databases) without unblinding the sponsor 
personnel or the clinical sites in a systematic way.  The sponsor will retain a global medical 
monitor through the contract research organization PPD.  The global medical monitor reviews 
and unblinds all SUSAR reports and, if he or she deems it necessary, may review and unblind 
selected SAE reports.  If the global medical monitor suspects that there is an unrecognized 
pattern in reported SUSARs and SAEs, then the global medical monitor will notify the local 
medical monitor who will convene the DSMB (this committee is normally responsible for 
unblinded SAE review).  If the SUSAR is reported for the active investigational study agent, the 
report is forwarded to the MedWatch database, or other regulatory databases. If the SUSAR is 
reported for an active control medicinal product, then it is reported to the manufacturer.  For all 
SUSARS the global medical monitor will make available to the sponsor and the clinical 
trial sites a completed CIOMS II form with the suspect drug absent or blacked out so that 
the sites and the sponsor may remain blinded. 
 
5.1.5 
Data and Safety Monitoring Committee (DSMB) 
The study will have a DSMB composed of a physician chairman/chairwoman, three member 
physicians and a DSMB statistician all of which may vote.  At least one physician should be an 
Infectious Disease or rabies expert. The voting members will not be directly involved with the 
conduct of the study.  Voting members will not be employees of the sponsor. Additional non-
voting subject area experts may be present at meeting to provide expertise if requested by the 
DSMB. The DSMB will operate according to its charter. 
 
The DSMB will have five responsibilities 

 
 
 
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1. Review of Study Drug pharmacodynamic activity in the Initial Enrollment of the LRG 
subjects and granting permission for general LRG enrollment (5.1.5.2). 
2. Review of safety and pharmacodynamics through Study Day 99 in the initial and general 
enrollment groups of the LRG (5.1.5.3) 
3. Review of Study Drug safety after 80 subjects have reached Study Day 9 (5.1.5.4)  
4. Review and confirmation of any possible rabies cases in trial participants. 
5. Management of safety issues during the trial. 
 
The DSMB will not determine exclusions from the per protocol population.  Exclusions from the 
per protocol population are determined by the Per Protocol Adjudication Board.  The DSMB 
may request review of any case by this board. 
 
5.1.5.1 DSMB Confirmation of Rabies Cases in the Trial 
A confirmed or probable case of rabies is an element of the composite endpoint for the trial 
(Section 3.9.1).  If a case of rabies occurs in the SYN023 treatment group of the per protocol 
population in the trial it will result in the failure of the primary objective and the cessation of 
Study Drug administration in the trial. The DSMB will review and confirm a rabies diagnosis in 
any study participant and determine if trial enrollment or Study Drug administration should be 
stopped.  The DSMB may require additional subjects in the Initial Enrollment. 
 
5.1.5.2 DSMB Evaluation of Safety and Pharmacodynamic Activity in the Initial 
Enrollment LRG 
The sponsor will collect blinded RVNA results and adverse events through Study Day 29 from 
the subjects in the LRG initial enrollment group and provide this information to the DSMB.  
Permission to enroll the General Enrollment of the LRG may be granted if  
 no protocol stopping rules are met (Section 6.3) and if  
 no severe related adverse events other than local injection site manifestations are 
encountered due to SYN023 in the initial enrollment of the LRG  
 the serum RVNA values are all in the protective range (≥ 0.5 IU/mL Section 3.9.2) on 
Study Days, 8 through 29 in the SYN023 recipients.    
 
The DSMB will issue a written determination permitting enrollment of the general enrollment 
group of the LRG and inform the sponsor of this determination.  It is acknowledged that some 
HRIG recipients may not have achieved ≥ 0.5 IU/mL RVNA by Study Day 8. 
 
5.1.5.3 DSMB Review of Safety and Pharmacodynamic Activity in the Initial and 
General Enrollment LRG 
The sponsor will collect blinded RVNA results and adverse events through Study Day 99 from 
all subjects in the LRG General and Initial enrollment groups and provide them to the DSMB.  
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 no protocol stopping rules are met (Section 6.3) and if  
 no severe related adverse events other than local injection site manifestations are 
encountered due to SYN023 in the initial and general enrollment of the LRG  
 The RVNA values are in the protective range in ≥ 75% of SYN023 recipients on Study 
Day 99 (Section 3.9.2). 
 
5.1.5.4 DSMB Review of Safety in the NRG 
The DSMB will assess the safety (while enrollment continues) after 80 subjects have completed 
Study Day 99.  If there are no adverse events or patterns of concern it will issue permission for 
the trial to continue. 
 
5.1.5.5 DSMB Management of Safety Issues in the Trial 
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, the DSMB will be 
convened.  The DSMB may review an individual SAE or it may choose to review adverse events, 
serious adverse events, solicited adverse events, and laboratory and vital signs data.  The DSMB 
may request unblinding any amount of safety information needed to conduct its safety 
assessment.  Only the DSMB 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 DSMB minutes.  
 
Based on its review and the protocol stopping rules (Section 6) the DSMB will make 
recommendations in the DSMB minutes to the sponsor regarding further conduct of the study, 
changes to the study protocol and further administration of Study Drugs.  The conclusions of the 
DSMB 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 DSMB and any directives issued by the national regulatory authority, the Institutional Review 
Board or Ethics Committee.   
 
If Study Drug administration is paused by the medical monitor or the global medical monitor, the 
DSMB will be convened.  Based on its review and the protocol stopping rules (Section 6) the 
DSMB will make recommendations in the DSMB minutes to the sponsor regarding further 
conduct of the study and further administration of Study Drug.  The DSMB may review an 
individual SAE or it may choose to review adverse events, serious adverse events, solicited 
adverse events, and laboratory and vital signs data.  The DSMB may unblind any amount of 
safety information needed to conduct their assessment.  All procedures associated with this 
review, including objectives, data handling, and elements to be included for review will be 
documented in DSMB minutes.  The conclusions of the DSMB will be communicated to the 
investigators and the IRB/Ethical Committees and the national regulatory authorities.  The 

 
 
 
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sponsor agrees to abide by the decision of its DSMB and any directives issued by the national 
regulatory authorities, the Institutional Review Boards or Ethics Committees. 
 
5.1.6 
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.   
 
5.1.7 
National Regulatory Authority 
Since the national regulatory authority (such as the US FDA for the 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 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.  
 
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 relative to 
the subject’s pretreatment baseline, whether or not it is considered to be related to the medicinal 
product.  All adverse events will be assessed for severity, causal relationship, expectedness and 
seriousness (below). 
 
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. 
 
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 1 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 

 
 
 
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the Toxicity Table (see protocol appendices), adverse changes in the general condition of the 
subject, signs and symptoms noted by the subject, 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 Section 3.12.1.  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 (SAER) 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 
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:  

 
 
 
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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 local medical monitor) will 
determine a causal relationship, to the Study Drug without knowledge, for blinded studies, of 
whether SYN023 or active control, HRIG was administered.  A number of factors will be 
considered in making this assessment, including:  1) the temporal relationship of the event to 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). 

 
 
 
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 
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 1 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 1 but may represent an adverse 
event if the intensity or duration of the event is worse than usual following Study Drug. 
 
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.  
 

 
 
 
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5.7 
Solicited Adverse Events 
Local Study Drug injection will be made in the immediate area of an animal bite.  Since the 
trauma and wound management will create confounding local findings they will not be solicited 
in this trial. The reporting period during which solicited adverse events will be evaluated is 
specified in Section 3.12.1.  The non-local symptoms that will be solicited include:  
 headache,  
 arthralgia, 
 myalgia,  
 rash,  
 pruritus,  
 urticaria,  
 dyspnea,  
 chest pain,  
 cough,  
 fever 
 chills  
 
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 

 
 
 
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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 
adverse reaction) and is subject to expedited reporting.  SUSARs may occur for marketed 
products such as HRIG if a reaction is not described in the product labeling. SUSARS for 
marketed products should be reported to the manufacturer of the product who has an obligation 
to notify the National Regulatory Authority through periodic pharmacovigilance.  
 
5.11 
Reporting of Serious Adverse Events 
Serious adverse events, which include SUSARs, are reported to the sponsor and to the 
pharmacovigilance (PVG) for the entire study period (see protocol appendix A). 
  
Pharmacovigilance (PVG), PPD Global Ltd. 
24 Hour Safety Hotline: +44 122 337 4240 
24 Hour Safety Hotline Fax: +44 122 337 4102  
EMEAASIASafetyCentral.SM@ppdi.com  
 
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 

 
 
 
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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 the Pharmacovigilance (PVG) at PPD 
(Appendix A).  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 local medical monitor immediately upon the 
investigator’s awareness of the event.  If the local 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 pharmacovigilance (PVG) 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  
 
The sponsor has authorized the PPD to be the pharmacovigilance (PVG) 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 DSMB of all SUSARs within 3 working days of becoming aware of 
an event and will provide all follow-up information in a timely manner. 
 

 
 
 
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5.12 
Immediately Reportable Events 
These are events that might affect randomization or analysis. The investigator must report the 
following events by faxing the appropriate form to the local 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 applied measures 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 1, 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. 
 
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. 

 
 
 
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5.14 
Pregnancy Safety Reporting  
Pregnancy is not an adverse event. 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. Follow-up should continue for pregnancy outcome including 
premature terminations, and data are to be included in the safety reports.  
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 Study 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. (Section 3.2.6.1 Pregnancy During The Study) 
 
5.15 
Immunological Adverse Events 
Adverse events that have a potential immunological cause should be investigated as safety risks.  
Blood tests such as anti-SYN023 antibodies and others as clinically indicated should be drawn to 
help understand the mechanism of the event. 
 
5.16 
Recognition of Anaphylaxis 
When the diagnosis of anaphylaxis is considered the following laboratory 
tests should be obtained: plasma tryptase, plasma histamine and urinary N-
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 
 

 
 
 
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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 subject (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 subject 
(minutes to several hours): 
 
o Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
 
5.17 
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 
necessary by the clinician.  Epinephrine may be administered subcutaneously or intramuscularly. 
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 receptor antagonists, 

 
 
 
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corticosteroids, and glucagon for individuals on β adrenergic blocking agents. (Sampson et al. 
2006) 
 
5.18 
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 complement 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 be observed.  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). 
 
 
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 
DSMB Efficacy Pausing Rules 
6.1.1 
Confirmation of Initial LRG Pharmacodynamic activity 
If the RVNA is found to be not adequate in the SYN023 initial LRG enrollment population then 
general LRG enrollment at that site will not be permitted by the DSMB until this has been 
resolved (Section 5.1.5.2). 
 
6.1.2 
Confirmation of Rabies in Trial Participants 
Any laboratory confirmed or clinically suspected case of rabies occurs in the blinded trial the 
administration of Study Drug will be paused for DSMB confirmation of rabies diagnosis and 
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unblinding of that case is considered. If a confirmed case of rabies occurs in the per-protocol 
unblinded SYN023 treated group the DSMB will issue a written communication permanently 
stopping enrollment and Study Drug administration.   A rabies case will not be reported as an 
adverse event since it is an element of the primary objective. 
 
6.2 
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 an adverse event pattern of grave 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 DSMB.  If additional clinical information becomes available during 
this pausing  process that reduces the principal investigator’s or local medical monitor’s 
assessment of causality, severity or toxicity grade such that study pausing is no longer required 
by pausing rules, in other word if the PI or medical monitor recognizes their pausing of the study 
was in error, then the principal investigator, with the agreement of the medical monitor, and 
DSMB chairman/chairwoman may resume Study Drug administration, record this in a 
memorandum to the study file, and notify the sponsor. 
 
Since the global medical monitor is unblinded and 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 grave 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 DSMB.  
 
6.3 
Safety Stopping Rules 
The DSMB must make a determination of relationship of death (or other below) to the Study 
Drug before determining a need for unblinding to discover if the subject was a SYN023 recipient.  
The rules for stopping further enrollment and Study Drug administration by the DSMB are below: 
 
Death in any subject unless the DSMB determines it is UNRELATED to a SYN023 adverse 
event. 
 
A life-threatening adverse event in any subject unless the DSMB determines it is 
UNRELATED to SYN023 

 
 
 
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 
A pattern of significant symptoms, physical findings or laboratory abnormalities (adverse 
events) that, although individually minor, collectively represent a grave safety concern in the 
opinion of the investigator or the medical monitor and are judged by the DSMB to be 
DEFINITELY, PROBABLY or POSSIBLY related to SYN023 
 
The DSMB may recommend resumption of Study Drug administration if the study pause was for 
reasons less severe than those in the DSMB stopping rules.  The DSMB 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 DSMB must follow the study safety stopping rules.  
 
If a decision to resume study enrollment and Study Drug administration is made the DSMB will 
record their judgment in a memorandum to the study file and notify the sponsor.  The DSMB 
memorandum will be forwarded to the medical monitors and principal investigators.  The clinical 
site will be allowed to resume activities upon receipt of written notification from the sponsor.   
 
The appropriate regulatory authority will be informed in writing when: 
1. The study is stopped  
2. The decision is made by the DSMB to 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 7.9). 
 
7.1 
Subject Populations 
 
As-Treated Population (Safety Population) 
Since post-exposure treatment of rabies is urgent and should not be delayed, randomization and 
prophylaxis will begin after a screening event that includes informed consent, urine pregnancy 
test and survey of inclusion criteria before some exclusion criteria have been confirmed.  High- 
risk rabies exposure victims that meet all initially knowable inclusion/exclusion criteria will be 
randomized receive Study Drug and begin a regimen of rabies vaccination.   All subjects who are 
randomized and receive Study Drug are included in the “as-treated” population.  
 
LRG Per-Protocol Population (Initial Enrollment) 
The LRG initial enrollment group is described in all subjects who   
1) are randomized as part of the initial enrollment group  
2) receive the correct Study Drug 

 
 
 
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3) have inclusion/exclusion criteria confirmed  
4) complete the rabies vaccinations schedule by Study Day 29 
6) lack major protocol deviations 
7) have adequate wound treatment and Study Drug injection of all exposure sites   
 
will be included in the “per-protocol” population. Exclusion criteria that must be confirmed are 
the species of the biting animal; a high risk exposure (WHO Category 3);  interval ≤ 54 hours 
from the bite to the start of prophylaxis; the absence of RVNA ≥ 0.1 IU  in serum obtained at 
Study Day 1, time “0” blood collection (WHO, 2013). Subjects who are discovered to not have 
satisfied criteria for the per-protocol population may be excluded from that population by the 
Per-protocol Adjudication Board.  
 
LRG Per-Protocol Population (General Enrollment) 
All subjects who   
1) are randomized as part of the LRG general enrollment 
2) receive the correct Study Drug 
3) have inclusion/exclusion criteria confirmed  
4) complete the rabies vaccinations schedule by Study Day 29 
6) lack major protocol deviations 
7) have adequate wound treatment and Study Drug injection of all exposure sites   
 
will be included in the “per-protocol” population. Exclusion criteria that must be confirmed are 
the species of the biting animal; a high risk exposure (WHO Category 3);  interval ≤ 54 hours 
from the bite to the start of prophylaxis; the absence of RVNA ≥ 0.1 IU  in serum obtained at 
Study Day 1, time “0” blood collection (WHO, 2013). Subjects who are discovered to not have 
satisfied criteria for the per-protocol population may be excluded from that population by the 
Per-protocol Adjudication Board.  
 
NRG Per-Protocol Population 
All subjects who  
1) are randomized to the NRG 
2) receive the correct Study Drug 
3) have inclusion/exclusion criteria confirmed  
4) complete the rabies vaccinations schedule by Study Day 29 
6) lack major protocol deviations 
7) have adequate wound treatment and Study Drug injection of all exposure sites  
8) are not part of the LRG enrollment  
 
will be included in the “per-protocol” population.  Initial exclusion criteria that must be 
confirmed are the nature of the exposure including the species of the animal; a high risk exposure 
(WHO Category 3);  interval ≤ 54 hours from the bite to the start of prophylaxis; the absence of 
RVNA ≥ 0.1 IU  in serum obtained at Study Day 1, time “0” blood collection (WHO, 2013). 

 
 
 
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Subjects who are discovered to not have satisfied criteria for the per-protocol population may be 
excluded from that population by the Per-protocol Adjudication Board.  
 
7.2 
Demographics and Protocol Compliance 
Demographic parameters (age, gender, and race/ethnicity) and other baseline characteristics will 
be summarized by treatment group for all subjects in the safety population. 
 
Subject enrollment to each study group will be conducted based on timing of completion of 
study eligibility requirements.  Randomization will be adjusted by the randomization center to 
maintain stratification and site allocation. Any resulting imbalance in baseline characteristics 
between study groups will be examined.  
 
Listings of randomized subjects who missed any dose of Study Drug or rabies vaccine and of 
subjects with protocol deviations (to be defined in the statistical analysis plan) will be provided. 
 
7.3 
Primary Objective: Efficacy Analyses 
The primary objective is a composite endpoint with four elements in three areas:  
 the geometric mean RVNA concentration for SYN023 recipients is superior to the 
geometric mean RVNA concentration for HRIG recipients on Study Day 8 
 the immune response to rabies vaccine on Study Day 99: RVNA GMT noninferiority 
SYN023 vs HRIG 
 the response to rabies vaccine on Study Day 99: RVNA ≥ 0.5 IU/mL % noninferiority 
SYN023 vs HRIG  
 the absence of clinical rabies.   
 
A similar analyses will be performed for both the per-protocol and the as-treated population for 
sensitivity analysis. 
 The first element is superiority of the geometric mean SYN023 on study Day 8 in serum.  
RVNA was selected because it is a generally accepted surrogate for rabies vaccine 
protection.  Animal and human studies suggest that tissue levels of RVNA may correlate 
with protection by neutralizing the rabies virus before the virus is taken up into peripheral 
nerves from where it gains fatal access to the central nervous system even in the presence 
of neutralizing antibodies (Watson et al. 1981, Schumacher et al. 1989, Shankar et al. 
1991).  It is logical that serum levels represent passive diffusion along a concentration 
gradient from sites of local infiltration.  Tissue RVNA concentrations are likely higher 
than serum RVNA concentrations. The reason for HRIG injection in addition to 
vaccination is to provide immediate rabies neutralizing antibodies in tissues to prevent 
the entry of rabies virus into nervous tissue before rabies vaccination has elicited 
neutralizing antibodies.  This practice in historical studies seems to have reduced 
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If it is possible to demonstrate quicker and higher concentrations in the blood of RVNA 
from SYN023 then this may be evidence of greater potency and perhaps effectiveness.  
 
The pharmacodynamic variable Synermore selected to assess the prompt availability of 
RVNA is the area under the curve for serum RVNA concentration (Synermore’s correlate 
of effectiveness) from Study Day 1 through Study Day 15 when vaccine antibodies will 
have begun to predominate. Synermore will demonstrate superiority of the AUEC1-8 with 
an 80% power of observing a 10% margin of superiority with a p value ≤ 0.025. 
 
 The second element is immune response to the rabies vaccine on Study Day 99 measured 
by the noninferiority of the Study Day 99 geometric mean concentrations of RVNA in 
SYN023 recipients compared to Study Day 99 geometric mean concentrations of RVNA 
in the HRIG recipients.  It is important that any immunoglobulin product administered be 
compatible with rabies vaccination and not significantly inhibit the immune response to 
rabies vaccination. When should this comparison of immunogenicity be performed and 
secondly what margin of non-inferiority should be employed? It is Synermore’s position 
that assessment of rabies vaccine immunogenicity should be performed on or around 
Study Day 99.  This interval is over four half-lives of human IgG. Anti-rabies antibodies 
administered for prophylaxis will have largely dissipated and Study Day 99 GMC RVNA 
values will reflect the long term immunogenicity of rabies vaccination.  Synermore 
defines non-inferiority rabies vaccine response of the as a 20% margin of non-inferiority 
and equal allowance (number of subjects in SYN023 = number of subjects in HRIG) and 
alpha is taken to be ≤0.025. 
 
 The third element is immune response to the rabies vaccine on Study Day 99 measured 
by the noninferiority percent of the study population RVNA ≥ 0.5 IU/mL SYN023 vs 
HRIG. This approach assesses the noninferiority of the percent of subjects who have a 
serum RVNA concentration that is generally recognized as protective, the more important 
measure of vaccine compatibility. 
 
 The fourth element is the absence of probable or confirmed cases of clinical rabies in the 
SYN023 recipients (Section 3.9.1). There is no need to specify “suspected” cases of 
rabies since entry into the protocol requires exposure to a possibly rabid animal and this 
is the factor that makes a case “probable” as opposed to “suspected.” It is likely that there 
will no cases of rabies in the per protocol population of either treatment arm therefore a 
non-inferiority test could not be done.  Synermore estimates the failure rate of properly 
administered PEP in adults to be between 1 in 1000 and 1 in 10,000 (Hemachudha et al. 
1999, Hampson et al. 2008, Quiambao et al. 2008, Quiambao et al. 2009 Shantavasinkul 
et al. 2010, Wilde et al. 2007).  A single case of rabies in a subject properly treated with 
PEP meeting the per-protocol conditions in a 160 subject sample of adults would be an 
occurrence rate of 0.63% and the 95% confidence interval extends from 0 to 2%.  This 
rate of failure would be evidence for a lack of effectiveness.   
 
 

 
 
 
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7.4 
Secondary Objectives: Clinical and Pharmacodynamic Efficacy. 
To demonstrate that the proportion of SYN023 recipients with blood RVNA concentrations that 
meet the generally accepted as adequate threshold  ≥ 0.5 IU/mL, for Study Days 8-99 in the per-
protocol population is not inferior to the same proportion in HRIG recipients.  A similar analysis 
will be performed for the as-treated population for sensitivity analysis. 
 
To demonstrate that SYN023 administered within 54 hours of rabies exposure with rabies 
vaccinations prevents all probable or confirmed clinical rabies cases. 
 
To describe the ratio of the geometric mean concentrations of RVNA at each time point in 
SYN023 recipients divided by the geometric mean concentrations of RVNA in HRIG recipients 
for the per-protocol and as-treated populations for each risk group. 
 
To describe ant effect of increasing BMI on RVNA concentrations. 
 
7.5 
Secondary Objective Pharmacokinetic Analysis  
To describe the pharmacokinetics of SYN023 in enrollees using non compartmental analysis, Vd, 
Cmax, Tmax, AUC0-t, AUC0-inf, t½, Cl, and λz will be calculated when possible in the per-protocol 
and as treated populations.   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. Vd, Cmax, Tmax, AUC0-t, AUC0-inf, t½, Cl, and λz will 
be calculated when possible in the per-protocol and as treated populations.   
 
7.6 
Secondary Objective: Immunogenicity Anti-SYN023 Antibodies  
All immunogenicity analyses will be based on per-protocol and as-treated subjects for each risk 
group who received at least one dose of Study Drug.  The presence and effect of anti-SYN023 
antibodies (anti-CTB011, anti-CTB012) will be evaluated.  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.  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.  Any effect of anti-SYN023 antibodies on 
pharmacokinetics, pharmacodynamics or safety will be described. 
 
7.7 
Secondary Objective Safety Analyses 
Safety analyses will be performed using the safety population as defined in Section 7.1.  
Summaries will be presented by risk group and treatment group for all subjects in the safety 
population. The safety profile of Study Drug will be described by treatment group.  The primary 
variable for evaluation of the safety profile will be the number and percentage of adverse events 

 
 
 
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recorded at all available post- Study Drug administration time points.  For all presentations of 
adverse events, additional summaries based on reporting period of adverse events following each 
Study Drug administration 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 PT at the greatest severity or most related state 
recorded for that term.   
 
Separate summaries of the number (percentage) of subjects with adverse events will also be 
presented.  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.   
 
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- Study Drug administration clinical laboratory 
values or vital sign values recorded as newly abnormal or increased by a toxicity grade following 
Study Drug administration and meeting toxicity mild criteria (Grade 1) or above as specified in 
the Toxicity Table  will be tabulated at each post- Study Drug administration 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. 
 
The sample size of 190 subjects per treatment group will also permit an initial estimate of 
general safety and tolerability.  An approximation to the upper 95% confidence bound on the true 
rate of occurrence for a Study Drug-associated adverse event not encountered in 190 subjects is 
1.6%. 
 
7.7.1 
Adverse Events 
The safety profile of the Study Drugs 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 Drug 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 

 
 
 
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number (percentage) of subjects with adverse events by severity and by relationship to Study 
Drug; each subject will be counted once per PT 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 PT 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 
criteria (Grade 1) or above as specified in the Toxicity Table (Appendix B) 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. 
 
7.7.2 
Clinical Laboratory and Vital Sign Parameters 
For each clinical laboratory parameter and vital sign parameter pre-specified in the protocol, 
summary statistics for continuous parameters will be presented by treatment regimen for all pre- 
and post-vaccination assessments and for change from pre-vaccination to post-vaccination 
assessments. 
 
7.8 
Sample Size Considerations Primary Objective: Composite Endpoint 
Element 
Since the primary objective is composite multiple endpoints will be determined.  Each endpoint 
will have different requirements on the Study sample size determination. The contribution of 
various endpoints to sample size is tabulated in Table 7.8-1.  The specific analyses are discussed 
in Sections 7.81 - . 
 
Table 7.8-1 Sample Size Estimates for Pharmacodynamic Endpoints (all 80% 
power, alpha ≤0.025) 

 
 
 
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7.8.1 
Superiority of Geometric Mean of RVNA Study Day 8 
 
Superiority test for the ratio of two geometric means is used for determining the sample size. The 
null hypothesis is that the ratio for the two treatments is less than the defined margin that is 
expressed as: 
 
 
Where, 
; GM is the geometric mean. 
 
The alternative hypothesis for superiority is expressed as: 
 .  The ratio of superiority is 
more than ten-fold. The sample size required for this comparison is less than 10.  
 
7.8.2 
Non-inferiority of Geometric Serum RVNA on Study Day 99 
The timepoint selected for non-inferiority in the current trial is based on need for a “later” 
timepoint at which to evaluate vaccine immunogenicity is from historical data from protocol 
SYN023-002 for which there are Study Day 84 and Study Day 112 timepoint (Table 7.8.2-1).  
The Study Day 99 is selected as being between these timepoints and closest for estimation.  
 
The 20% margin was selected since it is a recommended bioequivalence margin for a lower 
bound of 0.8 (FDA 2001).  Applying this margin to historical data near the Study Day 99 
timepoint shows RVNA concentrations both well above the 0.5 IU/mL and should provide 
protective concentration in all subjects (Table 7.8.2-1).   
RVNA GMC 
Priority 
Sample 
Size 
total  
1:1  
Mean ratio 
SYN/HRIG 
Margin 
CI 
CV % 
Superiority 
Study Day 8  
Primary 
<10 
>10.0 
10% 
95 
16.11 
Non inferiority 
Study Day 99 
GMC  
Primary 
138 
0.88 
20% 
95 
17.00 
Non inferiority 
Study Day 99 
percent subjects 
≥ 0.5 IU/mL 
Primary 
72 
1.0 
10%  
95 
NA 
Superiority 
Study Day 3 
Secondary 
<10 
>10.0 
10% 
95 
9.83 
Superiority 
AUEC1-15  
Secondary 
320 
1.45 
10% 
90 
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Table 7.8.2-1 RVNA Historical Values by Timepoint for SYN023-002 Protocol 
Visit 
SYN023 
HRIG 
N 
Geometric 
Mean 
95% CI 
N 
Geometric 
Mean 
95% CI 
Day 42 
73 
8.05 
(6.58, 9.85) 
76 
9.18 
(7.91, 10.66) 
Day 84 
72 
2.33 
(1.79, 3.03) 
75 
2.75 
(2.27, 3.33) 
Day 112 
73 
1.43 
(1.09, 1.87) 
76 
1.71 
(1.38, 2.11) 
 
Non-Inferiority test for ratio of two geometric means is used for determining the sample size. 
The null hypothesis is that the ratio for the two treatments is less than the defined margin which 
is expressed as:   
 
 
 
The alternative hypothesis for superiority is  
 .  The calculated ratio between 
SYN023/RIG and the 95% confidence intervals for the ratio are presented in Table 7.8.2-2 and 
were used as inputs for the sample size calculation in PASS 15 software.  
 
Table 7.8.2-2: Ratio (SYN023/HRIG) and 95% Geometric Confidence Intervals for 
Each Time-point for RVNA from SYN023-002 Protocol, Historical Data 
Time Point 
Ratio (SYN023/HRIG) 
for RVNA- SYN023-002 95% Geometric Means Ratio CI 
CV 
Day 35 
81.28% 
62.19% 
106.23% 
13.59% 
Day 42 
88.94% 
68.79% 
114.99% 
13.04% 
Day 84 
88.50% 
64.04% 
122.30% 
16.47% 
Day 112 
86.94% 
61.88% 
122.15% 
17.32% 
 
The sample size is calculated at 80% power with 20% margin of non-inferiority and equal 
allowance (number of subjects in group 1 = number of subjects in group 2) and alpha is taken to 
be 0.025.  
The non-inferiority of serum GMC RVNA on study day 84 in SYN023 recipients (above) with 
respect to HRIG recipients would require the sample size of 138 for 80% power with an expected 
true geometric means ratio 88.00%.   Note that based on historic data from protocol SYN023-
002 the geometric ratio from Study Day 42 through Study Day 112 is stable and therefore it is 
expected that a true ratio of 88.00% is reasonable to determine non-inferiority at Study Day 99. 

 
 
 
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7.8.3 
Non-inferiority of Percentage of Subjects with Serum RVNA ≥ 0.5 
IU/mL on Study Day 99 
20 % margin of noninferiority was selected since it is a recommended bioequivalence margin for a lower 
bound of 0.8 (FDA 2001). Historical SYN023 data is presented In Table 7.8.3-1. 
 
Table 7.8.3-1 Historical Percentage of Subjects with RVNA ≥ 0.5 IU/mL   
DAY 
SYN023 + Vaccine 
RIG + Vaccine 
≥ 0.5 IU/mL 
Count (percentage) 
Total 
≥ 0.5 IU/mL 
Count (percentage) 
Total 
0 
3 (4.0%) 
75 
1 (1.3%) 
76 
1 
67 (90.5%) 
74 
1 (1.3%) 
75 
3 
74 (98.7%) 
75 
1 (1.3%) 
76 
7 
75 (100.0%) 
75 
6 (7.9%) 
76 
14 
75 (100.0%) 
75 
75 (98.7%) 
76 
28 
75 (100.0%) 
75 
76 (100.0%) 
76 
35 
74 (100.0%) 
74 
74 (100.0%) 
74 
42 
73 (100.0%) 
73 
76 (100.0%) 
76 
84 
72 (100.0%) 
72 
75 (100.0%) 
75 
112 
70 (95.9%) 
73 
75 (98.7%) 
76 
 
Non-Inferiority test for ratio of two proportions is used for determining the sample size. The null 
hypothesis is that the ratio for the two treatments is less than the defined margin which is 
expressed as:   
 
  
 
The sample size is estimated for an 80% power of demonstrating noninferiority of a 20% margin 
of non-inferiority and equal allowance (number of subjects in group1 = number of subjects in 
group 2) with a p value = 0.025 (Table 7.8.3-2).  
 
7.8.3-2 Noninferiority Sample Size and Percentage of Subjects with RVNA ≥ 0.05 
IU/mL   
Assumed  
SYN023 
Proportion 
Assumed  HRIG 
Proportion 
Margin 
Total Sample Size 
1 
1 
0.2 
32 
1 
1 
0.1 
72 
 

 
 
 
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Samples sizes are shown for noninferiority for two proportions using a 20% margin that requires 
a total of 32 and a 10% margin that requires a total sample of 72 both of which can be 
demonstrated with the current 368 subject sample.     
 
7.8.4 
 Superiority of  Secondary endpoint AUEC1-15 
 
 
 
Where, 
; GM is the geometric mean. 
 
The alternative hypothesis for superiority is expressed as: 
 .  
 
The calculation of the sample size requires defining the range of the true mean ratio [AUEC1-15  
(SYN023/RIG): 147.55%, 90% CI: 115.10%, 189.14%], margin of superiority [10%], power 
[80%], coefficient of variation [CV: 108.78%] and alpha [0.025]. The calculation is done in 
PASS 15 software for the defined range of the true mean ratio and the results are presented for 
only those values for which the sample size is considered feasible. 
 
A true AUEC1-5 geometric mean ratio of SYN023/ HRIG of at least 1.45 and 80% power would 
therefore require a sample size of 320 with equal number of subjects in two groups for detecting 
the superiority with 10% of margin. Based on a true geometric mean ratio of at least 1.45, a total 
sample size of 320. A higher total sample of 368 allows for drop-outs and lost to follow up.  
 
7.8.5 
Absence of Rabies: 
Synermore estimates that any PEP failure rabies cases occurring in the trial will be more likely 
due to a failure of clinical management or failure to follow protocol specified procedures or less 
likely intrinsic resistance to post-exposure prophylaxis. Synermore estimates this possibility of 
rabies at approximately 0.1% to 0.01%.  This means there is a small chance of a single case of 
confirmed rabies occurs in the 184 subjects in the SYN023 NRG group.  If one case of PEP 
failure occurs the point incidence of PEP failure will be 0.6% and the 95% confidence interval 
will extend from 0% to 2.0%.  A 0.6% failure rate is high enough to be evidence of lack of 
efficacy and thus a failure of the primary objective. 
 
7.9 
Plan for Statistical Summaries and Analyses 
7.9.1 
Preliminary Data Reviews 
A preliminary blinded data review of RVNA immunogenicity data may be performed following 
completion of immunogenicity assessments through Study Day 365.  This review may present 

 
 
 
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individual and aggregate (mean or median [95% CI], as appropriate) RVNA immune response 
data, as well as change from pre-Study Drug to each post-Study Drug 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.   
 
A preliminary unblinded review of RVNA immune response and safety data will be conducted 
following completion of Study Day 365.  The database will be locked and the study will be 
unblinded for the preparation of this review.  The purpose of this review is to obtain preliminary 
immunogenicity and safety data for use in the decision-making process regarding Study Drug 
dose level and dosing regimens to be employed in future studies of the Study Drug.  This review 
will include all safety data, immune response data, clinical assessments, and concomitant 
medications through Study Day 365.  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.  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 365 data have been collected, reviewed and queries resolved.   
 
7.9.2 
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. 
 
7.10 
Computer Methods 
Statistical analyses will be performed using SAS®  version 9.1 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.  
 

 
 
 
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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 
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, 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 (or 
CTA, etc.).  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 the informed consent document will be reviewed and approved by the IRB or 
IEC of each participating clinical site prior to any protocol-specified procedures being conducted.  
All documents given to the subject will be reviewed and approved by the IRB/IEC.  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 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. Personal information may be difficult 
to remove from safety information but this data is kept under additional measures of data 
protection and is not part of the study database.  
 
 

 
 
 
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After the study has been unblinded, the subject should be informed by letter which treatment 
(SYN023 or HRIG) the subject received. The text of this letter will be submitted and approved 
by the relevant IRB/IEC before issuance to subjects. 
 
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 other than administrative changes and typographical errors in 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.    

 
 
 
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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 
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.  Subjects 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.   
 
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. 
 
9.4 
Payments and  Reimbursement of Human Research Subjects 
Trial participants will not be paid for participation in the trial.  Trial participants will be 
reimbursed for expenses that are incurred due to participation in the trial. 
These expenses may include but are not limited to: transportation costs, child care costs, costs of 
missed wages due to trial related activities, clinic appointments and other expenses at the 
discretion of the principal investigator and site IRB/IEC.  The amounts and payment schedules 
for payment shall be determined by the principal investigator and the IRB/IEC at each site. 
 

 
 
 
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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(s) 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.  From the sponsor.  All changes to the protocol must be submitted to the IRB/IEC 
and must be approved by the IRB/IEC unless they are administrative changes, typographical 
errors or required for subject safety prior to their implementation.  This is the third version of the 
protocol. 
 
 
12 
CHANGES IN THE CURRENT VERSION OF THE PROTOCOL 
The changes to Version 6.0 of the protocol are listed in Table 12-1.  Version 5.0 was never 
submitted to any clinical site but was used in discussions with the US FDA thus the last clinical 
protocol was Version 4.0.  Minor grammatical or orthographic changes may not be listed. The 
major changes to the protocol are: 
 
 The operation of the DSMB to permit enrollment of the NRG is revised to recognize that 
all subjects need not have a RVNA ≥ 0.5 IU/mL.   
 
Table 12-1 Table of Changes for Version 6.0 of Protocol 
Section 
Modified 
Version 4.0 
Version 6.0 
Page 
3.4.1 Blinding at 
the Study Level 
The LRG and the NRG are 
both blinded until Study 
Day 365. If the last subject 
in LRG reaches Study Day 
365 even if the NRG is still 
in progress, then the LRG 
group may be unblinded 
The LRG and the NRG are 
both blinded until Study Day 
365. If the last subject in LRG 
reaches Study Day 365 even if 
the NRG is still in progress, 
then the LRG group may be 
unblinded.  
 
The LRG may be unblinded to 
the extent recommended or 
49 

 
 
 
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Section 
Modified 
Version 4.0 
Version 6.0 
Page 
required by the DSMB for 
analysis of safety or efficacy 
data for Study Day 99 DSMB 
review. 
4.4 Study Rabies 
Vaccine in 
Philippines 
Study rabies vaccine in 
Philippines and Thailand   
Study rabies vaccine in 
Philippines 
62 
5.1.5.3 DSMB 
Review of Safety 
and 
Pharmacodynamic 
Activity in the 
Initial and 
General 
Enrollment LRG 
The sponsor will collect 
blinded RVNA results and 
adverse events through 
Study Day 99 from all 
subjects in the LRG General 
and Initial enrollment 
groups and provide them to 
the DSMB.  
Permission to enroll the 
General Enrollment of the 
NRG may be granted at 
Study Day 183 if  
 no protocol stopping 
rules are met 
(Section 6.3) and if  
 no severe related 
adverse events other 
than local injection 
site manifestations 
are encountered due 
to SYN023 in the 
initial and general 
enrollment of the 
LRG  
 The RVNA values 
are all in the 
protective range in 
SYN023 recipients 
Study Days 8 
through 99 (Section 
3.9.2). 
The sponsor will collect 
blinded RVNA results and 
adverse events through Study 
Day 99 from all subjects in 
the LRG General and Initial 
enrollment groups and 
provide them to the DSMB.  
Permission to enroll the 
General Enrollment of the 
NRG may be granted at Study 
Day 183 if  
 no protocol stopping 
rules are met (Section 
6.3) and if  
 no severe related 
adverse events other 
than local injection 
site manifestations are 
encountered due to 
SYN023 in the initial 
and general enrollment 
of the LRG  
 The RVNA values are 
in the protective range 
in ≥ 75% of SYN023 
recipients on Study 
Day 99 (Section 
3.9.2). 
65-66 
5.1.5.4 DSMB 
Review of Safety 
in the NRG 
The DSMB will assess the 
safety after 80 subjects have 
completed Study Day 99.  If 
The DSMB will assess the 
safety (while enrollment 
continues) after 80 subjects 
66 

 
 
 
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Section 
Modified 
Version 4.0 
Version 6.0 
Page 
there are no adverse events 
or patterns of concern 
 
have completed Study Day 
99.  If there are no adverse 
events or patterns of concern 
it will issue permission for the 
trial to continue. 

 
 
 
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13 
REFERENCES 
 
Baltazard M, Bahmanyar M, Ghodssi M, et al. Essai pratique du serum antirabique chez les 
mordus par loups enrages. Bull Wld. Hlth Org. 1955; 13,747-772. 
 
Bahmanyar M, Fayaz A, Nour-Salehi S, et al. Protection of humans exposed to rabies infection: 
Postexposure treatment with new human diploid cell rabies vaccine and antirabies serum.  JAMA. 
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Berger M1, Jolles S, Orange JS, Sleasman JW. Bioavailability of IgG Administered by the 
Subcutaneous Route. J Clin Immunol. 2013;33:984–990. 
 
Bharti OK; Madhusudana SN, Ganta P, Belludi AY. Local infiltration of rabies 
immunoglobulins without systemic intramuscular administration: an alternative cost effective 
approach for passive immunization against rabies. Human Vaccines and Immunotherapies. 
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Boland TA, McGuone D, Jindal J,  Rocha M,  Cumming M, et al.  Phylogenetic and 
epidemiologic Evidence of Multiyear Incubation in Human Rabies. Ann Neurol. 
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Buchy P, Preiss S, Singh E, et al. Heterogeneity of rabies vaccination recommendations across 
asia. Med Trop Infect Dis. 2017; 2(23):1-17. 
 
c-Equine rabies immunoglobulin (ERIG) soon to be available in South Africa. Communicable 
Diseases Communiqué. 2016;15(5). 
 
Cleaveland S, Fe`vre EM, Kaare M, Coleman PG. Estimating human rabies mortality in the 
United Republic of Tanzania from dog bite injuries.  Bulletin of the World Health Organization 
2002;80:304-310. 
 
Chomchay P, Khawplod P, Wilde H. Neutralizing Antibodies to Rabies Following Injection of 
Rabies Immune Globulin into Gluteal Fat or Deltoid Muscle. J Travel Med. 2000;7(4):187-188. 
 
Dean DJ, Baer GM, Thompson WR. Studies on the Local Treatment of Rabies-infected Wounds. 
Bull Wld Hlth Org. 1963;28:477-486. 
 
Fèvre EM, Kaboyo RW, Persson V, Edelsten M, Coleman PG, et al. The epidemiology of animal 
bite injuries in Uganda and projections of the burden of rabies. Tropical Medicine and 
International Health. 2005;10(8):790–798. 
 

 
 
 
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for Drug Evaluation and Research, Food and Drug Administration, Rockville. 
 
Gogtay NJ, Munshi R, Ashwath Narayana DH, Mahendra BJ, Kshirsagar V, et al. Comparison of 
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Postexposure Prophylaxis: A Phase 2/3, Randomized, Single-Blind, Noninferiority, Controlled 
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Gouin S, Patel H. Office management of minor wounds. Can Fam Physician 2001;47:769-774. 
 
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Habel K. Anti-serum in the prophylaxis of rabies. Bull. Wld Hlth Org. 1954;10:781-788. 
 
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Jentes ES, Blanton JD, Johnson KJ, et al. The Global Availability of Rabies Immune Globulin 
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a Lang J, Gravenstein S, Briggs D. et al., Evaluation of the safety and immunogenicity of a 
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b Lang J, Simanjuntak G, Soerjosembodo S, et al.  Suppressant effect of human or equine rabies 
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Zhao L, Ji P, Li, Z, Roy P, Chandrahas S.  The Antibody Drug Absorption Following 
Subcutaneous or Intramuscular Administration and Its Mathematical Description by Coupling 
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Model.  The Journal of Clinical Pharmacology. 2013;53(3):314-325. 

 
 
 
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APPENDIX A 
Protocol Facilities and Contact List 
 
Role in Study 
Name 
Contact Information 
Institutional Review 
Boards 
To be determined  
USA 
Philippines 
Clinical Study Manager 
Paul Grostal 
PPD 
Level 9,  5 Queens Road 
Melbourne VIC 3004, Australia  
(mobile) +61 (0)413 625 763 
Responsible Physicians 
To be determined  
USA 
Philippines 
Medical Monitor 
(Emergency Contact) 
J. Bruce McClain, M.D. 
James Fan, M.D. 
11673 Garnet Road 
Lovettsville, VA 20180 
(Mobile) 202-236-6975 
PPD  
No 155, Tianjin Road, Huangpu District, 
Shanghai, China +86 136 7198 4640 
Study Monitoring 
To be determined 
PPD local branches in USA, Philippines,  
 
Biomedical Laboratory 
Facilities (clinical 
safety laboratory tests) 
Edward Xue 
 
 
PPD® Laboratories 
25/F, Raffles City Beijing Office Tower 
No.1 Dongzhimen South Street 
Dongcheng District 
Beijing 100007, China 
Mobile +86 13601383815 
Safety Reporting 
Rowena Gracia Blaza 
(or PVG assigned 
personnel) 
Pharmacovigilance (PVG), PPD  
24H Safety Hotline: +44 122 337 4240 
24H Safety Hotline Fax:+44 122 337 4102 
EMEAASIASafetyCentral.SM@ppdi.com 
Clinical Sites 
To be determined 
USA 
Philippines 
Data Safety Monitoring 
Board 
Gil Price, M.D.  
Chief Medical Officer 
 
ProPharma Group 
2635 University Ave W Suite 195 
St. Paul, MN 55114 
M: 240-426-4695  
gil.price@propharmagroup.com 

 
 
 
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Rabies Virus 
Neutralizing Activity 
(RVNA) 
Stephanie Gatrell/ Hunter 
Wilkens  
Rabies Laboratory,  
Mosier Hall,  
Kansas State University, 
1800 Denison Avenue,  
Manhattan KS 66506-5600 
Bioanalytical Laboratory 
Facility (PK/ADA) 
 
Korin Cofsky 
Syneos Health 
301D College Rd East, Princeton,  
NJ 08540 
Phone: +1 609 806 4815 
korin.cofsky@syneoshealth.com 
 
 

 
 
 
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APPENDIX B 
Toxicity Table 
 
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 
8. 
* In addition to grading the local reaction at the greatest single diameter, the measurement should be recorded as a continuous variable. 
9. 
** 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 
10. * 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 

 
 
 
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Myalgia 
No interference 
with activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or hospitalization 
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 

 
 
 
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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 
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 
11. **  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. 
12. *** 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) 
13. **  “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 
 

 
 
 
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APPENDIX C 
Phlebotomy Volume by Visit 
 
Low Risk Group (volumes are approximate) 
Study Visit Day  
1 
4 
8 
15 
29 
43 
71 
99 
127 
155 
183 
274 
365 
Hepatitis B, C a 
4 
 
 
 
 
 
 
 
 
 
 
 
 
HIV a 
5 
 
 
 
 
 
 
 
 
 
 
 
5 
CBC, platelets a 
2 
2 
 
2 
 
2 
 
 
 
 
 
 
 
Serum chemistry a, c 
4 
4 
 
4 
 
4 
 
 
 
 
 
 
 
PT(INR), PTT a 
2 
 
 
 
 
2 
 
 
 
 
 
 
 
Serum RVNA 
10a 
10b 
10b 
10b 
10 
10 
10 
10 
10 
10 
10 
10 
10 
Anti-SYN023 serum assay  
5a 
 
 
5 
5 
 
 
5 
5 
5 
5 
5 
5 
SYN023 concentration  
5a  
5b 
5b  
5b 
5  
5  
 
5 
 
 
 
 
 
Per visit phlebotomy volume 
37 
21 
15 
26 
20 
23 
10 
20 
10 
10 
10 
10 
15 
Cumulative phlebotomy 
volume 
37 
58 
73 
99 
119 
142 
152 
172 
182 
192 
202 
212 
227 
 
 
Normal Risk Group (volumes are approximate) 
Study Visit Day  
1 
4 
8 
15 
29 
43 
71 
99 
127 
155 
183 
274 
365 
Hepatitis B, C a 
4 
 
 
 
 
 
 
 
 
 
 
 
 
HIV a 
5 
 
 
 
 
 
 
 
 
 
 
 
5 
CBC, platelets a 
2 
2 
 
2 
 
2 
 
 
 
 
 
 
 
Serum chemistry a, c 
4 
4 
 
4 
 
4 
 
 
 
 
 
 
 
PT(INR), PTT a 
2 
 
 
 
 
2 
 
 
 
 
 
 
 
Serum RVNA a 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
Anti-SYN023 serum assay  
5a 
 
 
5b 
 
 
 
5 
 
 
 
 
 
SYN023 concentration  
5a  
5b 
5b 
5 b 
 
 
 
5 
 
 
 
 
 
Per visit phlebotomy volume 
37 
21 
15 
26 
10 
18 
10 
20 
10 
10 
10 
10 
15 
Cumulative phlebotomy 
volume 
37 
58 
73 
99 
109 
127 
137 
157 
167 
177 
187 
197 
212 
 

 
 
 
Page 109 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
APPENDIX D 
Listing of Procedures by Study Visit 
 
LRG Group Study Day Procedure of Subject Evaluations  
LRG Study Day 1 (Randomization Date, Baseline) 
Before Study Drug administration 
Obtain informed consent 
Verify eligibility by review of inclusion/exclusion criteria 
Record medical history Including date of last immunization for tetanus  
Conduct and record physical examination and vital signs 
Perform Baseline EKG 
Collect urine sample for: 
Urine HCG (females only) must be confirmed negative before randomization 
Baseline Urinalysis 
Blood for: Baseline Hepatitis B, C, HIV-1, 2,  
Blood for Baseline PT (INR), PTT  
Blood for Baseline serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, 
sodium, potassium, chloride, bicarbonate, calcium and others if part of panel 
Blood for Baseline hematology: CBC including differential and platelets 
Blood for Baseline serum RVNA, SYN023 concentration and anti-SYN023 antibodies 
Bite wound washing or irrigation if no wound present 
Photographs of all wounds  
Confirmation visit scheduling if required  
Record concomitant medications 
Randomization  
 
Study Drug Administration 
Study Drug injection to wound or muscle if no wound 
Rabies Vaccination #1 
 
After Study Drug Administration 
Record AEs/SAEs and  

 
 
 
Page 110 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
Record Solicited AEs 
Wound or Site of injection examination 
LRG Study Day 4 
Blood for hematology: CBC including differential and platelets 
Blood for serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, 
potassium, chloride, bicarbonate, calcium and others if part of panel 
Blood for Serum RVNA, and SYN023 concentration  
Interval history  
Record solicited AEs 
Vital signs, focused physical examination 
Confirmation visit findings (bite time, animal capture, location animal specimens, immunization records 
etc.) 
Record AEs/SAEs  
Record concomitant medications 
Wound or site of injection examination  
Rabies vaccination #2 
 
LRG Study Day 8 
Blood for Serum RVNA and SYN023 concentration 
Interval history, 
Record solicited AEs 
Vital signs, focused physical examination 
Confirmation visit findings (bite time, animal capture, location animal specimens, immunization records 
etc.) 
Record AEs/SAEs  
Record concomitant medications 
Wound or site of injection examination  
Rabies vaccination #3 

 
 
 
Page 111 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
LRG Study Day 15 
Blood for hematology: CBC including differential and platelets 
Blood for serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, 
potassium, chloride, bicarbonate, calcium and others if part of panel 
Blood for Serum RVNA, SYN023 concentration and anti-SYN023 antibodies 
Interval history 
Focused physical examination 
Record AEs/SAEs  
Record concomitant medications 
Wound or site of injection examination  
Rabies vaccination #4 
LRG Study Day 29 (Visit window ± 2 days) 
Interval history  
Wound or site of injection examination 
Focused physical examination 
Blood for Serum RVNA, SYN023 concentration and anti-SYN023 antibodies 
Record AEs/SAEs 
Record concomitant medications 
Rabies vaccination #5 
LRG Study Day 43 (Visit window ± 4 days) 
Blood for hematology: CBC (including differential and platelets) 
Blood for PT (INR), PTT  
Blood for serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, 
potassium, chloride, bicarbonate, calcium and others if part of panel 
Blood for Serum RVNA, and SYN023 concentration  
Interval history 
Focused physical examination 
Record AEs/SAEs  
Record concomitant medications 

 
 
 
Page 112 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
LRG Study Day 99 (Visit window ± 7 days) 
Interval history 
Focused physical examination 
Blood for Serum RVNA 
Record SAEs  
Record concomitant medications 
LRG Study Day 71, 127, 155, (Visit window ± 7 days), 183, 274 (Visit window ± 14 days) 
Interval history 
Focused physical examination 
Blood for Serum RVNA, SYN023  concentration and anti-SYN023 antibodies 
Record SAEs  
Record concomitant medications 
LRG Study Day 365 (Visit window ± 14 days) 
Blood for HIV-1, 2 
Interval history 
Focused physical examination 
Blood for Serum RVNA and anti-SYN023 antibodies 
Record SAEs  
Record concomitant medications 

 
 
 
Page 113 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
 
NRG Group Study Day Procedure of Subject Evaluations  
NRG Study Day 1 (Randomization Date, Baseline) 
Before Study Drug administration 
Obtain informed consent 
Verify eligibility by review of inclusion/exclusion criteria 
Record medical history including date of last immunization for tetanus 
Conduct physical examination and vital signs 
Perform EKG 
Collect urine sample for: 
HCG (all females) 
Baseline Urinalysis 
Blood samples for baseline Hepatitis B, C, HIV-1, 2 
Blood for baseline PT (INR), PTT  
Blood for baseline serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, 
sodium, potassium, chloride, bicarbonate, calcium and others if part of panel 
Blood for baseline Hematology: CBC including differential and platelets 
Blood for baseline Serum RVNA, Anti-SYN023 antibody assay, SYN023 concentration 
Bite wound washing or irrigation 
Photographs of all wounds  
Schedule confirmation visit  
Record concomitant medications 
Randomization 
 
Study Drug Administration 
Study Drug Wound injection 
Rabies Vaccination #1 
 
After Study Drug Administration 
AEs/SAEs  
Record Solicited AEs 

 
 
 
Page 114 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
Wound or site of injection examination 
NRG Study Day 4 
Blood for hematology: CBC including differential and platelets 
Blood for serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, 
potassium, chloride, bicarbonate, calcium and others if part of panel 
Blood for Serum RVNA SYN023 concentration 
Vital signs 
Interval history 
Focused physical examination 
Rabies vaccination #2 
Confirmation visit 
AEs/SAEs 
Solicited AEs 
Record concomitant medications 
Wound or Site of injection examination 
NRG Study Day 8 
Vital signs 
Interval history 
Focused physical examination 
Blood for Serum RVNA and SYN023 concentration  
Confirmation visit 
Rabies vaccination #3 
AEs/SAEs and concomitant medications 
Solicited AEs 
Wound or Site of injection examination 
NRG Study Day 15 
Hematology: CBC including differential and platelets 
Serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, potassium, 
chloride, bicarbonate, calcium and others if part of panel 

 
 
 
Page 115 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
Interval history 
Focused physical examination 
Blood for Serum RVNA, Anti-SYN023 serum assay, SYN023 concentration 
Rabies vaccination #4 
AEs/SAEs  
Record concomitant medications 
Wound or Site of injection examination 
NRG Study Day 29 (Visit window ± 2 days) 
Interval history 
Focused physical examination 
Blood for Serum RVNA 
Record AEs/SAEs  
Record concomitant medications 
Wound or Site of injection examination 
Rabies vaccination #5 
 
NRG Study Day 43 (Visit window ± 4 days) 
Blood for Hematology: CBC including differential and platelets 
Blood for Serum chemistry: total bilirubin, AST, ALT, ALP, creatinine, blood urea nitrogen, sodium, 
potassium, chloride, bicarbonate, calcium and others if part of panel 
Blood for PT (INR), PTT  
Interval history 
Focused physical examination 
Blood for Serum RVNA 
Record AEs/SAEs  
Record concomitant medications 
NRG Study Day 71 (Visit window ± 7 days) 
Interval history 

 
 
 
Page 116 of 116 
 
Protocol SYN-023-004  
 
CONFIDENTIAL 
09/22/2020; Final Version 6.0 
 
Focused physical examination 
Blood for Serum RVNA 
SAEs  
Record concomitant medications 
NRG Study Day 99 (Visit window ± 7 days) 
Interval history 
Focused physical examination 
Blood for Serum RVNA, Anti-SYN023 serum assay, SYN023 concentration 
SAEs 
Record concomitant medications 
NRG Study Day 127, 155 (Visit window ± 7 days), 183, 274 (Visit window ± 14 days) 
Interval history 
Focused physical examination 
Blood for Serum RVNA 
SAEs  
Record concomitant medications 
NRG Study Day 365 (Visit window ± 14 days) 
Blood for HIV-1, 2  
Blood for Serum RVNA 
Interval history 
Focused physical examination 
SAEs 
Record concomitant medications