Clinical trial NCT03264157
Conditions: Healthy
Sponsor: Bio Products Laboratory
Start date: 2017-12-08; Completion date: 2018-07-13
Enrollment: 162 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A prospective, randomized, blinded, parallel-group, non-inferiority, phase II/III study of the safety and effectiveness of simulated post-exposure prophylaxis with BPL HRIG with co-administration of active rabies vaccine in healthy subjects.

Detailed description:
Each subject will undergo a total of 9 visits. Subjects' eligibility will be assessed at Screening, which can occur up to 28 days prior to dosing. Following a repeat eligibility check at Day 0, eligible subjects will be randomized and dosed with the randomized treatment (BPL HRIG + vaccine or Comparator HRIG + vaccine) on Day 0. Further assessments will be conducted on Days 3, 5, 7, 14, 28, 49 and the end of study assessment on Day 140. Vaccine will be administered on Day 0, 3, 7, 14 and 28.

Arms: arm 1: 20 IU/kg dose HRIG + active rabies vaccine arm 2: 20 IU/kg dose HRIG + active rabies vaccine
Interventions: intervention 1: HRIG intervention 2: HyperRAB intervention 3: RabAvert
Intervention descriptions: intervention 1: A 20 IU/kg dose of BPL HRIG will be given on Day 0 via IM injection. intervention 2: A 20 IU/kg dose of Comparator HRIG will be given on Day 0 via IM injection. intervention 3: A 1.0 ml dose of active vaccine (2.5 IU/ml) will be given IM on 5 occasions: on Days 0, 3, 7, 14, and 28.

Protocol documents:
Prot_000.pdf: 
RIG01 
 
CONFIDENTIAL 
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A Prospective, Randomized, Double-Blind Parallel-group, Non-inferiority 
Phase II/III Study of the Safety and Effectiveness of BPL HRIG With 
Co-administration of Active Rabies Vaccine in Healthy Subjects  
Study Code: RIG01 
IND Number: 17475 
NCT03264157
Version 1.0 
Version date: 26 Oct 2017 
BIO PRODUCTS LABORATORY LTD (BPL) 
DAGGER LANE 
ELSTREE 
HERTS WD6 3BX 
UNITED KINGDOM 


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CONFIDENTIALITY STATEMENT  
 
Information contained within this document will be treated as confidential at all times. It shall be used 
for the sole information of the Investigator’s team.  Staff must undertake not to disclose any such 
information to any person not involved in the study. 


CCI
CCI


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SPONSOR’S RESPONSIBLE CHIEF MEDICAL OFFICER 
Name: 
Dr Elizabeth Holmes 
Title: 
Chief Medical Officer 
Address: 
Bio Products Laboratory Ltd,  
Dagger Lane,  
Elstree,  
Hertfordshire, WD6 3BX,  
UK 
Telephone No.: 
 
Fax No.: 
 
 
 
CONTRACT RESEARCH ORGANISATION  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


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TABLE OF CONTENTS 
 
PROTOCOL APPROVAL SIGNATURES ............................................................................................ 3 
TABLE OF CONTENTS ........................................................................................................................ 5 
REVISION HISTORY ............................................................................................................................ 8 
LIST OF ABBREVIATIONS ................................................................................................................. 9 
1. 
SYNOPSIS ............................................................................................................................... 11 
2. 
INTRODUCTION ................................................................................................................... 15 
2.1. 
Rabies ......................................................................................................................... 15 
2.2. 
Current Treatment ....................................................................................................... 16 
2.3. 
Development of HRIGs for Post-Exposure Prophylaxis ............................................ 18 
2.4. 
BPL’s Human Rabies Immunoglobulin ...................................................................... 18 
2.5. 
Summary of Pre-Clinical and Clinical Experience with BPL HRIG .......................... 19 
2.6. 
Potential Risks and Benefits to Subjects of BPL HRIG ............................................. 19 
2.7. 
Potential Risks and Benefits to Subjects of Comparator HRIG .................................. 21 
2.8. 
Potential Risks and Benefits to Subjects of Rabies Vaccine ...................................... 21 
2.9. 
The Current Study ....................................................................................................... 21 
3. 
OBJECTIVES .......................................................................................................................... 24 
4. 
STUDY DESIGN .................................................................................................................... 25 
4.1. 
Study Design ............................................................................................................... 25 
4.2. 
Study Plan ................................................................................................................... 25 
4.3. 
Scheduled Visits ......................................................................................................... 27 
4.4. 
Endpoints .................................................................................................................... 27 
4.5. 
Unscheduled Visits ..................................................................................................... 28 
4.6. 
Duration of Treatment ................................................................................................ 28 
4.7. 
Assignment of Treatment ............................................................................................ 28 
5. 
TRIAL POPULATION ............................................................................................................ 29 
5.1. 
Subject Numbers ......................................................................................................... 29 
5.2. 
Inclusion Criteria ........................................................................................................ 29 
5.3. 
Exclusion Criteria ....................................................................................................... 29 
6. 
INVESTIGATIONAL AND AUXILIARY MEDICINAL PRODUCTS ............................... 32 
6.1. 
Product Presentation, Storage and Expiry .................................................................. 32 
6.1.1. 
Investigational Medicinal Product (IMP): BPL HRIG .................................. 32 
6.1.2. 
Comparator HRIG.......................................................................................... 32 
6.1.3. 
Active Rabies Vaccine ................................................................................... 32 


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6.2. 
Randomized Treatment ............................................................................................... 33 
6.3. 
Product Administration ............................................................................................... 34 
6.4. 
Concurrent Medication ............................................................................................... 35 
6.5. 
Drug Accountability ................................................................................................... 36 
6.6. 
Randomization and Blinding ...................................................................................... 36 
6.7. 
Emergency Unblinding of Study Treatment ............................................................... 37 
7. 
TRIAL PROCEDURES ........................................................................................................... 38 
7.1. 
Consent ....................................................................................................................... 38 
7.2. 
Screening Visit (up to Day -28) (Visit 1) .................................................................... 38 
7.3. 
Baseline Visit (Day 0) (Visit 2) .................................................................................. 39 
7.3.1. 
Before Dosing (Day 0) ................................................................................... 39 
7.3.2. 
Dosing on Day 0 ............................................................................................ 40 
7.3.3. 
After Dosing .................................................................................................. 40 
7.4. 
Visits 3 to 7: Injections of Rabies Vaccine ................................................................. 40 
7.4.1. 
Before Dosing ................................................................................................ 40 
7.4.2. 
Dosing of Active Rabies Vaccine .................................................................. 41 
7.4.3. 
After Dosing .................................................................................................. 41 
7.5. 
Visit 4 (Day 5 PK sample) .......................................................................................... 41 
7.6. 
Visit 8 (Day 49 PK) .................................................................................................... 42 
7.7. 
Visit 9 End-of-Study Assessment ............................................................................... 42 
7.8. 
Unscheduled Visits ..................................................................................................... 43 
7.9. 
Blood Sample Collection, Handling and Labeling ..................................................... 43 
7.9.1. 
Reserve Samples ............................................................................................ 43 
7.9.2. 
Archive Sample.............................................................................................. 43 
7.10. 
Recording Laboratory Results .................................................................................... 43 
7.11. 
Restrictions ................................................................................................................. 44 
8. 
OUTCOME MEASURES ....................................................................................................... 45 
8.1. 
Efficacy Measures ....................................................................................................... 45 
8.1.1. 
Primary efficacy endpoint .............................................................................. 45 
8.1.2. 
Secondary efficacy endpoints ........................................................................ 45 
8.1.3. 
Exploratory efficacy endpoints ...................................................................... 45 
8.1.4. 
Rabies virus neutralizing antibody................................................................. 46 
8.2. 
Safety Assessments ..................................................................................................... 46 
8.2.1. 
Adverse Events .............................................................................................. 47 
8.2.2. 
Injection Site Observations ............................................................................ 47 
8.2.3. 
Viral  Serology ............................................................................................... 48 


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8.2.4. 
Serum Biochemistry ...................................................................................... 48 
8.2.5. 
Hematology .................................................................................................... 49 
8.2.6. 
Urinalysis ....................................................................................................... 49 
8.2.7. 
Markers of Hemolysis .................................................................................... 50 
8.2.8. 
Vital Signs and Body Temperature ................................................................ 50 
8.2.9. 
Physical Examination .................................................................................... 51 
8.2.10. Pregnancy Test ............................................................................................... 51 
9. 
WITHDRAWAL OF SUBJECTS ........................................................................................... 52 
10. 
DATA ANALYSIS .................................................................................................................. 54 
10.1. 
Source Data ................................................................................................................. 54 
10.2. 
Data Recording ........................................................................................................... 54 
10.3. 
Statistical and Analytical Plans ................................................................................... 54 
10.4. 
Analysis Populations ................................................................................................... 55 
10.5. 
Efficacy Analysis ........................................................................................................ 55 
10.5.1. Primary PK Analysis ..................................................................................... 55 
10.5.2. Hypothesis for the Primary PK Analysis ....................................................... 56 
10.5.3. Secondary PK Analysis .................................. Error! Bookmark not defined. 
10.5.4. Exploratory PK Analysis ............................................................................... 57 
10.6. 
Safety Analysis ........................................................................................................... 57 
10.6.1. Adverse Events .............................................................................................. 57 
10.6.2. Injection Site Observations ............................................................................ 58 
10.6.3. Viral Serology Variables ............................................................................... 58 
10.6.4. Hematology, Serum Biochemistry, Urinalysis .............................................. 59 
10.6.5. Markers of Hemolysis .................................................................................... 59 
10.6.6. Vital Signs and Body Temperature ................................................................ 59 
10.6.7. Physical Examination .................................................................................... 59 
10.6.8. Other Safety Parameters ................................................................................ 59 
10.7. 
Sensitivity Analyses .................................................................................................... 59 
10.7.1. Non-Compliers and Missing Data ................................................................. 59 
10.7.2. Potential Interaction ........................................ Error! Bookmark not defined. 
10.8. 
Subgroup Analysis ...................................................................................................... 60 
10.9. 
Determination of Sample Size .................................................................................... 60 
10.10. Interim Analysis .......................................................................................................... 61 
11. 
INVESTIGATOR’S STATEMENT ........................................................................................ 62 
12. 
REFERENCES ........................................................................................................................ 63 
Appendix A. 
- ADVERSE EVENT DEFINITIONS AND REPORTING PROCEDURES ............ 65 


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Appendix B. 
- ADMINISTRATIVE REQUIREMENTS ................................................................ 84 
Appendix C. 
- INVESTIGATOR’S RESPONSIBILITIES BASED ON THE GUIDELINES FOR 
GOOD CLINICAL PRACTICE .............................................................................................. 98 
Appendix D. 
– COMPARATOR HRIG PRESCRIBING INFORMATION (2012 version) ......... 107 
Appendix E. 
– ACTIVE RABIES VACCINE PRESCRIBING INFORMATION (2015 version)
 
108 
Appendix F. 
– HRIG DOSING FOR CLINICAL TRIAL............................................................. 109 
Appendix G. 
–TRIAL PLAN FLOW CHART .............................................................................. 110 
 
 
REVISION HISTORY 
 
Version 
Number 
Version Date 
Description of Changes 
01 
26 October 2017 
Initial version 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AUC 
Area under the curve 
BPL 
Bio Products Laboratory Limited (The Sponsor) 
Bpm 
CBC 
Beats per minute 
Complete Blood Count 
CHMP 
Committee for Medicinal Products for Human Use 
CD4 
Cluster of differentiation 4 
Cmax 
Maximum/peak serum concentration 
CRP 
C-Reactive Protein 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CV 
Curriculum Vitae 
DEV 
Duck embryo origin IgG 
EMEA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
GMT 
Geometric Mean Titer 
h 
Hours 
HAV 
Hepatitis A Virus 
Hb 
Hemoglobin 
HBV 
Hepatitis B Virus 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HDCV 
Human diploid cell vaccine 
HIV 
Human Immunodeficiency Virus 
HRIG 
Human Rabies Immunoglobulin 
ICH 
International Conference on Harmonisation  
ID 
Identity 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IgA 
Immunoglobulin A 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IU 
International Units 
kg 
Kilograms 
LLOQ 
Lower Limit of Quantification 
Ltd 
Limited 
min 
Minutes 
ml 
Milliliters 
NAT 
Nucleic Acid Amplification Technology 
PCECV 
Purified chick embryo cell vaccine 


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PEP 
Post-exposure prophylaxis 
PK 
Pharmacokinetics 
RIG 
Rabies Immunoglobulin 
RVNA 
Rabies Virus Neutralizing Antibody 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SRM 
Study Reference manual 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Half-life 
Tmax 
Time of maximum concentration 
US 
United States (of America) 
 
 
 
 
 
 
 
 
 


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1. 
SYNOPSIS 
 
PROTOCOL NUMBER: 
RIG01 
INVESTIGATIONAL 
MEDICINAL PRODUCT (IMP): 
BPL Human rabies immune globulin (HRIG) 
 
TITLE: 
 
A Prospective, Randomized, Blinded, Parallel-group, 
Non-inferiority Phase II/III Study of the Safety and 
Effectiveness of BPL HRIG With Co-administration 
of Active Rabies Vaccine in Healthy Subjects  
 
PHASE: 
II/III 
 
OBJECTIVES: 
1. 
To demonstrate non-inferiority of BPL HRIG 
compared to an FDA-licensed HRIG product, in 
terms of the proportion of subjects achieving anti-
rabies antibody titer of ≥0.5 IU/mL at Day 14 
following treatment with HRIG in conjunction 
with active rabies vaccine.  
 
2. 
To compare the PK of BPL HRIG in conjunction 
with active rabies vaccine, with FDA-licensed 
HRIG product in conjunction with active rabies 
vaccine. 
 
3. 
To assess whether BPL HRIG interferes with the 
development of the host-immune response when 
given simultaneously with active rabies vaccine, 
relative to an FDA-licensed HRIG product. 
 
4. 
To evaluate the safety and tolerability of BPL 
HRIG in comparison with FDA licensed HRIG 
product. 
 
 
STUDY DESIGN: 
This will be a prospective, randomized, blinded, 
parallel-group, non-inferiority, phase II/III study of the 
pharmacokinetics and safety (and tolerability) of 
simulated post-exposure prophylaxis with BPL HRIG 
with co-administration of active rabies vaccine in 
healthy subjects. 
 
Screening visit (within 28 days prior to baseline) 
Screening evaluations will include viral serology, 
biochemistry, hematology and other tests to assess 
eligibility.   
 
Baseline (Day 0) 
Eligible subjects will be randomly assigned to one of 
two treatment groups:  


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● 
Treatment A: BPL HRIG + active rabies vaccine  
● 
Treatment B: Comparator HRIG + active rabies 
vaccine 
 
Pre-dose samples will be collected for anti-rabies 
antibody serum titer, markers of hemolysis, and long-
term archiving.  Subjects will then be administered their 
randomized treatment for Day 0. 
 
On-Study (Days 0-140) 
Pharmacokinetic assessments of anti-rabies antibody 
serum titer will be conducted at the following time 
points: days 3, 5, 7, 14, 28 (4 weeks), 49 (7 weeks) and 
140 (20 weeks).   
 
Additional doses of active rabies vaccine (will be 
administered, after the collection of the blood sample 
for anti-rabies antibody serum titer, on days 3, 7, 14, 
and 28. 
 
Adverse events will be monitored from the screening 
visit and throughout the study. 
 
End-of-Study Assessment (Day 140) 
End-of-Study evaluations will include viral serology, 
biochemistry, and hematology. A sample will be 
collected for long-term archiving. 
 
NUMBER OF SUBJECTS: 
Approximately 162 normal healthy volunteers, 81 per 
treatment group will be enrolled to achieve 146 
evaluable subjects.  
 
TREATMENTS: 
Treatment A 
Experimental:  
BPL HRIG, 20 IU/kg body weight once on Day 0, 
administered via intramuscular injection to the deltoid 
and/or lateral thigh muscle in divided doses 
Vaccine:  
FDA-approved active rabies vaccine, 1.0 mL 
(2.5 IU/mL) will be given on Days 0, 3, 7, 14, and 28, 
administered intramuscularly in the deltoid muscle 
(contralateral to the HRIG). 
 
Treatment B: 
Active comparator: 
Comparator HRIG, 20 IU/kg body weight once on Day 
0, administered via intramuscular injection to the 
deltoid and/or lateral thigh muscle in divided doses. 
Vaccine:  
FDA-approved active rabies vaccine, 1.0 mL 
(2.5 IU/mL) will be given on Days 0, 3, 7, 14, and 28, 
administered intramuscularly in the deltoid muscle 
(contralateral to the HRIG). 


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STUDY DURATION: 
24 weeks for the individual participant (20 weeks 
treatment plus a pre-study phase of up to 4 weeks).  
 
STUDY POPULATION: 
Healthy males and females, aged 18-75 years, not 
previously exposed to rabies virus or pre-or post-
exposure rabies prophylaxis. 
 
PRIMARY ENDPOINT: 
The proportion of subjects with anti-rabies titer ≥0.5 
IU/mL at 14 days following BPL HRIG + vaccine vs. 
active comparator + vaccine, using a non-inferiority 
margin of 10%. 
The above pharmacokinetic endpoint is a surrogate for 
efficacy, since a titer of ≥0.5 IU/mL is globally 
recognized as indicating adequate vaccine response. 
 
 
SECONDARY EFFICACY 
ENDPOINT(S): 
● Assessment of AUC0-7d for BPL HRIG and vaccine 
versus comparator HRIG and vaccine using a non-
inferiority margin of 20%. 
● Comparison of the geometric mean titers (GMTs) 
for rabies antibody titers at Days 3, 5, 7, 14 and 28 
after administration of BPL HRIG and vaccine 
versus comparator HRIG and vaccine 
● The proportion of subjects reaching anti-rabies titer 
≥0.5 IU/mL at Days 3, 5, 7, 14, 28, 49 and 140 after 
administration of BPL HRIG and vaccine versus 
comparator HRIG and vaccine    
● The proportion of subjects reaching anti-rabies titer 
of ≥ the lower limit of quantification of the assay at 
Days 3, 5, 7, 14, 28, 49 and 140 after administration 
of BPL HRIG and vaccine versus comparator 
HRIG and vaccine 
● Comparison of the geometric mean (GMTs) for 
anti-rabies titer at Days 14, 28, 49 and 140 after 
administration of BPL HRIG and vaccine versus 
comparator HRIG and vaccine will be compared 
between treatment groups. 
 
EXPLORATORY EFFICACY 
ENDPOINT: 
● Pharmacokinetic (PK) parameters: Cmax, tmax, area 
under 
the 
curve 
to 
the 
last 
measurable 
concentration (AUCT) and to infinity (AUC∞), 
apparent terminal rate constant (λz), AUC0-7days, 
Cmax/AUC, half-life (t½) of anti-rabies antibody 
concentrations (both groups) 


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SECONDARY   SAFETY 
ENDPOINT(S): 
 
 
● Adverse events from time of signing informed 
consent until end of study. 
● Injection site observations  
● Viral serology pre-dose and at end of study 
● Biochemistry, hematology and urinalysis pre-study 
and at end of study 
● Physical examination, including ECG, pre-study 
and at end of study 
● Vital signs  
 
STATISTICAL METHODOLOGY 
Analysis populations:  
ITT population: The intent-to-treat (ITT) population 
will include all randomized subjects. All analyses will 
be performed using the ITT population. 
Safety population: all subjects who receive at least one 
dose of BPL HRIG / comparator HRIG / active rabies 
vaccine. The safety population will be used for all 
safety analyses. 
Per protocol population: 
Primary PK population: all subjects who receive the full 
dose of BPL HRIG / comparator HRIG and the first 3 
doses of active rabies vaccine on Visits 2, 3 and 5, and 
for whom the PK sample at Visit 6  is taken. This 
population will be used for the primary analysis and 
selected secondary PK analyses. 
Secondary PK population: all subjects who receive the 
full dose of BPL HRIG / comparator HRIG and all 5 
doses of active rabies vaccine, and for whom all 
required PK samples are taken. This population will be 
used for selected secondary PK analyses. 
Primary analysis: 
The primary hypothesis is that the proportion of 
subjects receiving BPL HRIG + active vaccine with an 
anti-rabies titer of ≥0.5 IU/mL  will not be less than the 
corresponding proportion for subjects receiving 
comparator HRIG + active vaccine by more than 0.1 at 
visit 6. The Farrington and Manning test statistic will 
be used to assess the statistical comparison at a one-
sided significance level of 0.025. 
Secondary analysis: 
Efficacy endpoints will be assessed by a combination 
of statistical and descriptive analyses, as appropriate. 
Safety parameters will be compared descriptively. 
The trial will be conducted in compliance with the protocol, FDA Code of Federal Regulations 21 CFR 
parts 50, 54, 56, 312 and 314, EU Clinical Trial Directives 2001/20/EC and 2005/28/EC, Good Clinical 
Practice Guidelines and applicable local regulatory requirements BPL is committed to satisfying the 
requirements of the ICH-GCP Guidelines regarding the responsibilities of the Sponsor. 


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2. 
INTRODUCTION 
2.1. 
Rabies  
Rabies is a disease caused by RNA viruses in the genus Lyssavirus (family Rhabdoviridae).  
Currently, 14 species of lyssa-viruses have been identified. However, only 1 species, Rabies 
virus, has been detected in the western hemisphere1  All species of mammals are susceptible to 
rabies virus infection, but only a few species are important as reservoirs for the disease. The 
vast majority of rabies cases reported to the Centers for Disease Control and Prevention (CDC) 
each year occur in wild animals like raccoons, skunks, bats, and foxes1 . 
Transmission of rabies virus usually begins when infected saliva of a host is passed to an 
uninfected animal. The virus is typically present in the saliva of clinically ill mammals and is 
transmitted through a bite.  In humans, transmission has also been documented via other routes 
such as contamination of mucous membranes (i.e., eyes, nose, mouth), aerosol transmission, 
and corneal and organ transplantations2 . 
In the absence of prophylactic treatment, the rabies virus infects the central nervous system, 
ultimately causing acute, progressive encephalomyelitis which is almost invariably fatal. The 
incubation period in humans is usually several weeks to months, but ranges from days to years.  
Early symptoms of rabies are similar to those of many other illnesses, including fever, 
headache, and general weakness or discomfort. As the disease progresses, more specific 
symptoms appear and may include insomnia, anxiety, confusion, slight or partial paralysis, 
excitation, hallucinations, agitation, hyper salivation, difficulty swallowing, and hydrophobia.  
Death usually occurs within days of the onset of these symptoms3. 
Worldwide, approximately 55,000 people die of rabies each year, primarily in developing 
countries, where the dog is the most important animal reservoir3.   Exposure to rabid dogs is the 
cause of over 90% of human exposures to rabies and of over 99% of human deaths3. 
 In the United States, where vaccination of domestic animals is a component of a successful 
rabies prevention and control program, approximately 16,000-39,000 persons come in contact 
with potentially rabid animals annually4.  However, due to the success of post-exposure 
prophylactic treatment, just 37 cases of human rabies were diagnosed between 2003 and 
20151,5,6  . 


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2.2. 
Current Treatment  
Human rabies can be prevented by pre- and post-exposure prophylaxis using vaccinations. Pre-
exposure prophylaxis relies on active vaccination against the virus.  Subsequent exposure to the 
rabies virus is then treated with repeat doses of the vaccine.  
Pre-exposure vaccination is advised for those at increased risk of exposure, such as 
veterinarians, people whose activities bring them into frequent contact with rabid animals, and 
to international travelers if likely to come into contact with the rabies virus in regions where 
access to appropriate medical care might be limited. 
For vaccination after exposure, post-exposure prophylaxis (PEP), people who have not received 
pre-exposure vaccination, should receive both passive antibody and vaccine. Passive antibodies 
are purified preparations of Human Rabies Immune Globulin (HRIG). Vaccines currently 
available in the United States include Human Diploid Cell Vaccine (HDCV) and Purified Chick 
Embryo Cell Vaccine (PCEC) (see Table 1)2. 
Table 1: 
Rabies Vaccines and Immunoglobulin Available in the United States 
Type 
Name 
Route 
Indications 
Human Diploid Cell 
Vaccine (HDCV) 
Imovax® 
Rabies 
Intramuscular 
Pre-exposure 
or Post-
exposure 
Purified Chick 
Embryo Cell 
Vaccine (PCEC) 
RabAvert® 
Intramuscular 
Pre-exposure 
or Post-
exposure 
Human Rabies 
Immune Globulin 
Imogam® 
Rabies-HT 
Local infiltration at wound 
site, with additional amount 
intramuscular at site distant 
from vaccine 
Post-
exposure 
Human Rabies 
Immune Globulin 
HyperRAB®  
S/D 
Local infiltration at wound 
site, with additional amount 
intramuscular at site distant 
from vaccine 
Post-
exposure 
 
This post-exposure prophylaxis consists of a dose of HRIG and vaccine given on the day of the 
exposure (day 0), and then a dose of vaccine given again on days 3, 7, 14 and 28, following the 
regimen shown in Table 22.     
HRIG is administered only once, at the beginning of anti-rabies post-exposure prophylaxis. 
This will provide immediate antibodies until the body can respond to the vaccine by actively 
producing antibodies of its own. If possible, the full dose of HRIG should be thoroughly 
infiltrated in the area around and into the wounds. Current guidelines recommend infiltration 
in and around the wound to prevent progression of rabies virus along neural pathways into the 


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central nervous system7. Any remaining volume should be injected intramuscularly at a site 
distant from vaccine administration.  
Effectiveness of rabies treatment is measured by serological testing of the rabies virus 
neutralizing antibody (RVNA), of which the gold standard is the Rapid Fluorescent Focus 
Inhibition Test (RFFIT)3,8.  Animal studies have shown that survival against rabies infection is 
more likely to occur the higher an animal’s RVNA titer was at the time of infection, but it is 
not a definitive indicator of survival.  Nonetheless in humans a titer of 0.5 IU/mL is globally 
recognized as indicating adequate vaccine response9. 
Table 2: 
Rabies Post-Exposure Prophylaxis (PEP) Schedule for Not Previously 
Vaccinated Individuals 
Intervention Regimen* 
Wound 
cleansing 
All PEP should begin with immediate thorough cleansing of all 
wounds with soap and water. If available, a virucidal agent (e.g., 
povidine-iodine solution) should be used to irrigate the wounds. 
Human 
rabies 
immune 
globulin 
(HRIG) 
Administer 20 IU/kg body weight. If anatomically feasible, the full 
dose should be infiltrated around and into the wound(s), and any 
remaining volume should be administered at an anatomical site 
(intramuscular [IM]) distant from vaccine administration. Also, HRIG 
should not be administered in the same syringe as vaccine. Because 
RIG might partially suppress active production of rabies virus 
antibody, no more than the recommended dose should be administered. 
Vaccine 
Human diploid cell vaccine (HDCV) or purified chick embryo cell 
vaccine (PCECV) 1.0 mL, IM (deltoid area†), 1 each on days 0§ 3, 7 
and 14, and 28.  
* These regimens are applicable for persons in all age groups, including children.  
† The deltoid area is the only acceptable site of vaccination for adults and older children. For younger 
children, the outer aspect of the thigh may be used. Vaccine should never be administered in the gluteal 
area.  
§ Day 0 is the day dose 1 of vaccine is administered.  
 
Current CDC recommendation for rabies PEP vaccination are 4 doses of vaccine on Day 0, 3, 
7 and 147. Manufacturers’ recommendations for rabies PEP are 5 doses, which will be the 
regimen for the clinical trial.  
Adverse reactions to rabies vaccine and immune globulin are not common. Newer vaccines in 
use today cause fewer adverse reactions than previously available vaccines. Mild, local 
reactions to the rabies vaccine, such as pain, redness, swelling, or itching at the injection site, 
have been reported. Rarely, symptoms such as headache, nausea, abdominal pain, muscle 
aches, and dizziness have been reported. Local pain and low-grade fever may follow injection 
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2.3. 
Development of HRIGs for Post-Exposure Prophylaxis 
The usefulness of prophylactic rabies antibody in preventing rabies in humans when 
administered immediately after exposure was demonstrated in a group of persons bitten by a 
rabid wolf in Iran in 195410,11.  A series of clinical studies helped determine the optimal 
conditions under which anti-rabies serum of equine origin and rabies vaccine could be used in 
humans12,13,14,15.  These studies showed that the anti-rabies serum could interfere with the 
active immunity induced by the vaccine, but could be minimized by booster doses of vaccine 
after the end of the usual dosage series. 
Later development was the preparation of rabies immune globulin of human origin with 
adequate potency16. In carefully controlled clinical studies, this globulin was used in 
conjunction with rabies vaccine of duck-embryo origin16,17.  The recommended dose for HRIG 
of 20 IU/kg was established in clinical studies comparing the rabies IgG titer following various 
doses of HRIG and vaccine16,17,18.  A lower dose of 10 IU/kg was suboptimal for early 
protection and a higher dose of 40 IU/kg interfered with the development of active immunity 
conferred by the vaccine.  At the dose of 20 IU/kg, anti-rabies antibody titers were detectable 
from Day 1 after the injection.  Without injection of vaccine, passive antibody titers reached a 
peak of 30 IU/mL 13 days after Day 0 and declined with a half-life of approximately 3 weeks.  
However, when HRIG was administered with a course of rabies vaccine, rabies IgG levels 
continued to rise, peaking at Day 40 with a titer of 111 IU/mL17. 
2.4. 
BPL’s Human Rabies Immunoglobulin 
BPL’s Human Rabies Immunoglobulin (BPL HRIG) contains human protein, 40-180 g/L, of 
which at least 98% is IgG.  The concentration of specific IgG to rabies virus is not less than 
150 IU/mL in nominal 500 IU vials.  This product is prepared from plasma from screened 
donors, selected from the USA, who have been hyperimmunized with rabies vaccine. 
BPL HRIG has been licensed in the UK since 1991.  This formulation contains a solvent-
detergent virus-reduction step, which is considered effective against enveloped viruses such as 
human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV).  
Recently, the addition of a virus filtration step in the manufacturing process has improved the 
virus reduction further, providing effective reduction of small non-enveloped viruses such as 
parvovirus B19.  For more information, see the Investigator’s Brochure19. 
HRIG must always be used for post-exposure prophylaxis in combination with an approved 
rabies vaccine.  One dose of immunoglobulin (20 IU/kg body weight) is given intramuscularly, 
prior to a full course of rabies vaccination, and as soon as possible after exposure.  If a large 
volume (> 2mL for children or > 5 mL for adults) is required, it is recommended to administer 


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this in divided doses at different sites.  The immunoglobulin and the vaccine should be 
administered at two different sites of the body (Table 2).   
HRIG administered intramuscularly is bioavailable in the recipient's circulation after a delay of 
2-3 days and has a half-life of about 3 – 4 weeks (although this may vary from patient to 
patient)19.  However, the pharmacokinetics (PK) of BPL HRIG has not been studied.   
2.5. 
Summary of Pre-Clinical and Clinical Experience with BPL HRIG  
HRIG is a preparation of human plasma proteins, thus safety testing in animals is not applicable 
to the safety of use in man. Acute toxicity studies of BPL immunoglobulin in rat and mouse 
showed species specific reactions which bear no relevance to administration in humans.  
Repeated dose toxicity testing and embryo-fetal toxicity studies are impracticable due to the 
induction of, and interference with, antibodies to human protein.  Clinical experience provides 
no sign of tumorigenic and mutagenic effects of immunoglobulins19 . 
No clinical trials have been performed with BPL HRIG.  The first approval for marketing 
worldwide was United Kingdom on 06 June 1991.  The product is currently approved in four 
countries (UK, Chile, Colombia and Malta). However, BPL HRIG is predominantly distributed 
in the UK. 
The safety of this product in patients exposed to the rabies virus is well-established. Exposure 
data prior to 2000 is not available.  From January 1, 2000  to June 28, 2017, a total of 26,716 
vials of rabies immunoglobulin have been sold. The recommended dose of the product is 20IU 
per kg, corresponding to 1400 IU for a typical 70kg adult. Based on this assumption, a typical 
adult dose would be equivalent to three vials of the product.  On this basis, an estimated 8,905 
patients were exposed to human rabies immunoglobulin during the period and only one case 
report describing 3 non-serious adverse reactions (fatigue, influenza like illness, and urticaria) 
has been reported. 
2.6. 
Potential Risks and Benefits to Subjects of BPL HRIG 
BPL HRIG is made from human plasma.  Products made from human plasma may contain 
infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob Disease (CJD) agent 
that can cause disease. Standard measures to prevent infections resulting from the use of 
medicinal products prepared from human blood or plasma include selection of donors, 
screening of individual donations and plasma pools for specific markers of infection and the 
inclusion of effective manufacturing steps for the inactivation/removal of viruses.  Despite this, 
when medicinal products prepared from human blood or plasma are administered, the 
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unknown or emerging viruses and other pathogens.  The investigator will discuss the risks and 
benefits of this product with the participant, before administration. 
BPL HRIG should not be administered into a blood vessel because of the risk of shock; 
investigators/site staff will be trained how to administer the BPL HRIG for this study.  Although 
systemic reactions to immunoglobulin preparations are rare, epinephrine should be available 
for treatment of acute anaphylactoid symptoms. Rarely, human rabies immunoglobulin can 
induce a fall in blood pressure with anaphylactic reaction, even in patients who have tolerated 
previous treatment with human immunoglobulin.  Suspicion of allergic or anaphylactic type 
reactions requires immediate discontinuation of the injection. In case of shock, standard 
medical treatment for shock should be implemented. 
Although true hypersensitivity is rare, BPL HRIG should be given with caution to patients with 
a history of prior systemic allergic reactions following the administration of human 
immunoglobulin preparations.  This trial will therefore exclude participants with a history of 
prior systemic allergic reactions following administration of blood, blood products, or human 
plasma-derived products. 
Participants with isolated immunoglobulin A (IgA) deficiency (who have increased potential 
for developing antibodies to IgA and could have anaphylactic reactions to subsequent 
administration of blood products that contain IgA) will be excluded from the study. 
As with all preparations administered by the intramuscular route, bleeding complications may 
be encountered in patients with thrombocytopenia or other bleeding disorders, therefore 
participants with thrombocytopenia or other bleeding disorders will be excluded from the study. 
Other antibodies in the BPL HRIG preparation may interfere with the development of an 
immune response to live attenuated vaccines such as measles, mumps, varicella or rubella. 
Therefore, immunization with live vaccines should not be given within 3 months after BPL 
HRIG administration.  However, inactivated influenza vaccinations may be administered. 
Animal reproduction studies have not been conducted with BPL HRIG. It is also not known 
whether BPL HRIG can cause fetal harm when administered to a pregnant woman or can affect 
reproductive capacity.  Females of childbearing potential will have a pregnancy test prior to 
inclusion in the study and must be using adequate contraception for the duration of the clinical 
trial.     
There are no robust data on the frequency of undesirable effects of BPL HRIG from clinical 
trials. The following undesirable effects are class effects that are common to all HRIG products 
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Table 3: 
Class effects that are common to all HRIG products 
MedDRA Standard 
System Organ Class 
Undesirable Effects 
Frequency* 
Immune system disorders 
Hypersensitivity, anaphylactic shock 
Rare 
Nervous system disorders 
Headache 
Rare 
Cardiac disorders 
Tachycardia 
Rare 
Vascular disorders 
Hypotension 
Rare 
Gastrointestinal disorders 
Nausea, vomiting 
Rare 
Skin and subcutaneous 
disorders 
Skin reaction, erythema, pruritus 
Rare 
Musculoskeletal and 
connective tissue disorders 
Arthralgia 
Rare 
General disorders and 
administration site 
conditions 
Fever, malaise, chill, fatigue, influenza 
like illness 
At injection site: swelling, pain, 
erythema, induration, warmth, pruritus, 
rash 
Rare 
* rare is defined as a frequency of >1/10,000 to <1/1,000 
Deep intramuscular injection may reduce the risk of local induration. Subjects receiving BPL 
HRIG in this study will not have been exposed to the rabies virus and so the post-exposure 
prophylaxis will not provide any direct benefit.  However, subjects who complete all 
vaccinations may have protection against rabies infection should they be exposed in the future, 
but this cannot be guaranteed.  Therefore, subjects will be informed that there are no direct 
therapeutic benefits of participation in this study, regardless of the treatment received according 
to the randomized treatment schedule. 
2.7. 
Potential Risks and Benefits to Subjects of Comparator HRIG 
In this study, a licensed comparator HRIG, HyperRAB® S/D, will be used.  HyperRAB® S/D 
is a plasma-derived product and therefore the same class effects are expected as listed in section 
2.5.  Refer to the prescribing information in Appendix D .   
2.8. 
Potential Risks and Benefits to Subjects of Rabies Vaccine 
In this study, a licensed vaccine RabAvert® will be used.  RabAvert® is a sterile freeze-dried 
 vaccine obtained by growing the fixed -virus strain Flury LEP in primary cultures of chicken  
fibroblasts. The most common adverse reactions are injection site reactions, such as injection 
 site erythema, induration, pain, and flu-like symptoms, such as asthenia, fatigue, fever, 
headache, myalgia and malaise. Refer to the prescribing information in Appendix E . 
2.9. 
The Current Study 
The purpose of the current study is to obtain data required for a license application in the US.  
This will be achieved by comparing the safety and efficacy of BPL HRIG, administered in 


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conjunction with rabies vaccine in accordance with the licensed dosing schedule for post-
exposure prophylaxis, with the safety and efficacy of a licensed comparator HRIG, also given 
in conjunction with rabies vaccine.  A randomized, blinded, parallel group study design will 
ensure an unbiased comparison is made between treatments. 
The doses of BPL HRIG and comparator HRIG to be administered in this study, of 20 IU/kg, 
are consistent with the licensed doses.  Unlike the licensed method of administration, which 
requires the HRIG to be administered around the wound, in this study HRIG will be 
administered to the lateral thigh muscles and, if required by the volume to be administered, to 
the deltoid muscle.  This will result in a more consistent absorption of antibody from the 
intramuscular compartment between subjects and therefore allow an accurate analysis of the 
PK of HRIG. 
It is unethical to investigate the efficacy of BPL HRIG in patients exposed to rabies virus due 
to the almost invariably fatal nature of the disease.  Therefore, in this study, PK of HRIG when 
given in conjunction with active rabies vaccine to healthy volunteers will be used as a surrogate 
marker of HRIG efficacy. The pharmacokinetic goal of rabies post-exposure prophylaxis is to 
achieve a serum rabies antibody titer of ≥0.5 IU/mL (WHO, 2007) on study Day 14.  A 
comparison of the proportion of subjects receiving BPL HRIG who meet this important clinical 
endpoint, with the proportion of subjects receiving FDA-licensed comparator HRIG who meet 
the same endpoint, is therefore the primary objective of the trial. The aim of the study will be 
to demonstrate the non-inferiority of BPL HRIG with a 10% margin.   
Secondary endpoints will include rabies antibody titer at days 3, 5, 7, 14 and 28, for both HRIGs 
(in conjunction with rabies vaccine).  PK sampling will take place prior to dosing of HRIG and 
rabies vaccine (Day 0) at each of the timepoints at which rabies vaccine is administered (Days 
3, 7, 14 and 28), with an additional PK timepoint at Day 5 to study to study the early response 
to HRIG.  Additional PK timepoints at Days 49 and 140 will enable collection of a complete 
the PK profile.  In order to compare the effects of HRIG at early timepoints before active 
antibody is generated in response to the rabies vaccine, the AUC0-7d will be assessed.  Additional 
secondary endpoints will be the proportion of subjects in each treatment group reaching a serum 
rabies antibody titer of ≥0.5 IU/mL and ≥ the Lower Level of Quantification (LLOQ) at each 
timepoint.  PK parameters for both treatment groups will be compared in an exploratory 
analysis. 
As mentioned in Section 2.3, a dose of 40 IU/kg was shown to interfere with the development 
of active immunity conferred by the vaccine16.  At a dose of 20 IU/kg, as given during this 
study, any attenuation observed was insignificant and did not interfere materially with active 
immunity22,23.  Moreover, any attenuation was clinically insignificant since serum anti-rabies 


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IgG remained considerably higher than the protective titer of 0.5 IU/mL. However, as a 
secondary endpoint, the possible attenuation effect of BPL HRIG on the development of the 
host-immune response will be studied by comparing the Day 14, 28, 49 and 140 rabies antibody 
titer for both treatments.  Any observed attenuation will be described by comparing PK 
parameters of HRIGs in conjunction with rabies vaccine. Although the safety of BPL HRIG is 
well-established from many years of marketed use, this study will assess the safety of BPL 
HRIG, in conjunction with rabies vaccine.   
 In order to maintain blinding of treatment, the study will be blinded to the subject, investigator 
and site staff, to reduce bias in the identification and causality assessments of adverse events 
and laboratory abnormalities. An unblinded pharmacist or licensed medical professional will 
be responsible for preparation of the correct treatments according to the randomization code. In 
this study, actual (rather than nominal) HRIG potency will be used to calculate the volume of 
HRIG to be administered.  Since there will be differences in the volume of the HRIGs the nurse 
administrator will also be unblinded.  This modified blinding technique was successfully used 
in a completed study comparing PK and safety of two rabies vaccine formulations, both in 
conjunction with licensed HRIG24 . 
A study duration of five times the half-life of the experimental treatment is usually considered 
adequate to identify safety issues relating to the product.  The half-life of HRIG is 3-4 weeks19, 
therefore study duration of 15 to 20 weeks is considered appropriate both to obtain a full PK 
profile and for appropriate safety follow up.  A duration of 140 days (20 weeks) has therefore 
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3. 
OBJECTIVES 
The objectives of this study are:  
1. To demonstrate non-inferiority of BPL HRIG compared to an FDA-licensed HRIG product, 
in terms of the proportion of subjects achieving anti-rabies antibody titer of ≥0.5 IU/mL at 
Day 14 following treatment with HRIG in conjunction with active rabies vaccine.  
2. To compare the PK of BPL HRIG in conjunction with active rabies vaccine, with 
FDA-licensed HRIG product in conjunction with active rabies vaccine. 
3. To assess whether BPL HRIG interferes with the development of the host-immune response 
when given simultaneously with active rabies vaccine, relative to an FDA-licensed HRIG 
product 
4. To evaluate the safety and tolerability of BPL HRIG in comparison with FDA-licensed 
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4. 
STUDY DESIGN 
4.1. 
Study Design 
This will be a prospective, randomized, double-blind, parallel-group, non-inferiority, phase 
II/III study of the safety and effectiveness of simulated post-exposure prophylaxis with BPL 
HRIG with co-administration of active rabies vaccine in healthy subjects.  This is intended to 
be a multi-center study in the US.  
Subjects will be randomly assigned to one of 2 treatment groups, as follows: 
Table 4: 
Treatment groups assigned 
Treatment 
group name 
HRIG treatment 
Rabies vaccine treatment 
Number of 
subjects 
A 
BPL HRIG 
active rabies vaccine 
81 
B 
comparator HRIG 
active rabies vaccine 
81 
 
Prior to randomizing a participant, all screening and baseline evaluations must be completed 
and the participant determined to be eligible for inclusion in the study. Randomization and the 
baseline visit (Day 0) should occur no later than 28 days after the completion of the screening 
visit.  
All medicinal product preparation will be performed by the unblinded pharmacist/ or licensed 
medical personnel using aseptic techniques and according to a standardized procedure on Day 
0. The nurse administrator will quality check the calculations, and dose/treatment assignment 
prior to administration. Treatments on Day 0 will be administered by an unblinded nurse 
administrator. All study assessments and Post Day 0 treatment administration will be performed 
by blinded study personnel. Investigators and subjects will be blinded to treatment assignment. 
Subjects will be identified by a unique five-digit number as follows:  each site will be allocated 
a two-digit site number (e.g. Site 01, etc.) and each subject will be allocated a three-digit subject 
number (e.g. 001) at the Screening Visit.  Each subject will be identified by the unique site and 
subject number combination (e.g. 01001).   
4.2. 
Study Plan 
See Figure 1 . 
 


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Figure 1: 
Study Plan 
Visit 1 
 
      Visit 2 
 
Visit 3 
 
Visit 4 
 
Visit 5 
1 weeks 
 
 
Visit 6 
2 weeks 
Visit 7 
4 weeks 
Visit 8 
7 weeks 
Visit 9 
20 weeks 
Screening 
Day (-28 to 
-0 days) 
 
Baseline   Day 0 
 
 
 
 Day 3 
 
Day 5 
 
 
Day 7 
 
 
 
Day 14 
 
 
Day 28 
(±2 days) 
 
Day 49 
(±4 
days) 
 
Day 140 
(±7 days) 
Eligibility 
 
 Repeat eligibility  
Randomization 
HRIG+ vaccine or 
Comparator +vaccine 
 PK 
 
 
 
Vaccine  
PK 
 
 
PK 
 
Vaccine  
PK 
 
Vaccine  
PK 
 
   Vaccine  
     PK 
 
 
PK 
 
 
 
 
 
End-of-
study 
Actual treatment by assigned Treatment Group: 
 
 
 
 
 
 
 
 
 
 
 
A 
 
BPL HRIG + 
rabies vaccine 
      
rabies 
vaccine 
 
rabies 
vaccine 
 
rabies 
vaccine 
 
rabies 
vaccine 
 
 
 
 
 
B 
 
comparator HRIG 
+ rabies vaccine 
 
rabies 
vaccine 
 
rabies 
vaccine 
 
rabies 
vaccine 
 
rabies 
vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.3. 
Scheduled Visits 
For full details of assessments performed at scheduled visits see flow chart in Appendix G. 
Each subject will undergo a total of 9 visits.  Subjects’ eligibility will be assessed at Screening 
(Visit 1), which can occur up to 28 days prior to dosing.  Following a repeat eligibility check at 
Day 0 (Visit 2), eligible subjects will be randomized and dosed with the randomized treatment 
(BPL HRIG /vaccine or Comparator HRIG/vaccine on Day 0.  Further administration of rabies 
vaccine, PK sampling and safety assessments will be conducted on Days 3 (Visit 3), 5 (Visit 4) 
(PK sampling only), 7 (Visit 5), 14 (Visit 6) and 28 (Visit 7).   An additional visit for PK 
sampling and safety assessment will take place on Day 49 (7 weeks/Visit 8) and Day 140 (20 
weeks/Visit 9).  The last visit will be the End-of-Study Assessment which will take place on 
Day 140 (20 weeks).  This visit will comprise the final PK sample and safety assessments.  The 
end of the trial is defined as the last subject’s last End-of-Study Assessment (or the date of their 
last data collected, if the subject has an AE at the End-of-Study Assessment that needs to be 
followed, see Appendix A  section 4). 
4.4. 
Endpoints  
The trial’s primary endpoint will be the proportion of subjects with anti-rabies antibody titer 
≥ 0.5 IU/mL at 14 days following BPL HRIG + vaccine or comparator HRIG + vaccine. The 
primary endpoint will be designed to determine non-inferiority with a 10% margin (see 
Section 8.1.1). 
Additional time points are included for secondary end points, including pharmacokinetic (PK) 
parameters of anti-rabies antibody levels in serum at time points (Days 0, 3, 5, 7, 14, 28, 49 and 
140), safety and tolerability.   
As the primary endpoint is assessed at Day 14, subjects who withdraw from the study after Day 
14 may still be eligible for the primary analysis, if all planned assessments up to and including 
Day 14 were performed.   
 


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4.5. 
Unscheduled Visits 
At the discretion of the investigator, subjects may return between visits as required, additional 
safety laboratory measures may be undertaken as required. 
4.6. 
Duration of Treatment 
The duration of the study for an individual participant is expected to be 24 weeks.  This 
comprises a screening period of up to 4 weeks (28 days) followed by a treatment period of 20 
weeks.  The ± 7-day allowable window on the final study visit results in a maximum study 
duration for any subject of 25 weeks. 
4.7. 
Assignment of Treatment 
The randomization code will be prepared by a statistician. Subjects will be enrolled using an 
interactive web response system (IWRS), which will assign each subject to a treatment group 
after the demographic and eligibility data have been entered into the system. The system will 
allow emergency UNBLINDING, the process for which will be documented. 
Manual back-up procedures and instructions are provided for use in the event that the site 
temporarily loses access to the Internet or the online enrollment system is unavailable. 


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5. 
TRIAL POPULATION 
5.1. 
Subject Numbers 
The trial will enroll approximately 162 healthy volunteers, 81 in each treatment arm to achieve 146 
evaluable subjects 
Enrolled subjects who withdraw from the study will not be replaced. 
5.2. 
Inclusion Criteria 
All   the following criteria must be met for the subject to be eligible:  
a) Able and willing to sign an informed consent form. 
b) Healthy male or female subjects aged 18 - 75 years inclusive.  
c) No previous exposure to rabies virus, rabies vaccine and/or rabies immunoglobulin. 
d) No significant abnormalities in hematology, biochemistry, or urinalysis according to the 
Principal Investigator's judgment. 
e) No significant abnormalities in ECG according to the Investigator's judgment. 
f) Females of child-bearing potential (defined from the onset of menstruation to one-year post-
menopause and not surgically sterilized) who are (or become) sexually active must agree to 
practice contraception by using a highly effective (>98%) method for the duration of the study. 
g) Females of child-bearing potential (defined from the onset of menstruation to one-year post-
menopause and not surgically sterilized) must have a negative result on a serum at screening 
visit and a urine HCG-based pregnancy test at Day 0. 
5.3. 
Exclusion Criteria 
Any one of the following criteria makes the subject ineligible:  
a) 
Female subjects who are pregnant and/or lactating. 
b) 
History of live virus vaccination, e.g., measles, mumps, varicella or rubella vaccine, within the 
last 3 months. 
c) 
Planned live virus vaccination, e.g., measles, mumps, varicella or rubella vaccine, within the 3 
months after Day 0. 
d) 
History of anaphylactic or anaphylactoid hypersensitivity reactions to chicken egg; history of 
mild allergic reactions to chicken egg, e.g., skin rash only, is not an exclusion criterion 
e) 
History of hypersensitivity reaction to any of the following components of active rabies vaccine 
(US-FDA approved) e.g.: neomycin, bovine gelatin, trace amounts of chicken protein, 
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f) 
History of life-threatening allergy, anaphylactic reaction, or systemic response to human 
plasma derived products. 
g) 
History of life-threatening allergy to blood or blood products. 
h) 
Fever at the time of the start of the injection (oral temperature >38ºC.) or acute illness at the 
time of the start of the injection. * 
i) 
History of or ongoing bleeding disorder. 
j) 
Previous organ transplant recipient. 
k) 
Ongoing immunosuppressive illness. 
l) 
Clinically significant illnesses including: cardiac, hepatic, renal, endocrine, neurological, 
hematological, neoplastic, immunological, skeletal or other) that in the opinion of the 
investigator, could interfere with the safety, compliance or other aspects of this study. 
m) All types of malignancies except for basal and squamous cell (scaly or plate-like) skin cancer, 
in- situ cervical carcinoma must be in remission for a minimum of 5 years prior to Day 0. For 
non-melanoma skin cancers and carcinoma in-situ of the cervix may be enrolled if treated and 
cured at the time of screening. 
n) 
Evidence of active systemic infection that requires treatment with antibiotics within 2 weeks 
prior to Day 0. 
o) 
Currently receiving or have received within the past 6 months (prior to Day 0):  
• 
immunosuppressive drugs 
• 
immunomodulatory drugs 
 
p) Currently receiving or have received oral or IV steroids within 14 days (prior to DAY 0) or 
expected to require oral or IV steroids during the study. 
q) 
Evidence of uncontrolled hypertension (systolic blood pressure of >150 mmHg, and/or diastolic 
blood pressure of >100 mmHg). 
r) 
Heart rate >120/min. 
s) 
Weight > 95.5 kg   
t) 
History of IgA deficiency. 
u) 
Is positive for any of the following at screening: serological test for HIV 1&2, HCV or HBsAg. 
v) 
Presence of psychiatric disorder, other mental disorder or any other medical disorder which 
might impair the subject's ability to give informed consent or to comply with the requirements 
of the study protocol. 
w) Previous enrollment in this study. 


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x) 
Participation in an interventional clinical trial within 30 days prior to baseline visit (Day 0). 
y) 
Evidence of alcohol abuse or history of alcohol abuse or illegal and/or legally prescribed drugs 
in the past 2 years. 
z) 
Any other factor that, in the opinion of the investigator, would prevent the subject from 
complying with the requirements of the protocol. 
* Subjects with fever on Day 0 may have entry to the study re-scheduled (see Section 7.3.1). 
Subjects may withdraw their consent or discontinue from the study at any time (refer to Section 9). 
 


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6. 
INVESTIGATIONAL AND AUXILIARY MEDICINAL PRODUCTS 
In this study, ‘study medication’ is defined as all products administered: BPL HRIG, 
comparator HRIG, and active rabies vaccine.  
6.1. 
Product Presentation, Storage and Expiry 
6.1.1. 
Investigational Medicinal Product (IMP): BPL HRIG  
BPL HRIG is a liquid concentrate of rabies human immunoglobulin.  BPL HRIG is obtained 
from blood from screened donors, who are selected from within the United States of America.  
BPL HRIG is manufactured, packed and labelled by the sponsor according to the requirements 
of FDA CFRs, Directive 2001/20/EC and Good Manufacturing Practice.   
BPL HRIG is presented in 5 ml glass vials, each of which is packed in a carton.  The 
concentration of specific IgG to Rabies virus is not less than 150 IU/mL solution for injection 
in nominal 500 IU vials.  The actual fill volume will be printed on the vial label. The shelf-life 
of BPL HRIG is specified in the Investigator’s Brochure.  The expiry date is printed on the vial 
label and carton; product must not be used beyond the expiry date. Dosing for BPL HRIG will 
be based on the actual potency (see pharmacy manual). 
Vials of BPL HRIG should be stored in the original container at 2°C to 8°C (36°F to 46°F).  
Storage for up to one week at 25°C (77°F) in the original container is not detrimental. DO NOT 
FREEZE.  Store in the original vial.  Keep vial in the outer carton to protect from light.  The 
product should be brought to room or body temperature before use. 
The colour can vary from colourless to pale-yellow and is either clear or slightly opalescent. 
Do not use solutions that are cloudy or have deposits. 
Further information can be found in the Investigator’s Brochure. 
6.1.2. 
Comparator HRIG 
FDA-approved HRIG comparator HyperRAB® S/D will be presented in 10 mL vials, at a 
nominal potency of 150 IU/mL. Dosing for HyperRAB® S/D will be based on the actual 
potency (see pharmacy manual). 
Vials of HyperRAB® S/D should be stored at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE.  
The expiry date is printed on the vial label; product must not be used beyond the expiry date. 
Further information can be found in the approved Prescribing Information, Appendix D. 
6.1.3. 
Active Rabies Vaccine 
The FDA-approved rabies vaccine, RabAvert®, is presented as a freeze-dried vaccine 
containing 2.5 IU of rabies antigen for reconstitution with 1 mL diluent.  Each pack contains 


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one vial of freeze-dried vaccine, 1 disposable pre-filled syringe of sterile diluent, 1 small 
needle for injection and 1 long needle for reconstitution.   
RabAvert® is a white, freeze-dried vaccine for reconstitution with the water for injection 
diluent prior to use; the reconstituted vaccine is a clear to slightly opalescent, colorless to 
slightly pink solution. 
RabAvert should be stored protected from light at 2°C to 8°C (36°F to 46°F).  After 
reconstitution, the guidance in the prescribing information (PI) should be followed.  The vaccine 
may not be used after the expiration date given on the package and container. 
Further information can be found in the approved Prescribing Information, Appendix E. 
6.2. 
Randomized Treatment 
Subjects will be randomized to receive one of two treatments described below.   
Treatment A: BPL HRIG + rabies vaccine (RabAvert®). 
A 20 IU/kg dose of BPL HRIG will be given on Day 0 via IM injection.  The volume to be 
injected will be based upon the subject’s weight on Day 0 and BPL HRIG actual potency (see 
pharmacy manual). A maximum of 5 mL will be administered to each lateral thigh and a 
maximum 2.0 mL to the deltoid muscle.  The gluteal muscle will not be used for IM injection 
due to the increased variability of absorption from this injection site and the risk of injury to the 
sciatic nerve.   
The total volume will be split between the injection sites as follows: 
Table 5: 
Treatment A -total volume to be split between the injection sites 
Injection number 
Volume to be injected 
Site of injection 
1 
up to 5 mL depending on 
bodyweight 
left lateral thigh muscle 
2 
up to 5 mL depending on 
bodyweight 
right lateral thigh muscle 
3 (if required) 
up to 2 mL depending on 
bodyweight 
left deltoid muscle 
 
A 1.0 ml dose of active vaccine (2.5 IU/ml) will be given IM on 5 occasions: on Days 0, 3, 7, 
14, and 28.  On day 0, the vaccine will be administered to the right deltoid muscle.  The 
subsequent doses of vaccine on days 3, 7, 14, and 28 may be administered to the right or the 
left deltoid muscle. 
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Treatment B: FDA-approved comparator HRIG (HyperRAB® S/D) + rabies vaccine 
(RabAvert®) 
A 20 IU/kg dose of comparator HRIG will be given on Day 0 via IM injection.  The volume to 
be injected will be based upon the subject’s weight on Day 0 and BPL HRIG actual potency 
(see pharmacy manual).  A maximum of 5 mL will be administered to each lateral thigh and a 
maximum 2.0 mL to the deltoid muscle.  The gluteal muscle will not be used for IM injection 
due to the increased variability of absorption from this injection site and the risk of injury to the 
sciatic nerve. 
The total volume will be split between the injection sites as follows: 
Table 6: 
Treatment B -total volume to be split between the injection sites 
Injection number 
Volume to be injected 
Site of injection 
1 
Up to 5 mL depending on 
body weight 
left lateral thigh muscle 
2 
up to 5 mL depending on 
bodyweight 
right lateral thigh muscle 
3 (if required) 
up to 2 mL depending on 
bodyweight 
left deltoid muscle 
 
A 1.0 ml dose of active vaccine (2.5 IU/ml) will be given on 5 occasions: on Days 0, 3, 7, 14, 
and 28.  On day 0, the vaccine will be administered to the right deltoid muscle.  The subsequent 
doses of vaccine on days 3, 7, 14, and 28 may be administered to the right or the left deltoid 
muscle. 
6.3. 
Product Administration 
HRIG will be drawn into 2 or 3 (as appropriate according to the calculated volume) 5.0 mL 
syringes and injected to the lateral thighs and, if required, the left deltoid muscle. 
Vaccine will be drawn into a 1.0 mL syringe and injected to the right deltoid muscle. 
The selection of HRIG products to be administered (BPL HRIG or comparator HRIG) as per 
the randomized treatment, the calculation of the volume to be administered, and the drawing 
up of the appropriate volume into syringe(s), will be performed by the unblinded pharmacist/or 
licensed medical personnel.  The selection of products to be administered, calculation of volume 
to be administered, and the volume in the syringe will be checked by the unblinded nurse 
administrator prior to administration to the subject.  
For the BPL HRIG, comparator HRIG, the following details will be recorded:  
• 
name of product 
• 
lot number 


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• 
total dose required in IU, calculated from body weight (20 IU/kg)  
• 
total dose required in mL, calculated from the actual potency  
• 
for each specified injection site, actual dose administered in mL (this should not exceed 
5.0 mL for each lateral thigh muscle and 2.0 mL for the left deltoid muscle) 
• 
date and time of  injection on Day 0 
See the pharmacy manual for additional information on calculations, potency and details to be 
recorded.  Certificates of analysis for both products will be kept in BPL files. 
For the rabies vaccine, the following details will be recorded: 
• 
name of product 
• 
lot number 
• 
confirmation of actual dose given in mL (this should be 1.0 ml) 
• 
date, time, and location of injection, on Days 0, 3, 7, 14, and 28 
See the pharmacy manual for additional information on details to be recorded.  For any given 
subject, every effort must be made to use the same lot of active rabies vaccine throughout the 
study.   
For additional details on administration of BPL and comparator HRIG using actual 
potency versus nominal potency refer to Appendix F and the pharmacy manual. 
6.4. 
Concurrent Medication 
Concomitant medication is defined as any medication, other than the study drug, which is taken 
during the trial, including prescription and over-the-counter medicines. For the purposes of the 
study, nutritional supplements including vitamins and minerals are not considered concomitant 
medications. The generic names of medications should be used where possible. 
Concomitant medication will be recorded in the subject notes with indication, dose information, 
and dates of administration.  Any new medications taken or any changes to the form, frequency 
or dose of existing medication occurring during the study will also be recorded. 
Corticosteroids, other immunosuppressive agents or treatments, and immunosuppressive 
illnesses can interfere with the development of active immunity and, in patients exposed to the 
rabies virus, predispose the patient to developing rabies. Immunosuppressive agents should not 
be administered during the study, unless essential for the treatment of other conditions. Oral or 
IV steroids should not be taken within 14 days prior to Day 0, and if required during the study 
the subject will be withdrawn from the study. Topical or inhaled steroids are permitted. 
Other antibodies in the BPL HRIG or comparator preparation may interfere with the response 
to live vaccines such as measles, mumps, polio or rubella. Therefore, immunization with live 


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vaccines should not be given within 3 months of BPL HRIG administration. Inactivated 
Influenza vaccination is allowed, see Investigator Brochure. 
6.5. 
Drug Accountability  
 
The investigator is responsible for ensuring that a record is maintained for every vial of study 
medication and licensed product provided to the site for the study.  Accounts must be kept for 
each subject of the identity (lot#) and number of vials administered, used and returned to 
pharmacy, to demonstrate full drug accountability.  The unblinded staff at the study center 
will confirm receipt of the study supplies, indicating dates of receipt, expiration dates, 
temperature conditions, lot numbers and quantities of all study supplies received from the 
Central Drug Distributor.  Records will be kept of medication administered to each subject, as 
well as amounts remaining at the study conclusion.  The study monitor will arrange for the 
collection of unused supplies for return to the Sponsor / Central Drug Distributor upon 
completion of the study or before if appropriate.  Alternatively, if a documented drug 
destruction policy exists; unused supplies may be destroyed at the investigational site. 
The following records will therefore need to be maintained to provide complete accountability: 
• 
Dispatch notes or invoice slips 
• 
Receipt forms 
• 
Dispensing log   
• 
Returns to BPL / Central Drug Distributor OR destruction logs 
It is essential that all study product administered to the subject is recorded in the subject’s clinic 
notes including amount administered. 
Used and partly used vials will be retained at the pharmacy and reserved for drug accountability 
purposes, until written confirmation is received from the monitor that they may be disposed of 
locally.  
The products provided for the study must be used solely as indicated in the protocol and must 
never be used for subjects not participating in the study. 
A log of daily temperatures in the pharmacy storage area must be maintained to demonstrate 
that the products have been stored under the specified conditions. 
6.6. 
Randomization and Blinding 
Subjects will be assigned to one of the treatment groups according to a randomization schedule 
prepared before the study start.  Each subject’s randomization number will correspond to the 
treatment assigned.  Therefore, subjects and investigators will be blinded to the treatment 
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An unblinded pharmacist or licensed medical personnel will be responsible for preparing study 
treatments in accordance with the randomized treatment assignment. As the volume differs 
between the HRIGs, the staff responsible for administration of the treatment will be unblinded.  
Different, blinded study personnel will be responsible for observing any reactions and 
interviewing subjects about potential reactions.  
Information on roles and responsibilities of blinded and unblinded study personnel will be 
detailed in the Blinded Project Plan. 
6.7. 
Emergency Unblinding of Study Treatment 
To maintain the integrity of the trial, emergency unblinding should occur only in exceptional 
circumstances when knowledge of the actual treatment is essential for further management of 
the subject. Investigators are encouraged to discuss with the Medical monitor if he/she believes 
that the unblinding is necessary. 
If unblinding is deemed to be necessary, the investigator should follow the procedures for 
emergency unblinding as described in the Study Reference Manual (SRM). 
The investigator is encouraged to maintain the blind as far as possible. The actual allocation 
must not be disclosed to the subject and/or other study personnel. Unblinding should not 
necessarily be a reason for study drug discontinuation.  
 


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7. 
TRIAL PROCEDURES 
A detailed flowchart showing the assessments to be performed are in Appendix G. Study days 
are defined as calendar days. 
7.1. 
Consent 
 
An oral explanation of the study covering its nature, purpose, risks and requirements will be 
given to the subject prior to any study-specific procedures being performed. Written 
information will also be provided to the subject in the appropriate language. 
The subject will be given adequate time to consider their participation in the study and will be 
given the opportunity to ask the investigator about any aspect of the study.  If participation is 
agreed, a Consent Form will be signed.   If appropriate, a letter will be sent to the subject’s 
primary care doctor informing him/her that the subject is to participate in the study. 
Consent may be obtained at the Screening Visit, if appropriate. The informed consent form 
must be signed before any screening procedures are performed. 
7.2. 
Visit 1: Screening Visit (up to Day -28)  
The screening visit may be performed up to 28 days before first dose of investigational 
product.  
The following assessments will be performed: 
- 
Medical history, concomitant medications check 
- 
Demography, gender 
- 
Physical examination including 12-lead ECG, height and body weight  
- 
Vital signs: sitting blood pressure (mmHG) after a 5-min rest, pulse rate and respiration 
rate  
- 
Blood samples will be taken for the following assessments:  
o virology: anti-HIV1&2, HBsAg, anti-HCV (see Section 8.2.3) 
o serum biochemistry (see Section 8.2.3) 
o hematology (see Section 8.2.5)  
o serum pregnancy test for all females of child-bearing potential  
- 
Reserve blood samples will be taken (see Section 7.9.1) 
- 
A urine sample will be collected for urinalysis (see Section 8.2.6).  
 
There will be a review of eligibility criteria.  At the investigator’s discretion, one or more 
screening laboratory tests may be repeated prior to Day 0 (Visit 2) and if not clinically 
significant and otherwise qualifying to determine eligibility.  


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For full details of sample collection, labeling, processing and storage for all laboratory tests 
please see the separate Laboratory Manual.  
7.3. 
Visit 2: Baseline Visit (Day 0)  
Dosing will take place within 28 days of the Screening Visit.  
7.3.1. 
Before Dosing (Day 0) 
The following procedures will be performed prior to dosing: 
- 
Review of continued eligibility, including:  
o 
elements of informed consent 
o 
interim medical history 
o 
concomitant medications 
o 
Vital Signs 
- 
Oral temperature. If the participant is febrile (oral temperature >38.0°C [100.4°F]) 
or has an acute illness, their enrollment must be re-scheduled. The decision to delay 
vaccinations because of a current or recent acute illness depends on the severity of 
the symptoms and their cause. Although a moderate or severe acute illness is 
sufficient reason to postpone vaccination, minor illnesses  are not necessarily 
contraindications to vaccination. If re-scheduled. Day 0 must be within 28 days of 
all screening procedures; if greater than 28 days the subject must undergo a repeat 
screening visit. A new subject number will be assigned for repeat screening visits 
(see Study Reference Manual (SRM) for instructions on repeat screening). 
- 
Body weight will be measured for reassessment of eligibility and calculation of the dose 
of HRIG in IU/kg  
- 
A urine pregnancy test in females of childbearing potential  
- 
A urine sample will be taken for urine hemosiderin (see Section 8.2.7) 
- 
Blood samples will be taken for the following assessments:  
o 
rabies virus neutralizing antibodies (see Section 8.1.4) 
o 
markers of hemolysis (DCT, LDH, plasma free hemoglobin, serum haptoglobin and 
serum bilirubin) (see Section 8.2.7) 
- 
Reserve blood samples will be taken (see Section 7.9.1) 
- 
An archive serum sample will be taken (see Section 7.9.2) for long-term storage at -70oC 
for approximately 15 years. 
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7.3.2. 
Dosing on Day 0 
Immediately prior to dosing, each injection site for the HRIG will be examined for pain, 
tenderness, erythema and induration (see Section 8.2.2) by the blinded site personnel, to establish 
a baseline for local tolerance. 
According to the subject’s randomized treatment, an IM injection of 20 IU/kg body weight 
BPL HRIG or HyperRAB® S/D will be administered.  This will be followed by an IM injection 
of 1.0 ml licensed active rabies vaccine. Treatments for injection will be prepared and 
administered by unblinded site staff, who will remain separate to the study team as described 
in Section 6.6).   
The volume and location of administration of HRIG to each injection site will be recorded.  The 
location of administration of active rabies vaccine, which must be a separate site to the HRIG 
injections, will also be recorded. 
7.3.3. 
After Dosing 
Study subjects will be observed in the clinic for a minimum of 30 minutes post-dose.  Any 
adverse events will be assessed by the clinic staff and will be recorded in the subject notes.  
At 30 minutes (± 5 minutes), all injection sites will be examined for pain, tenderness, erythema 
and induration by qualified clinical staff. (see Section 8.2.2).  
 
7.4. 
Visits 3 to 7: Injections of Rabies Vaccine  
The subject will return to the clinic on the following days: 
Day 3 (Visit 3) 
Day 7 (Visit 5) 
Day 14 (Visit 6) 
Day 28 ± 2 days (Visit 7)  
7.4.1. 
Before Dosing 
The following assessments will be performed at all visits: 
o Check for any new or changed adverse events and concomitant medications since the 
last visit 
o Oral temperature. If the participant is febrile (oral temperature >38.0°C (100.4°F) or 
has an acute illness, active rabies vaccine must not be given.  The subject may continue 
in the study but should receive no further doses of active rabies vaccine and will not be 
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o  Injection site assessment (only if symptoms were observed at the previous visit) 
o Blood samples will be taken for rabies virus neutralizing antibodies (see Section 8.1.4) 
Reserve blood samples will be taken (see Section 7.9.1)  
In addition, the following assessments will be performed at the specified visits (see also the 
Schedule of Assessments in Appendix G): 
- 
Vital signs: sitting blood pressure (mmHg) after a 5-min rest, pulse rate and respiration 
rate – Day 28 (see Section 8.2.8) 
- 
Blood samples will be collected for the following assessments: 
o markers of hemolysis (DCT, LDH, plasma free hemoglobin, serum 
haptoglobin and serum bilirubin) on Day 3. These tests including CBC 
may be repeated on Day 5, Day 7 and Day 14 depending on results 
obtained at the previous visit (see Section 8.2.7).   
- 
A urine sample for hemosiderin – Day 3. This test may be repeated on Day 5, 7 and Day 
14 depending on results obtained at the previous visit (see Section 8.2.7).   
7.4.2. 
Dosing of Active Rabies Vaccine  
According to the subject’s randomized treatment, an IM injection of 1.0 ml licensed active 
rabies vaccine will be administered.  It may be administered to either the left or the right deltoid 
muscle, as long as there are no injection symptoms from previous HRIG or active rabies vaccine 
injections.  The location of administration of active rabies vaccine will be recorded. 
7.4.3. 
After Dosing 
Study subjects will be observed in the clinic for a minimum of 30 minutes post-dose.  Any 
adverse events will be assessed by the clinic staff and will be recorded in the subject notes.  
7.5. 
Visit 4: Day 5 PK sample 
The subject will return to the clinic on Day 5.  The following assessment will be performed: 
- 
Check of any new or changed adverse events and concomitant medications since the last 
visit. 
- 
Blood sample will be taken for rabies virus neutralizing antibodies (see Section 8.1.4) 
- 
Blood samples will be collected for markers of hemolysis (DCT, LDH, plasma free 
hemoglobin, serum haptoglobin and serum bilirubin), and CBC if the Day 3 DCT result 
was positive or missing (see Section 8.2.7). 
- 
A urine sample for hemosiderin will be collected if the Day 3 DCT result was a positive or 
missing (see Section 8.2.7).   


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- 
Reserve blood samples will be taken (see Section 7.9.1 ) 
7.6. 
Visit 8: Day 49 PK sample 
The subject will return to the clinic on Day 49 (± 4 days).  The following assessments will be 
performed: 
- 
Check of any new or changed adverse events and concomitant medications since the last 
visit 
- 
Physical examination (see Section 8.2.9) 
- 
Vital signs: sitting blood pressure (mmHg) after a 5min rest, pulse rate and respiration rate 
(see Section 8.2.8) 
- 
Blood samples will be taken for the following assessments:  
o rabies virus neutralizing antibodies (see Section 8.1.4) 
- 
Reserve blood samples will be taken (see Section 7.9.1) 
 
7.7. 
Visit 9: End-of-Study Assessment  
An End-of-Study assessment will be conducted at Day 140 (±7 days). The following 
assessments will be performed: 
- 
Check of any new or changed adverse events and concomitant medications since the last 
visit 
- 
Physical examination including 12-lead ECG and body weight  
- 
Vital signs: sitting blood pressure (mmHg) after a  5 min rest, pulse rate and respiration 
rate (see Section 8.2.8) 
- 
Blood samples will be taken for the following assessments:  
o hematology and serum biochemistry (see Sections 8.2.4 and 8.2.5)  
o Serum Pregnancy 
o virology: anti-HIV1&2, HBsAg, anti-HCV (see Section  8.2.3) 
o rabies virus neutralizing antibodies (see Section 8.1.4) 
- 
Reserve blood samples will be taken (see Section 7.9.1) 
- 
A urine sample will be collected for urinalysis 
- 
An archive serum sample will be taken (see Section 7.9.2) for long-term storage at -70oC or 
lower for 15 years. 


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7.8. 
Unscheduled Visits 
Subjects will also attend the investigational site as required for collection of repeat blood 
samples. 
7.9. 
Blood Sample Collection, Handling and Labeling 
Full details on blood sampling collection, handling, storage and shipment of samples can be 
found in the Laboratory Manual. 
7.9.1. 
Reserve Samples 
Two reserve plasma/serum samples will be collected at all timepoints, for re-analysis if needed, 
e.g. if an original sample is spoiled or if results are discrepant.  Additional reserve plasma 
samples will be taken pre-dose at Day 0 and Day 140 in case viral nucleic acid testing is required 
to confirm viral serology results (see Section 8.2.3). Human DNA testing will not be performed 
on any samples. Reserve samples will be stored at the study site at -70°C or lower for the 
duration of the study and sent to the central laboratory when requested by the sponsor (BPL).  
Reserve samples may be stored at a central laboratory archive until the license for BPL HRIG 
is granted in the US and EU (European Union) or other territories and will be used, if required, 
for repeat assays at the request of a regulatory agency. 
7.9.2. 
Archive Sample 
An archive serum sample will be collected pre-dose on Day 0 and at the End-of-Study 
Assessment.  Archive serum samples will be sent to the central laboratory for storage at -70oC 
and later by batch shipment to a central laboratory archive for storage at -70oC or lower  for 15 
years.  The archive sample serves as a safety measure for subjects receiving human plasma-
derived product, for investigation of risk factors which may potentially be identified in the 
future. 
7.10. 
Recording Laboratory Results 
All laboratory tests, except for the urine dipstick pregnancy test on Day 0, will be performed at 
a central laboratory.  Test results will be emailed to the investigator. All reports must be 
reviewed by the investigator as soon as possible after receipt, and printed, signed and dated by 
the investigator.   
Abnormal laboratory values considered to be clinically significant by the Investigator must be 
repeated as soon as possible after receiving the laboratory report to rule out laboratory error.  
Any values outside the normal range should be assessed for clinical significance, and any 
clinically significant results must be commented upon by the investigator.   


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7.11. 
Restrictions 
There are no restrictions on study subjects, except for certain concurrent medications 
(Section 6.4). 
 
 


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8. 
OUTCOME MEASURES 
8.1. 
Efficacy Measures 
8.1.1. 
Primary efficacy endpoint  
The primary efficacy endpoint is to demonstrate non-inferiority of BPL HRIG compared to an 
FDA-licensed HRIG product, in terms of: 
• 
the proportion of subjects with anti-rabies antibody titer of ≥ 0.5 IU/mL on day 14 after 
administration of BPL HRIG and vaccine / active comparator and vaccine using a non-
inferiority margin 10%. 
8.1.2. 
Secondary efficacy endpoints  
The following secondary efficacy endpoints will be assessed: 
1) Assessment of AUC0-7d for BPL HRIG and vaccine versus comparator HRIG and vaccine 
using a non-inferiority margin of 20%. 
2) Comparison of the geometric mean titers (GMTs) for anti-rabies antibody titer at Days 3, 
5, 7, 14, and 28 after administration of BPL HRIG and vaccine versus comparator HRIG 
and vaccine.  
3) The proportion of subjects reaching anti-rabies antibody titer of ≥0.5 IU/mL at Days 3, 5, 
7, 14, 28, 49, and 140 after administration of BPL HRIG and vaccine versus comparator 
HRIG and vaccine. 
4) The proportion of subjects reaching anti-rabies antibody titer of ≥ the lower limit of 
quantification (LLOQ) of the assay at Days 3, 5, 7, 14, 28, 49 and 140 after administration 
of BPL HRIG and vaccine versus comparator HRIG and vaccine.   
5) Comparison of the geometric mean titers (GMTs) for anti-rabies antibody titer at Days 14, 
28, 49, and 140 after administration of BPL HRIG and vaccine versus comparator HRIG 
and vaccine to assess the inhibitory effects of BPL HRIG on active immunization relative 
to that of the comparator HRIG. 
8.1.3. 
Exploratory efficacy endpoints  
The following PK parameters for anti-rabies antibody concentrations for both treatment groups 
will be assess as an exploratory endpoint:  
• 
Cmax [IU/mL] 
• 
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• 
area under the concentration vs time curve to the last measurable concentration (AUC0-
t) [day*IU/mL] 
• 
apparent terminal rate constant (λz) [day-1] 
• 
AUC0-7 days [day*IU/mL] 
• 
area under the concentration vs time curve to infinity (AUC0-∞), if appropriate 
• 
Cmax/AUC0-∞ [or Cmax/AUC0-t if AUC0-∞ cannot be estimated] 
• 
half-life (t½), if appropriate 
8.1.4. 
Rabies virus neutralizing antibody 
Rabies virus neutralizing antibody (RVNA) levels will be measured at 
 
 by the rapid fluorescent focus inhibition test (RFFIT). This 
serum neutralization test measures the ability of rabies specific antibodies to neutralize rabies 
virus and prevent the virus from infecting cells, and is the current gold standard serological 
assay3,8. The WHO 2nd international reference serum for rabies immunoglobulin will be used 
to titrate as a standard reference each time serum samples are tested.  This reference serum can 
vary in titer level for each batch of testing.  Therefore   serum samples at each PK timepoint 
(pre-dose on Days 0, 3, 5, 7, 14, 28, 49 and 140) will be batched by subject, tested for rabies 
RVNA titer after the subject’s study completion, and reported in IU/ml.   
The lowest RVNA level that can be accurately and precisely (the lower limit of quantification) 
measured at 
 is approximately 0.1 IU/mL. A RVNA level of equal to 
or above 0.5 IU/mL is globally recognized as indicating adequate vaccine response,4,9 . 
The laboratory staff will be blinded to study treatment.  Details for collection and processing 
of each blood sample will be documented separately in the Laboratory Manual. 
8.2. 
Safety Assessments 
The following will be used to assess the safety of BPL HRIG and vaccine, versus comparator 
HRIG and vaccine: 
• 
Adverse events 
• 
Injection site observations 
• 
Viral serology 
• 
Serum biochemistry, hematology and urinalysis 
• 
Markers of hemolysis 
• 
Physical examination 
CCI
CCI
CCI


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• 
Vital signs 
The following additional tests will additionally be performed: 
• 
pregnancy tests (for females of childbearing potential). 
8.2.1. 
Adverse Events 
All adverse events that appear or worsen during the study, from the time of signing informed 
consent, will be recorded in the CRF.  If a subject has a recurring condition, then this should be 
recorded at the Screening Visit in the Medical History pages of the CRF.  Fluctuations or re-
occurrences of the condition, that are considered normal for that subject and are recorded in the 
medical history, and need not be reported as an adverse event.  However, if the condition were 
to deteriorate during the study this would then be recorded as an adverse event.   
Adverse events will be reported in terms of their type, duration, treatment and/or severity. 
For further information on the definition and reporting of adverse events, see Appendix A. 
8.2.2. 
Injection Site Observations 
Each HRIG and vaccine injection site will be examined, and injection site observations will be 
assessed, pre-dose and 30 min [± 5 min] post-dose on Day 0 and at each subsequent clinic visit 
unless no symptoms are observed.   
For injection site reaction (ISR) assessment criteria, refer to the table below: 
Local Reaction 
to Injectable 
Product  
Mild  
(Grade 1)  
Moderate  
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life 
Threatening 
(Grade 4)  
Pain  
Does not interfere 
with activity  
Repeated use of 
non- narcotic pain 
reliever > 24 
hours or 
interferes with 
activity  
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity  
Emergency room 
(ER) visit or 
hospitalization  
Tenderness  
Mild discomfort 
to touch  
Discomfort with 
movement  
Significant 
discomfort at rest  
ER visit or 
hospitalization  
Erythema/ 
Redness *  
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or 
exfoliative 
dermatitis  
Induration/ 
Swelling **  
2.5 – 5 cm and 
does not interfere 
with activity  
5.1 – 10 cm or 
interferes with 
activity  
> 10 cm or 
prevents daily 
activity  
Necrosis  
* In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement.  
 


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For the complete guidance (see Appendix A, Section 7): Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials25 : 
All injection site reactions (ISR) will be recorded and graded on the ISR eCRF page.  However, 
the investigator will determine if these are AEs. Injection site reactions will be recorded as AEs 
when the sign/symptoms require concomitant medications, or have an impact on the general 
condition of the subject as judged by the Investigator. The investigator will use their judgement 
to record the severity of the AE, using the appended toxicity scale to guide their assessment. 
8.2.3. 
Viral  Serology 
Serum samples for viral serology testing will be collected at the Screening Visit and at 
the End-of-Study Assessment.  Subjects with a positive serological test for HIV 1&2, 
HCV or HBsAg at the Screening Visit will be excluded from the study. 
Samples will be tested for the following panel of serological markers: 
• 
Anti-HIV1 
• 
Anti-HIV2 
• 
HBsAg 
• 
Anti-HCV 
In addition, a reserve sample will be taken pre-dose at the Baseline Visit and at the 
End-of-Study Assessment specifically for nucleic acid testing (NAT) if required (see 
below). 
If any of the above serological tests are positive at the End-of-Study Assessment, 
suggesting a change in viral status of the subject, the sample will be tested by NAT 
(reflex testing).  If a change in viral status is confirmed by NAT, the central 
laboratory will inform the investigator, Sponsor and the designated CRO within one 
business day. The reserve samples taken pre-dose at the Baseline Visit and at the End-
of-Study Assessment will then be tested in the same laboratory in the same batch. 
8.2.4. 
Serum Biochemistry 
Blood samples for serum biochemistry assessments will be collected at the Screening Visit and 
at the End-of-Study Assessment.  Results at the Screening Visit will be used to determine 
eligibility for the study.  The following variables will be assessed for each biochemistry sample 
collected: 
• 
Albumin 


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• 
Alkaline phosphatase (ALP) 
• 
Alanine transferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
Blood Urea Nitrogen (BUN) 
• 
bicarbonate 
• 
Bilirubin (direct and total) 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
Creatinine Phosphokinase (CPK) 
• 
Gamma-glutamyl-transferase (GGT) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Potassium  
• 
Sodium 
• 
Total protein 
8.2.5. 
Hematology 
Blood samples for hematology assessments will be collected at the Screening Visit and at the 
End-of-Study Assessment.  Results at the Screening Visit will be used to determine eligibility 
for the study.  The following variables will be assessed for each hematology sample collected: 
• 
Hemoglobin 
• 
Hematocrit 
• 
Red blood cell count 
• 
White blood cell count (total and differential) 
• 
Mean cell volume 
• 
Mean corpuscular hemoglobin concentration 
• 
Platelet count 
8.2.6. 
Urinalysis 
Urine samples will be collected for urinalysis, including microscopic examination, at the 
Screening Visit and at the End-of-Study Assessment. Microscopic examination will be 


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performed in case of positive dipstick results or abnormal findings. Significant abnormalities at 
the Screening Visit will exclude the subject from the study.  
8.2.7. 
Markers of Hemolysis 
Blood samples for the following markers of hemolysis will be collected pre-dose on  
Days 0 and 3: 
• 
direct Coomb’s test (DCT) 
• 
serum lactate dehydrogenase (LDH)  
• 
plasma free hemoglobin  
• 
serum haptoglobin 
• 
serum bilirubin 
A urine sample for urine hemosiderin will be collected at the same timepoints.   
If the DCT result at Day 3 is positive or not available by Day 5, blood and urine samples will 
be collected pre-dose on Day 5 for testing of all the above markers, as well as an unscheduled 
CBC.  If any result at Day 5 is suggestive of hemolysis (i.e., positive DCT; plasma free 
hemoglobin, LDH, serum bilirubin, or urine hemosiderin above the normal reference range; 
haptoglobin below the normal reference range) all markers including CBC will be tested pre-
dose at Day 7.  Similarly, if any result at Day 7 is suggestive of hemolysis; all markers including 
CBC will be tested pre-dose at Day 14. 
Markers of hemolysis will be reviewed regularly by the medical monitor, and any 
potential signs of hemolysis will be reported to the investigator, sponsor and dedicated 
CRO by the central laboratory within one business day. 
8.2.8. 
Vital Signs and Body Temperature 
 
Vital signs will be assessed at Screening, Day 0, Day 28, and Day 49 and at the End-of-Study 
Assessment.  Vital signs will include the following assessments: 
• 
Sitting blood pressure (mmHg) after a 5-min rest. 
• 
Pulse rate (bpm). 
• 
Respiration rate (breaths/respirations per minute). 
 
Results at the Screening Visit will be used to determine eligibility for the study.  Evidence of 
uncontrolled hypertension (systolic blood pressure of >150 mmHg, and/or diastolic blood 
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Oral body temperature will be assessed pre-dose on Days 0, 3, 7, 14 and 28.  If the subject is 
febrile (oral temperature >38.0°C [100.4°F]) or has an acute illness at Day 0, their enrollment 
must be re-scheduled (see Section 7.3.1).  If re-scheduled, Day 0 must be within 28 days of all 
screening procedures; if outside of this window the subject must undergo a repeat screening visit. 
A new subject number will be assigned. (See SRM for instructions on repeat screening). 
If the subject is febrile at any subsequent visit, active rabies vaccine must not be given.  The 
subject may continue in the study but should receive no further doses of active rabies vaccine 
and will not be eligible for the per protocol population. 
8.2.9. 
Physical Examination 
A physical examination will be performed at the Screening Visit, on Day 49, and at the 
End-of-Study Assessment.  The following body systems will be examined: Head, ears, eyes, 
nose, throat, chest, cardiovascular, respiratory, abdomen, musculoskeletal, skin and general 
appearance.  
In addition, a 12-lead ECG in a semi-recumbent position following at least 5 minutes of rest 
will be performed at Screening and the End-of-Study Assessment. Results at the Screening 
Visit will be used to determine eligibility for the study.  Based upon the investigator’s 
judgement, significant abnormalities will exclude the subject from the study.   
Any changes in physical examination or ECG from the Screening assessment will be recorded, 
and any adverse changes will be reported as adverse events.  
Body weight and height will be measured at Screening, and body weight only will be repeated 
pre-dose on Day 0 and at the End-of-Study Assessment. Body weight at Screening or Day 0 
which exceeds 95.5 kg will exclude the subject from the study.  
8.2.10. 
Pregnancy Test 
 
A pregnancy test will be performed on all females of child-bearing potential (i.e. all those who 
are not more than 1 year post-menopausal or surgically sterilized).  Pregnancy testing will be 
performed on a serum sample at the Screening Visit, by the central laboratory. Pregnancy 
testing will be repeated on a urine sample pre-dose at the Baseline visit (Day 0) and serum 
sample at   End-of-Study Assessment by the central laboratory. A negative result at screening 
and Day 0 must be obtained to confirm the subject is eligible for the study.  


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9. 
WITHDRAWAL OF SUBJECTS 
Subjects may stop study treatment for any of the following reasons: 
• 
Withdrawal of consent. 
• 
Significant protocol deviation. 
• 
Occurrence of an adverse event which interferes with the subject’s ability to continue 
in the trial. 
• 
Occurrence of adverse events (AEs) not compatible with the continuation of subject 
participation in the study, in the investigator’s opinion (e.g. anaphylactic or other 
severe/serious reaction to injection).   
• 
Investigator’s request. 
• 
Pregnancy. If pregnancy occurs, the subject should be monitored and the outcome of 
delivery reported. 
• 
Requirement for therapeutic intervention prohibited by the protocol, for example, 
immunosuppressive agents. 
• 
Potential exposure to the rabies virus during the study, which would necessitate 
treatment with licensed HRIG. 
• 
Presenting with fever (oral temperature >38.0°C [100.4°F]) on Day 3, 7, 14 or 28.   
• 
Premature termination of the trial by BPL (e.g. if special circumstances concerning the 
IMP or BPL occur, making further treatment of subjects impossible, or if serious 
adverse events occur that are considered to make further treatment of subjects 
impossible).  If this occurs, BPL or BPL’s representatives will notify the regulatory 
authorities, ethics committees and investigators of the reason for premature study 
termination, within 15 days from the study being halted. 
• 
Reason not provided (subject lost to follow-up) 
The clinical investigator may also remove a subject if, in his/her opinion, it is in the best 
interests of the subject.  In exceptional circumstances relating to safety, the sponsor may 
withdraw subjects at any time. 
Subjects are free to withdraw from the study at any time without providing reason(s) for 
withdrawal and without prejudice to further treatment.  The reason(s) for withdrawal will be 
documented where possible, particularly where withdrawal is a consequence of an adverse 
event (see Appendix A).  The subject’s primary care physician will be informed of the reason 
for withdrawal if follow-up care is needed for safety. The subject will be informed if this is 
required. 


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Data collected up until a subject’s withdrawal from the study will be used in the analysis.  Data 
on screen failures will be collected. 
Subjects withdrawing from the study will be requested to complete the same End-of-Study 
assessments as subjects completing the study according to the protocol, particularly safety 
assessments.  If there is a medical reason for withdrawal, the subject will remain under the 
supervision of the investigator until in satisfactory health or the subject’s condition has 
stabilized. 
Reasonable efforts will be made to contact subjects who are lost to follow-up.  These efforts 
must be documented in the subject’s medical records.  


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10. 
DATA ANALYSIS 
10.1. 
Source Data 
The collection and analysis of high quality data is dependent on accurate documentation in the 
study subjects’ hospital notes, to allow accurate verification of CRF data.  See Appendix B 
(Administrative Requirements) for more detail on the recording of data in subject notes and 
maintenance of other study documents. 
10.2. 
Data Recording 
All data from the study will be entered into a eCRF at the study site.  All key data must be 
entered into the subjects’ medical records before they are entered in eCRF (see Appendix B, 
Section 11.4). 
10.3. 
Statistical and Analytical Plans 
All tables, figures and listings will be produced using SAS (v9.4 or a more recent version). 
Unless otherwise stated, categorical data will be presented using counts and percentages, whilst 
continuous variables will be presented using the mean, 95% confidence interval for the mean, 
standard deviation (SD), median, minimum, maximum, number of subjects (n) and number of 
missing subjects or data points.  Minima and maxima will be quoted to the number of decimal 
places as recorded in the CRF; means, SDs and medians will be quoted to one further decimal 
place.  Percentages will be rounded to one decimal place. 
Subjects who withdraw from the analysis will have their data analyzed to the point of 
withdrawal.   
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10.4. 
Analysis Populations 
The following analysis populations will be defined for this study. 
Intent-to-Treat (ITT) Population 
The intent-to-treat (ITT) population will include all randomized subjects.  All analyses will be 
performed using the ITT population. 
Safety Population 
The safety population will be defined as all subjects who receive at least one dose of BPL HRIG 
/ comparator HRIG.  Safety data will be analyzed up to the point of withdrawal for applicable 
subjects.  The safety population will be used for all safety analyses. 
Per Protocol Population 
The per protocol population will be split into the primary and secondary PK populations. 
The primary PK population will be defined as all subjects who receive the full dose of BPL 
HRIG / comparator HRIG and the first 3 doses of active rabies vaccine on Visits 2, 3, and 5, 
and for whom the PK sample at Visit 6 is taken.  This population will be used for the primary 
PK analysis and selected secondary analyses. 
The secondary PK population will be defined as all subjects who receive the full dose of BPL 
HRIG / comparator HRIG and all 5 doses of active rabies vaccine and for whom all required 
PK samples are taken.  This population will be used for selected secondary PK analyses and 
the exploratory PK analysis. 
Subjects with a pre-dose RVNA of ≥ the LLOQ will be excluded from all analyses.   
Subjects not meeting eligibility criteria or for whom major protocol deviations are 
reported may be excluded from the per protocol population if considered to potentially 
impact on the PK analysis. Any such cases will be fully justified in the clinical study 
report. 
 
10.5. 
Efficacy Analysis 
PK is a surrogate for efficacy, since a titer of ≥ 0.5 IU/mL is well-established as protective 
against the rabies virus.  RVNA titers will be listed for each subject, and summary statistics for 
each timepoint presented by treatment group. 
10.5.1. 
Primary PK Analysis 
The primary efficacy analysis will be based on the primary PK population.  


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The primary hypothesis is that the proportion of subjects receiving BPL HRIG + active vaccine 
with an anti-rabies titer of ≥ 0.5 IU/mL will not be less than the corresponding proportion for 
subjects receiving comparator HRIG + active vaccine, by more than 0.1 at Visit 6.  The 
Farrington and Manning test statistic will be used to assess the statistical comparison at a one-
sided significance level of 0.025. It will be concluded that the BPL HRIG is non-inferior to the 
comparator HRIG if the lower limit of an exact binomial 95% confidence interval calculated 
from the Farrington-Manning score test is greater than the a priori set -10% non-inferiority 
margin. 
An additional analysis will be performed to assess the impact of dosing/PK sampling not being 
performed on the designated day.  See Section 10.7.2. 
10.5.2. 
Hypothesis for the Primary PK Analysis 
The null hypothesis is p-p0 ≤ -0.1; 
The alternative hypothesis is p-p0 > -0.1,  
where p is the proportion of subjects with anti-rabies titer of  >0.5 IU/mL at Visit 6 in subjects 
receiving BPL HRIG + vaccine and p0 is the proportion receiving comparator HRIG + vaccine. 
We reject the null hypothesis at the one-sided 0.025 significance level, and conclude that p-p0 
> -0.1, if the lower bound of an exact 95% binomial confidence interval exceeds -0.1. 
10.5.3. 
Secondary PK Analysis 
Secondary efficacy analyses 2 and 5 will be based on the secondary PK population.  
Secondary efficacy analyses 1, 3, and 4 will be based on the primary PK population, since  
timepoints post-Visit 6 are not included in these analyses.  
The secondary PK endpoints will be analyzed as follow: 
1) the assessment AUC0-7d for BPL HRIG and vaccine versus comparator HRIG and vaccine 
using a non-inferiority margin of 20%.  
2) the geometric mean titers (GMTs) for RVNA titer  up to peak serum level after 
administration of BPL HRIG and vaccine or comparator HRIG and vaccine will be assessed 
using a mixed model repeated measure [MMRM] analysis.  
3) the proportion of subjects reaching anti-rabies antibody titer of ≥0.5 IU/mL at Visits 3-6 
after administration of BPL HRIG and vaccine versus comparator HRIG and vaccine will 
be assessed using a generalized estimated equation [GEE] for a repeated measure analysis.   
4) the proportion of subjects reaching anti-rabies antibody titer of ≥ the lower limit of 
quantification (LLOQ) of the assay at Visit 3-6 after administration of BPL HRIG and 


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vaccine versus comparator HRIG and vaccine will be assessed using a generalized 
estimating equation [GEE] for a repeated measure analysis.   
5) the GMTs for anti-rabies antibody titer at Visits 6-9 will be compared between treatment 
groups.  Descriptive statistics and visual inspections will be reported as appropriate.  No 
formal hypothesis testing will be performed. 
10.5.4. 
Exploratory PK Analysis 
The PK parameters for anti-rabies antibody concentrations as described in Section 8.1.3 will be 
statistically compared as appropriate between treatment groups. 
Non-compartmental PK methods will be utilized to calculate the subject level PK 
parameters.  Cmax, AUC0-t, AUC0-7d, AUC0-∞, apparent terminal rate constant (λz), and t1/2 
will be dose normalized by dividing the raw PK parameters by the actual dose the 
subject received.  A t-test will compare the PK and dose-normalized PK parameters 
between treatment groups.  Log-transformations will be performed as necessary during 
statistical analysis when appropriate. 
10.6. 
 
Safety Analysis 
The safety analysis will be based on the safety population. The general strategy of the safety 
evaluation will be to examine the summaries for any clinically relevant imbalance of safety 
events between the treatment groups.  Safety parameters for the two treatment groups will be 
compared descriptively.  Summary data will be presented by Treatment Group.  No formal 
hypothesis testing will be carried out.   
10.6.1. 
Adverse Events 
Adverse events (AEs) will be reported by the MedDRA system organ class and preferred term.  
Only treatment-emergent AEs, defined as those events with onset date from dosing with BPL 
HRIG / vaccine   or comparator HRIG / vaccine will be included in the summary tables.  All 
AEs will be included in the data listings.   
Treatment-related AEs will be defined as events recorded as having a possible, probable or very 
likely/certain causality to treatment.  AEs leading to withdrawal will be defined as events where 
the subject’s participation in the study was discontinued as a result of the AE. 
AEs will be summarized descriptively for all subjects and by treatment group.  The denominator 
used for the calculation of percentages will be the number of subjects in the safety population 
per treatment group.  For all AE summaries described below, counting will be performed by 
subject and event.  For counts by subject, subjects experiencing the same event more than once 


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will have that event counted only once within each system organ class and once within each 
preferred term. 
The following summaries of treatment-emergent AEs will be provided: 
Summary of AEs 
1) The number and percentage of subjects reporting AEs, serious AEs, study medication 
related AEs, AEs leading to withdrawal and AEs leading to death. 
2) The number of AEs, serious AEs, study medication-related AEs, AEs leading to withdrawal 
and AEs leading to death. 
Summary of AEs by Severity of Event 
The number and percentage of subjects reporting AEs, and study medication-related AEs, will 
be summarized by the system organ class and by the preferred term. The severity of event will 
be recorded once per subject for each term as the maximum severity experienced by each 
subject (i.e. where the order of most severe to least severe is given by: severe, moderate and 
then mild). 
Summary of AEs by Causality 
The number and percentage of subjects reporting AEs will be summarized by the system organ 
class and by the preferred term. The causality will be recorded once per subject for each term 
giving the most likely relationship to study medication (i.e. in the order: very likely/certain, 
probable, possible, unlikely and then unrelated). 
10.6.2. 
Injection Site Observations  
Injection site observations data will be summarized as appropriate.   
 Summary by Product 
The number and percentage of subjects reporting injection site reactions will be summarized 
by preferred term and product (HRIG or vaccine). 
Summary by Number of Injections 
The number and percentage of subjects reporting injection site reactions will be summarized 
by preferred term, product (HRIG or vaccine) and number of injections.    
10.6.3. 
Viral Serology Variables 
Viral serology variables will be summarized. Shift tables for virology will present the number 
of subjects with positive and negative results and those for whom the results change during the 
study. 


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10.6.4. 
Hematology, Serum Biochemistry, Urinalysis 
Hematology, serum biochemistry and urinalysis variables will be summarized, including 
changes from baseline. 
Shift tables for hematology and biochemistry variables will be provided for the number and 
percentage of subjects with values below, within and above the reference range.  
10.6.5. 
Markers of Hemolysis 
Markers of hemolysis will be summarized, including changes from baseline.   
10.6.6. 
Vital Signs and Body Temperature 
Sitting diastolic and systolic blood pressure, pulse rate, body temperature and respiration rate 
will be summarized, including changes from baseline (i.e. pre-dose on Visit 2 for body 
temperature, Screening for all other parameters).  In addition, the number of subjects with 
“substantial” increases or decreases from baseline in blood pressure (>20 mmHg) and pulse 
(>15 bpm) will be summarized. 
10.6.7. 
Physical Examination  
Physical Examination and ECG findings will be summarized. The shift from Screening to Visit 
8 and Screening to the End-Study Assessment will be summarized. Body weight data will be 
fully listed.   
10.6.8. 
Other Safety Parameters  
Pregnancy test results will be listed. 
10.7. 
Sensitivity Analyses 
Sensitivity analyses will be performed to assess the impact on the primary PK 
analysis of non-compliers within the ITT population, missing primary endpoints, and 
timing of vaccine dosing. 
10.7.1. 
Potential Interaction 
Before treatment unblinding, timing of vaccine dosing at Visits 3-5 and PK sampling 
at visit 6, if not performed on the designated day, will be assessed as potential effect 
modifiers on the association between RVNA levels and treatment group in the primary 
PK analysis.  A chi-square or fisher’s exact test, as appropriate, will be used to measure 
the association between the dichotomous indicator of receiving dose/PK sampling on 
the intended day [yes/no] and target level of RVNA titer reached [yes/no].  If the 
association is significant at the 0.05 level, a subgroup analysis including only subjects 


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who were dosed/sampled on the target day will be reported in addition to the full 
analysis. 
10.7.2. 
Non-Compliers and Missing Data  
Non-compliers will be defined as subjects who meet one of the following: 
• subjects who did not receive the full dose of BPL HRIG/comparator HRIG 
[not eligible for primary PK population]; 
• subjects who did not receive the first 3 doses of active rabies vaccine at the 
time specified [not eligible for primary PK population]; 
• randomized without meeting all eligibility criteria [may be eligible for primary 
PK population]; 
• subjects with any major protocol deviations reported [may be eligible for 
primary PK population]. 
Specifically, the following two analyses will be performed to assess impact on 
primary PK analysis: 
• 
The primary PK analysis will be repeated assuming that non-compliant subjects 
did not attain an RVNA titer of > 0.5 IU/mL at Visit 6.  [worst case scenario] 
• 
The primary PK analysis will be repeated assuming that non-compliant subjects 
successfully attain an RVNA titer of > 0.5 IU/mL at Visit 6. [best case 
scenario] 
10.8. 
Subgroup Analysis 
Subgroup analyses will be performed as appropriate, due to either imbalance 
randomization in baseline subject demographics and/or clinical relevance to primary 
and secondary PK analyses and safety analysis.  Factors including, but not limited to, 
age, race, and sex will be considered. Subgroups will be defined based on population 
median. 
 
10.9. 
Determination of Sample Size 
Statistical calculations indicate a minimum of 73 subjects per group is necessary.  To allow for 
subject withdrawals or unevaluable data, approximately 81 subjects will be enrolled per group.   
This study is powered based on a one-sided test with an overall study α of 0.05.  A total of 162 
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This computation accounts for an expected 10% dropout rate resulting in 146 evaluable 
subjects.  The following table outlines the underlying assumptions: 
Table 7: 
The underlying assumptions 
 
Day 14 ≥ 0.5 IU/mL 
Non-inferiority margin 
10% 
Difference 
0% 
% success 
98% 
10.10. 
Interim Analysis 
An interim analysis is not planned.


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11. 
INVESTIGATOR’S STATEMENT 
 
 
A Prospective, Randomized, Double-Blind, Parallel-group, Non-inferiority 
Phase II/III Study of the Safety and Effectiveness of BPL HRIG With 
Co-administration of Active Rabies Vaccine in Healthy Subjects  
 
 
Study Code: RIG01 
 
Version 1.0 
Date: 26 Oct 2017 
 
       
 
 
I have carefully read this protocol and the clinical investigator’s brochure and I confirm that 
they contain all the information necessary to perform the study I agree to carry out the study in 
compliance with the protocol, ICH GCP and applicable regulatory requirements. 
 
 
 
Signature: 
 
    Date: 
 
Principal Investigator 
 
 
Name: 
 (Printed) 
 
 
 


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12. 
REFERENCES 
1. Dyer JL et al.  Rabies Surveillance in the United States during 2013.  JAVMA (2014); 
245(10): 1111-1123. 
2. Manning SE et al.  Human Rabies Prevention – United States, 2008: Recommendations of the 
Advisory Committee on Immunization Practices.  MMWR (2008); 57(RR-3). 
3. Center for Disease Control and Prevention. http://www.cdc.gov/rabies/  accessed 18 Nov 
2016. 
4. Krebs JW, Long-Marin SC, Childs JE.  Causes, Cost, and Estimates of Rabies Post Exposure 
Prophylaxis Treatments in the United States.  J Public Health Manage Pract (1998); 4: 56-62 
5. Monroe BP et al. Rabies Surveillance in the United States during 2014. JAVMA (2016); 
248(7): 777-788. 
6. Moore SM, Hanlon CA. Rabies -Specific Antibodies: Measuring Surrogates of Protection 
against a Fatal Disease. PLOS Neglected Tropical Diseases 2010; 4(3): 1-6. 
7. Ruprecht CE, Briggs D, Brown CM et al. Use of reduced (4-dose) vaccine schedule for post 
exposure prophylaxis to prevent human rabies: Recommendations of the Advisory Committee 
in Immunization practices. Recommendations of the Advisory Committee on Immunization 
Practices. 2010. Morbidity and Mortality Weekly Report 59 No. RR-2. 
8. Smith JS, Yeager PA, Baer GM. A rapid reproducible test for determining rabies neutralizing 
antibody. Bull World Health Org. 197;; 48: 535-541. 
9. World Health Organization.  Rabies Vaccines WHO Position Paper.  Weekly Epidemiological 
Record No.49/50 (2007); 8:, 425-436. 
10. Baltazard M, Bahmanyar M, Ghodssi M, et al: Essai pratique du sérum antirelief chez les 
murus par loups enragés. Bull WHO 1955; 13:747-72. 
11. Hubel K, Koprowski H: Laboratory data supporting the clinical trial of ant rabies serum in 
persons bitten by a rabid wolf. Bull WHO 1955; 13:773-9. 
12. Artenasiu P, Bahmanyar M, Baltazard M, et al: Rabies neutralizing antibody response to 
different schedules of serum and vaccine inoculations in non-exposed persons. Bull WHO 
1956; 14:593-611. 
13. Artenasiu P, Bahmanyar M, Baltazard M, et al: Rabies neutralizing antibody response to 
different schedules of serum and vaccine inoculations in non-exposed persons: Part II. Bull 
WHO 1957; 17: 911-32. 
14. Artenasiu P, Cannon DA, Dean DJ, et al: Rabies neutralizing antibody response to different 
schedules of serum and vaccine inoculations in non-exposed persons: Part 3. Bull WHO 
1961; 25: 103-14. 
15. Aretenasiu P, Dean DJ, Habel K, et al: Rabies neutralizing antibody response to different 
schedules of serum and vaccine inoculations in non-exposed persons: Part 4. Bull WHO 
1967; 36:361-5. 


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16. Cabasso VJ, Loofbourow JC, Roby RE, et al: Rabies immune globulin of human origin: 
preparation and dosage determination in non-exposed volunteer subjects. Bull WHO 1971; 
45: 303-15. 
17. Loofbourow JC, Cabasso VJ, Roby RE, et al: Rabies immune globulin (human): clinical trials 
and dose determination. JAMA 217(13): 1825-31, 1971. Plotkin SA: New rabies vaccine halts 
disease — without severe reactions. Mod Med 1977; 45(20): 45-8. 
18. Rubin Rh, Sikes RK, Gregg MB: Human rabies immune globulin. Clinical trials and effects 
on serum anti-globulins. JAMA 1973; 224: 871-4. 
19. Investigator’s Brochure, Human Rabies Immunoglobulin, Bio Products Laboratory Ltd 
20. Kuwert EK, Werner J, Marcus I & Cabasso VJ.  Serovaccination by Human Immune Globulin 
and HDCS-Vaccine Against Rabies.  Develop. biol. standard 1977; 4: 129-136. 
21. Lang J, Gravenstein S, Briggs D, Miller B, Froeschle J, Dukes C, et al.  Evaluation of the Safety 
and Immunogenicity of a New, Heat-treated Human Rabies Immune Globulin Using a Sham, 
Post-exposure Prophylaxis of Rabies.  Biologicals 1998; 2: 7-15. 
22. Helmick CG, Johnstone C, Sumner J, Winkler WG & Fager S.  A Clinical Study of Merieux 
Human Rabies Immune Globulin.  Journal of Biological Standardization 1982; 10: 357-367. 
23. Mertz GJ, Nelson KE, Vithayasai V, Makornkawkeyoon S, Rosanoff EI, Tint H, et al.  
Antibody Responses to Human Diploid Cell Vaccine for Rabies With and Without Human 
Rabies Immune Globulin.  Journal of Infectious Diseases 1982; 145(5): 720-727. 
24. Jones RL, Froeschle JE, Atmar RL, Matthews JS, Sanders R, Pardalos J et al.  Immunogenicity, 
safety and lot consistency in adults of a chromatographically purified Vero-cell rabies vaccine: 
a randomized, double-blind trial with human diploid cell rabies vaccine.  Vaccine 2001; 19: 
4635-4643. 
25. FDA Guidance for Industry: Toxicity Grading Scale for Heathy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Trials 2007 
 
 


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APPENDIX A. - ADVERSE EVENT DEFINITIONS AND REPORTING 
PROCEDURES 
 
1. 
ABBREVIATIONS 
 
ADR 
 
- Adverse Drug Reaction 
AE 
 
- Adverse Event 
BPL 
 
- Bio Products Laboratory Limited 
CRF 
 
- Case Record Form 
CRO 
 
- Contract Research Organisation 
eCRF  
- Electronic Case Record Form 
ECG 
 
- Electrocardiogram 
FDA 
 
- Federal Drug Agency 
ICF 
 
- Informed Consent Form 
IEC 
 
- Independent Ethics Committee 
IRB 
 
- Institutional Review Board 
IMP 
 
- Investigational Medicinal Product 
SAE 
 
- Serious Adverse Event 
SmPC  
- Summary of Product Characteristics 
SUSAR  
- Suspected Unexpected Serious Adverse Reaction 
 
2. 
DEFINITIONS OF ADVERSE EVENTS 
2.1 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with this 
treatment.  An adverse event can therefore be any unfavourable and unintended sign including an 
abnormal laboratory (or vital sign, ECG, etc.) finding, symptom or disease temporally associated with 
the use of study medication.  All adverse events, whether considered by the investigator to be related to 
study medication must be described and recorded on the appropriate Adverse Event forms in the CRF/e-
CRF.  Where possible, a diagnosis should be made.  Anticipated fluctuations of pre-existing conditions, 
including the disease under study that does not represent a clinically significant exacerbation or 
worsening need not be considered AEs.   
 
2.2 
Adverse Events Temporally Associated with the Injection  
Unless clearly attributable to other causes any AEs that occur from the injection until Day 3 after the 
injection will be recorded as temporally related to the injection. 
 


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2.3 
Clinical Laboratory and Other Adverse Events 
If a laboratory result is considered by the investigator to be clinically significant or have a clinically 
significant pathological change from baseline it should be recorded as an AE. 
Other abnormal results (e.g. x-rays, scans, physical examination findings) that worsen from baseline 
and/or are considered clinically significant should also be recorded as AEs. 
The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
AEs should be reported and documented in accordance with the procedures outlined below.  All AEs 
occurring during the study must be documented on the relevant CRF/e-CRF pages.  The following data 
should be documented for each AE: 
• 
Description of the symptom event 
• 
Classification of ‘serious’ or ‘not serious’ 
• 
Severity 
• 
Date of first occurrence and date of resolution (if applicable) 
• 
Action taken 
• 
Causal relationship 
• 
Outcome of event (unknown, recovered, not recovered, recovered with sequelae, death [with 
date and cause reported]) 
2.4 
Pregnancy 
Subjects will be instructed that known or suspected pregnancy occurring during the study should be 
reported to the investigator.  The investigator should also be notified of pregnancy occurring during the 
study but confirmed after completion of the study.  If a subject is found to be pregnant after inclusion 
in the study, the subject must be withdrawn from the study.  Any pregnancy will be followed to term 
and the status of mother and child will be reported to the Sponsor after delivery.  
Full details of any pregnancy will be recorded on the AE page of the CRF/eCRF, and a Pregnancy & 
Outcome Report Form will be completed.  A copy of the Pregnancy Report Form must be completed 
and faxed to the appropriate contact (as detailed in the Study Reference Manual (SRM)) within 
24 hours. 
 
2.5 
Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose administered.  The 
phrase ‘response to a medicinal product’ means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility. 
 


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2.6 
Serious Adverse Event (SAE) or Drug Reaction 
A Serious Adverse Event or reaction is any untoward medical occurrence that at any dose: 
• 
results in death, 
• 
is life-threatening (patient at risk of death at time of event; not hypothetically life-
threatening), 
• 
requires inpatient hospitalization or prolongation of existing hospitalisation, 
• 
results in persistent or significant disability or incapacity, 
• 
is a congenital anomaly or birth defect?  
• 
is an important medical event (see below for definition)? 
The term “life-threatening” in the definition of “serious” refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
Medical and scientific judgement must be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should also 
usually be considered serious.   
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of 
drug dependency or drug abuse. 
The following medical conditions will be automatically regarded as serious, regardless of the 
classification assigned by the clinical trial investigator reporting the case: 
• 
Anaphylaxis or anaphylactoid reaction 
• 
Myocardial infarction 
• 
Stroke 
• 
Pulmonary embolism 
• 
Infection with any blood borne virus 
• 
Any transmissible spongiform encephalopathy 
In general, information that might materially affect the risk-benefit assessment of a medicinal product 
or that would suggest changes in the way it is to be administered or to the way a clinical investigation 
should be conducted should be reported in an expedited manner.  Examples include: 
• 
Single case reports of an expected adverse reaction with an unexpected outcome e.g. fatal 
outcome 
• 
For an expected serious adverse reaction, an increase in the rate of occurrence which is judged 
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• 
A significant hazard to the patient population, such as lack of efficacy in treating life-
threatening diseases or an event which is significant enough to lead to important changes in the 
way a medicine is developed e.g. change in dose, monitoring, consent forms. 
• 
A major new safety finding from a newly completed animal study. 
• 
A serious adverse event associated with a study procedure that could modify the conduct of the 
trial. 
2.7 
Unexpected ADRs 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator’s Brochure for an unapproved investigational product or summary of 
product characteristics (SmPC) for an authorised product).  Reports which add significant information 
on specificity, severity or frequency about a listed ADR would be classed as ‘unexpected’, for example, 
a report of interstitial nephritis when acute renal failure is the listed ADR or a report of fulminant 
hepatitis when the product information only lists hepatitis.   
Expectedness for BPL HRIG will be assessed against the Investigator’s Brochure, for HyperRAB® will 
be assessed against the USPI (Appendix D) and rabies vaccine will be assessed against the USPI 
(Appendix E). 
2.8 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
All suspected adverse reactions related to an IMP (the tested IMP, comparators or active vaccine) which 
occur that are both unexpected and serious (SUSARs) are subject to expedited reporting.  BPL and / or 
the designated CRO will be responsible for reporting these to the concerned Competent Authorities and 
to the Ethics Committee concerned, as detailed in the Study Reference Manual. 
3. 
DETECTING ADVERSE EVENTS 
Subjects will be carefully monitored for adverse events that occur after the Informed Consent Form 
(ICF) has been signed until the last day of the study.  The Investigator or delegate will question the 
subjects about adverse events using a non-leading question such as “How are you feeling?”  The 
Investigator will also record adverse events reported spontaneously by the subjects. Clinically 
significant changes in the findings of physical examination, and clinically significant abnormalities in 
the result of objective tests (e.g. laboratory variables, ECG) should be recorded as AEs.   
3.1 
Causality 
All AEs will be recorded in the CRF/eCRF, whether considered to be related or unrelated to the 
treatment.  The record will include the following: brief description of event (preferably a diagnosis), 
date and time started and stopped severity, outcome, actions taken and classification of the AE.  The 
Investigator should also evaluate the probability of a causal relationship of the AE to each medication 
administered during the study according to the following criteria as: 
 


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1. Unrelated 
Clinical event with an incompatible time relationship to study medication 
administration, or that could be explained by underlying disease or other drugs or 
chemicals, or is incontrovertibly not related to the IMP. 
2. Unlikely 
Clinical event whose time relationship to study medication administration makes a 
causal connection improbable, but that could plausibly be explained by underlying 
disease or other drugs or chemicals.   
3. Possible 
Clinical event with a reasonable time relationship to study medication 
administration, but that could also be explained by concurrent disease or other drugs 
or chemicals.   
4. Probable 
Clinical event with a reasonable time relationship to study medication 
administration, and is unlikely to be attributed to concurrent disease or other drugs 
or chemicals.   
5. Very likely / 
certain 
Clinical event with plausible time relationship to study medication administration, 
and that cannot be explained by concurrent disease or other drugs or chemicals.   
Study medication is defined as those investigational compounds or their controls and vaccines used in 
the study. 
It will be assumed that for all adverse events classified as “probably related”, “possibly related” or “very 
likely / certainly related” to the study medication, there is reasonable likelihood that the adverse event 
was causally related to the product.  All such adverse events will be regarded as “causally related” to 
the study medication. 
3.2 
Outcome of AEs 
The outcome of the AE should be documented as: 
• 
Recovered / resolved 
• 
Recovering / resolving 
• 
Not recovered / not resolved 
• 
Recovered / resolved with sequelae 
• 
Fatal   
• 
Unknown 
3.3 
Action taken 
The action taken by the Investigator or study staff should be documented as: 
• 
Drug withdrawn 
• 
Dose reduced 
• 
Dose increased 
• 
Dose not changed 
• 
Unknown 


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• 
Not applicable 
3.4 
Grading Severity of AE** 
Severity refers to the grading of adverse events to assess the severity of symptoms as evaluated by the 
Investigator or as experienced by the subject. The Investigator will make an assessment of severity (e.g. 
Grade 1 (mild)-Grade 4 (potentially life threatening)) for each AE and SAE reported during the study 
in accordance with the following definitions: 
 
Mild/Grade 1: No interference with activity 
 
 
Moderate/ Grade 2:  Some interference with activity not requiring medical intervention  
 
Severe/ Grade 3: Prevents daily activity and requires medical intervention. 
 
Potentially Life Threatening/Grade 4: Emergency room visit or hospitalization 
 
**Any adverse event resulting in Death will be classified as a Grade 5 
For further information (see Appendix A, Section 7): FDA Guidance on Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials25  
 
 
 
4. 
ADVERSE EVENT FOLLOW UP 
All adverse events will be followed: 
• 
to resolution  
or 
• 
until an underlying condition has been diagnosed 
or 
• 
until the patient’s condition has stabilised 
or 
• 
for a period of 28 days following the last administration of the study drug (HRIG or rabies 
vaccine) or the last study visit, whichever is soonest. 
Any new or unresolved AEs noted at the last study visit will be followed up for a further 28 days unless 
they fulfil the above criteria. 
All pregnancies will be followed up until birth and any birth defects will be reported as in the procedures 
for SAEs (see section 3 and 4). 
If the subject becomes pregnant while participating in the study, the pregnancy will not be recorded as 
an SAE, but will be captured on a Pregnancy Report Form and followed through until delivery or 
elective/spontaneous termination. 
5. 
REPORTING SERIOUS ADVERSE EVENTS 


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When an Adverse Event occurs, which fulfils the definition of serious (see Section 2.6 for definition) 
the Investigator must complete and sign the serious adverse event form and send it within 24 hours to 
the appropriate contact.,  
Medical cover for urgent queries relating to adverse events will be provided on 24 hours / 7 days a week 
by the following: 
 
All SAE reports must be e-mailed or faxed directly to 
 at 
 or  
(see study reference manual for guidance on providing documentation of SAE). 
The Investigator is responsible for expedited reporting of all Serious Adverse Events immediately to 
BPL and / or the designated CRO except for those that the protocol or Investigator’s Brochure identifies 
as not requiring immediate reporting.  This reporting requirement covers any serious adverse events 
that develop at any point between the date when a subject provides informed consent and up to 28 days 
after the last administration of the investigational medicinal product (HRIG or rabies vaccine).  The 
investigator is also responsible for reporting to BPL and / or the designated CRO   any serious adverse 
events with an onset date more than 28 days after the last administration of the product if he/she judges 
the serious adverse event to be possibly, probably or very likely/certainly related to the product.   
The immediate report should contain the following as a minimum: 
• 
a suspected investigational medicinal product 
• 
study subject number 
• 
details of the serious adverse event 
• 
classification of SAE  
• 
causality of SAE (if available) 
The immediate SAE form should be followed by a detailed, complete SAE form as soon as possible.  
The immediate report and follow-up reports shall identify subjects by unique code numbers assigned to 
the latter. 
Adverse events and/or laboratory abnormalities identified in the protocol as critical to the evaluation of 
safety must be reported to BPL and / or the designated CRO by the Investigator according to the 
reporting requirements within the time periods specified in this protocol. 
The investigator must not wait to receive additional information to document fully the event before 
notification of a SAE, though additional information may be requested.  Where applicable, information 
from relevant laboratory results, hospital case records and autopsy reports should be obtained. 
Instances of death, congenital abnormality or an event that is of such clinical concern as to influence 
the overall assessment of safety, if brought to the attention of the investigator at any time after cessation 
CCI
CCI
CCI
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of IMP administration and linked by the investigator to this study should be reported to BPL or the 
designated CRO. 
BPL and / or the designated CRO will promptly notify all relevant investigators and the regulatory 
authorities of findings that could adversely affect the safety of patients, affect the conduct of the study 
or alter the IEC/IRB approval/favourable opinion of the study. In addition, the sponsor (or designated 
CRO), will expedite the reporting to all concerned investigators, to the IECs/IRBs, where required, and 
to the regulatory authorities of all adverse events that are serious, unexpected, and in the opinion of the 
investigator, related to the IMP.  
The investigator will comply with local requirements related to the reporting of SAEs, IND Safety 
Notification Letters, and other safety information related to the trial to their local IRB. 
For reported deaths of a subject, the investigator shall supply BPL and / or the designated CRO 
(as stated in the Study Reference Manual) and the Independent Ethics Committee (IEC) / 
Institutional Review Board (IRB) with any additional information requested. 
5.1 
Completing Serious Adverse Event Forms 
Serious Adverse Event (SAE) forms must be completed in a timely manner and contain the following 
information: 
• 
subject number, randomization number, sex, date of birth, study centre, trial code, 
• 
description of event (where possible a diagnosis should be made rather than just listing 
symptoms), 
• 
dose, route, date and time of start and last dose, 
• 
date and time of adverse event, 
• 
all concomitant medication (copy of concomitant medication page can be appended), 
• 
causal relationship to study medication (as in Section 3.1), 
• 
outcome (as in Section 3.2), 
• 
action taken and treatment given (as in Section 3.3), 
• 
severity (as in Section 3.4), 
• 
classification of serious adverse event (as in Section 2.6), 
The SAE form must be signed and dated by the person reporting the SAE.  The final report must be 
signed and dated by the Principal Investigator from the site. 
6. 
BPL’S RESPONSIBILITIES 
BPL and / or the designated Contract Research Organisation (CRO) will be responsible for reporting 
all relevant safety information (including a listing of all SUSARs) to the competent authorities and to 
the IEC / IRB concerned.  In the case of blinded studies, the IEC / IRB and Competent Authority will 
be provided with an unblinded listing and in order not to bias the study the listing will be provided by 


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an independent person.  Safety reports will be issued in accordance with local relevant procedures (as 
a minimum on an annual basis).   
BPL and / or the designated CRO will inform the relevant Competent Authority(ies) in line with 
regulatory guidelines on adverse events occurring during the trial. The investigator retains the right to 
inform the relevant Competent Authority(ies) if he/she so desires but must inform BPL and / or the 
designated CRO (as stated in the Study Reference Manual) so that duplicate reports to the competent 
authority(ies) can be highlighted. 
BPL and / or the designated CRO will inform all investigators of all suspected unexpected serious 
adverse reactions occurring during the study or findings that could adversely affect the safety of 
subjects.   
 
7. 
TOXICITY GRADING SCALE FOR HEALTHY ADULT AND 
ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE 
CLINICAL TRIALS    
 


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APPENDIX B. - ADMINISTRATIVE REQUIREMENTS 
 
1. 
ABBREVIATIONS AND DEFINITIONS 
 
ARSAC 
- Administration of Radioactive Substances Committee 
BPL 
 
- Bio Products Laboratory Limited 
CA 
 
- Competent Authority 
COI 
 
- Coordinating Investigator 
CI 
 
- Chief Investigator 
CRA 
 
- Clinical Research Associate 
CRF 
 
- Case Record Form 
e-CRF  
- Electronic Case Record Form 
CV 
 
- Curriculum Vitae 
DQF 
 
- Data Query Form 
EU 
 
- European Union 
FDA 
 
- Food and Drug Administration 
GCP 
 
- Good Clinical Practice 
GMC  
- General Medical Council 
HIV 
 
- Human Immunodeficiency Virus 
ICH 
 
- International Conference on Harmonisation 
ID 
 
- Identification 
IEC 
 
- Independent Ethics Committee 
IMP 
 
- Investigational Medicinal Product 
IRB 
 
- Institutional Review Board 
PI 
 
- Principal Investigator 
R&D 
 
- Research and Development 
SOP 
 
- Standard Operating Procedure 
 
CA – ‘Competent Authority’, synonymous with ‘Regulatory Authority’: the Government body that has 
the power to regulate.  In the context of ICH GCP, the term ‘Competent Authority’ includes the 
authorities that review submitted clinical data and those that conduct inspections. 
 
CI – ‘Chief Investigator’: in relation to a clinical trial conducted at a single trial site, the Investigator 
for that site.  In relation to a clinical trial conducted at more than one trial site, the authorised health 
care professional, whether or not he/she is an Investigator at any site, who takes primary responsibility 
for the conduct of the trial. 
 


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COI – ‘Coordinating Investigator’: an investigator assigned the responsibility for the coordination of 
investigators at different centres participating in a multicentre trial. 
 
PI - ‘Principal Investigator’: a doctor or person following a profession for investigations because of the 
scientific background and the experience in subject care it requires.  The Principal Investigator is 
responsible for the conduct of the trial at the trial site.  If a trial is conducted by a team of individuals at 
a trial site, the Principal Investigator is the leader responsible for the team.   
 
IEC – ‘Independent Ethics Committee’:  a review board or a committee, institutional, regional, national 
or supranational, constituted of medical/scientific professionals and non-medical/non-scientific 
members, whose responsibility it is to ensure the protection of the rights, safety and well-being of 
human subjects involved in a clinical trial and to provide public assurance of that protection, by, among 
other things, reviewing and approving / providing favourable opinion on, the trial protocol, the 
suitability of the Investigator(s), facilities and the methods and material to be used in obtaining and 
documenting informed consent of the trial subjects. 
 
IRB – ‘Institutional Review Board’: an independent body constituted of medical, scientific and non-
scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being 
of human subjects involved in a clinical trial by, among other things, reviewing, approving and 
providing continuing review of the trial protocol and amendments and of the methods and material to 
be used in obtaining and documenting informed consent of the trial subjects. 
 
IMP – ‘Investigational Medicinal Product’: a pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical trial, including products already with a marketing 
authorisation but used or assembled in a way different from the authorised form, or when used for an 
unauthorised indication, or when used to gain further information about the authorised form. 
 
2. 
ETHICAL CONSIDERATIONS 
 
The study will be performed in accordance with the guidelines of the Declaration of Helsinki on 
biomedical research involving human subjects and in accordance with GCP guidelines (ICH), EU 
Directives 2001/20/EC1 and 2005/28/EC2 and FDA’s Code of Federal Regulations (CFR)3 21 CFR parts 
50, 54, 56, 312 and 314 as well as the demands of national drug and data protection laws, other 
applicable regulatory requirements and any new directives or regulations which become enforceable 
during the course of the study.   
 
Before the study can begin the Investigator must have submitted to an Independent Ethics Committee 
(IEC) / Institutional Review Board (IRB) the study protocol, Investigator’s Brochure, subject 


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information leaflet, consent form (and any updates), subject recruitment procedures and any other 
relevant study documentation as outlined in the guidance document (‘Detailed guidance on the 
application format and documentation to be submitted in an application for an Ethics Committee 
opinion on the clinical trial on medicinal products for human use’, ENTR/CT 2) for EU Directive 
2001/20/EC1.  Written approval of the study must be obtained before the study centre can be initiated 
or the investigational medicinal product (IMP) can be released to the Investigator.  Any necessary 
extensions or renewals of IEC / IRB approval must be obtained for changes to the study such as 
modification of the protocol, the informed consent form, the written information provided to subjects 
and/or other procedures. 
 
The Investigator will report promptly to the IEC / IRB any new information that may adversely affect 
the safety of the subjects or the conduct of the study.  The Investigator will submit written summaries 
of the study status to the IEC / IRB annually, or more frequently if requested by the IEC / IRB, in 
accordance with local regulatory requirements.  On completion of the study, the sponsor will notify the 
IEC / IRB that the study has ended. 
 
3. 
INFORMED CONSENT 
 
No study-related procedures will be performed prior to the subject’s and subject’s parent/legal 
guardian’s (if applicable) signed consent to participate in the study being obtained.  Before the decision 
to participate, the Investigator or a duly authorised deputy will provide both an oral and a written full 
explanation of the study and the subject’s rights.  The written consent must be given by the subject and 
the parent/legal guardian (if applicable) of the subject, after detailed information about the study has 
been given as outlined above in EU Directive 2001/20/EC1 and in accordance with any national 
provisions on the protection of clinical study subjects.  The verbal explanation will cover all the 
elements specified in the written information provided for the subject.   
 
For subjects not qualified to give legal consent, written consent must be obtained from the subject's 
parent/legal guardian.  If appropriate, children old enough to understand the risks and benefits of the 
study (generally for children above 6 years of age) should also be informed and provide their written 
assent.  In addition, the subject/subject’s parent or legal guardian will sign consent and child’s assent 
form authorizing release of the subject’s HIV test results to appropriate authorities.  All consent and 
assent forms must be approved in advance by the IRB/IEC. 
 
If the legal guardian is unable to read, an impartial witness should be present during the entire informed 
consent discussion.  After the informed consent form and any other written information is provided, 
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capable of doing so, the subject’s legal guardian should sign and date the informed consent form, and 
where appropriate written assent should be obtained from the subject.  The witness should also sign and 
date the consent form.  In addition, the subject’s legal guardian should, if possible, sign an additional 
form confirming that the materials provided have been read and explained to them. The witness should 
also sign and date this additional form. 
 
The Investigator or designated personnel will inform the subject of the objectives, methods, anticipated 
benefits and potential risks and inconveniences of the study.  The subject and parent/legal guardian (if 
applicable) must be given every opportunity to clarify any points they do not understand and, if 
necessary, to ask for more information.  At the end of the interview, the subject and parent/legal 
guardian (if applicable) will be given time to consider the study if this is required, or if they request 
more time.  Subjects and parents/legal guardians (if applicable) will be required to sign and date the 
informed consent form.  After signatures are obtained, the informed consent forms will be kept and 
archived by the Investigator in the Investigator’s study file for possible inspection by regulatory 
authorities, the IEC or IRB, BPL or BPL’s representative’s personnel, auditors.  The subject will keep 
an identical signed copy.  A letter will be sent to the subject’s primary care physician informing him/her 
that the subject is to participate in the study, as appropriate. 
 
It should be emphasised to the subject that he/she is at liberty to withdraw from the study at any time, 
without penalty or loss of benefits to which the subject is otherwise entitled.  Subjects who withdraw 
consent should not continue in the study, but will be asked to attend an end-of-study visit, if possible. 
 
The IEC / IRB will review and approve the subject information sheet and informed consent form.  If 
the Investigator intends to use his/her own information leaflet (for non-interventional studies only) 
he/she must ensure that it contains all the information outlined in Section 4.8 of the ICH-GCP 
guidelines. 
 
4. 
CONFIDENTIALITY 
 
The investigator will ensure that the subject's anonymity is preserved.  
In order to protect the subject’s identity, identification codes will be used in lieu of subject’s name.  
Personal information will be treated as confidential but may need to be reviewed by BPL or BPL’s 
representatives such as the CRA or auditor, or by representatives of IEC / IRBs or regulatory authorities.  
The subject’s consent to direct access to their personal notes must be obtained prior to participation in 
the trial.  Each subject’s Primary Care Physician will be informed of the nature and timing of the study, 
as appropriate. 
 


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All unpublished documents including the protocol, the case record form (CRF/eCRF) and the 
Investigator’s Brochure are confidential.  Those documents cannot be disclosed to a third party without 
the written consent of BPL.  However, submission of those documents to the IEC / IRB is expressly 
permitted. 
 
5. 
COMPENSATION/INDEMNITY 
 
Compensation will not be provided for injury or medical conditions that are unrelated to this study. 
BPL will indemnify the Institute and the Investigator with respect to 
 
 brought against it resulting from the administration to subjects, of source materials supplied by 
BPL, provided that the protocol and Investigator Agreement have been adhered to, and the event has 
not been occasioned by malpractice or negligence.  BPL will take out private insurance in respect of its 
potential liability.   
 
6. 
PROTOCOL ADHERENCE 
 
Adherence to the protocol is a fundamental part of the conduct of the study.  Deviations from the 
protocol, including deviations from the inclusion / exclusion criteria, might erode the scientific and 
ethical value of the protocol and its authorization and might have an impact on the processes put in 
place for the care and safety of the study subjects. 
 
Where a deviation has been made to eliminate an immediate hazard, the Investigator must submit a 
report of the implemented deviation and the reasons for it to the IEC / IRB and must notify relevant 
members of the Medical Department of BPL or the designated Contract Research Organisation.  
All deviations must be adequately documented. 
 
7. 
PROTOCOL AMENDMENTS 
 
A decision will first be made by BPL as to whether a protocol amendment is ‘Substantial’ or ‘Non-
substantial’.  Amendments to the protocol are regarded as ‘Substantial’ where they are likely to have 
significant impact on: 
• 
the safety or physical or mental integrity of the subjects; 
• 
the scientific value of the trial; 
• 
the conduct or management of the trial; or 
• 
the quality or safety of any investigational medicinal product (IMP) used in the trial. 
 
CCI
CCI


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Competent Authority (CA) and IEC / IRB written approval (if applicable) will be obtained prior to any 
protocol amendment being adopted.   
 
When a sponsor and/or Investigator must take urgent safety measures to protect the trial subjects from 
immediate hazard BPL or the designated CRO must be notified within 24 hours and the IEC / IRB and 
CA must be notified within 3 calendar days after appropriate safety measures have been taken.  For any 
period during which a disease is pandemic and is a serious risk to human health or potentially a serious 
risk to human health, the IEC/IRB and CA should be informed as soon as possible.   Where the 
amendment affects the risk/benefit ratio of continued participation for subjects already enrolled in the 
study, informed consent should be obtained again from such subjects using the new information 
leaflet/consent form.  The updated version of the information leaflet/consent form should be used for 
all new subjects recruited on to the trial. 
 
8. 
SERIOUS BREACHES 
 
A Serious Breach is a breach which effects to a significant degree either the safety or physical or mental 
integrity of the subjects in the clinical trial or the scientific value of the clinical trial.  The Investigator 
or participating laboratory must notify BPL or the designated Contract Research Organisation promptly 
(within 24 hours) of becoming aware of any Serious Breaches of the conditions and principles of GCP 
or the clinical trial protocol and any protocol amendment(s).  BPL (or designated Contract Research 
Organisation) will be responsible for informing the CA and IEC / IRB of any Serious Breach in line 
with applicable national laws and regulations.   
 
9. 
TRIAL TERMINATION 
 
BPL reserve the right to stop the trial if: 
• 
Recruitment is too slow to allow accrual of an adequate number of subjects within a reasonable 
length of time. 
• 
Evidence is gained that the subjects are being exposed to an unacceptable risk. 
• 
For any reason, it is not possible to continue to supply trial material. 
• 
An advancement in knowledge makes the trial redundant. 
 
If the study is terminated, BPL, the CRO and the investigator will ensure that adequate consideration is 
given to the protection of the subjects' interests. 
 
10. 
MONITORING VISITS 
 


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The BPL Clinical Research Associate (CRA) or representative CRA will monitor the study by 
telephone, correspondence, and regular visits to the investigational sites.  In accordance with ICH-GCP 
guidelines, the study monitor will carry out source document verification at regular intervals to ensure 
that the data collected in the CRF/eCRF are accurate, to carry out drug accountability and to ensure all 
documentation and study procedures comply with the protocol and with ICH-GCP.  The frequency of 
monitoring visits will be determined by the rate of subject recruitment.  
 
The CRA will ensure that: 
• 
the facilities remain adequate 
• 
the Investigator adheres to the protocol and ethical responsibilities 
• 
source documents are legible and agree with entries in the CRF/eCRF 
• 
adverse events are adequately documented and reported 
• 
investigational medicinal product is properly stored and accountability is being maintained 
• 
laboratory samples are identified, handled and stored appropriately. 
 
The Investigator must permit the CRA, the IEC / IRB, BPL appointed auditors and representatives from 
regulatory authorities direct access to all study-related documents and pertinent hospital or medical 
records for confirmation of data contained within the CRF/eCRFs.  The Investigator will agree to make 
himself/herself available to correct or discuss any discrepancies.  Subject confidentiality will be 
protected at all times. 
 
A “Site Delegation of Duties and Signature Log” will be completed and signed by the responsible 
investigator.  In accordance with this authority log, study site staff (e.g. co-investigators and nurses) 
will be authorised to enter data into the CRF/eCRF.  The monitor will visit the study centres as required. 
 
11. 
AUDIT/INSPECTION 
 
Access to documentation and facilities used during the study may be required by BPL appointed 
auditors or by regulatory authorities. 
In the event that the regulatory authorities schedule an audit the Investigator must notify BPL 
immediately.  BPL will in turn notify the Investigator if they are informed of an audit at an Investigator’s 
site. 
The main purposes of an audit or inspection are to confirm that the rights and welfare of the subjects 
have been adequately protected, and that all data relevant for the assessment of safety and effectiveness 
of the investigational product have been reported to the sponsor.  
 


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The verification of the CRF/e-CRF data may be performed by direct inspection of source documents, 
after the investigator has protected all confidential personal subject information not related to the study, 
in accord with local regulations. 
 
12. 
REQUIRED PRE-STUDY DOCUMENTATION 
 
Before the start of the study, BPL will require, as a minimum, the following documentation: 
1. A signed copy of the protocol and signed amendments approved by the IEC/IRB. 
2. A signed Clinical Trial Agreement, including any host R&D approval. 
3. Other signed financial agreements (e.g. laboratory, pharmacy). 
4. Signed Confidentiality Agreements for study team. 
5. A signed Secrecy Agreement (if applicable). 
6. A completed Investigator Financial Disclosure / Certification Statement and a Statement of 
Investigator (Form FDA 1572), if applicable. 
7. An Indemnity Form signed and dated by both parties unless indemnity is covered by other 
signed agreements for the study. 
8. Insurance policy or statement that this is not required. 
9. IEC / IRB written approval. 
10. Assurance that the IEC / IRB is organised and operates according to GCP and the applicable 
laws and regulations. 
11. ARSAC approval (if applicable). 
12. CA Approval. 
13. Signed CVs of Investigators and sub-Investigators showing current position and Licence/ 
registration number, as appropriate. 
14. Normal Ranges for: 
Laboratory parameters. 
Medical or technical procedures. 
Tests included in the protocol. 
15. Evidence of validation of procedures/tests to be performed e.g.: 
Accreditation 
Certification 
SOPs for specialised tests 
16. IEC / IRB approved subject information sheet and consent forms, identified with version 
number and date, plus any other written information given to subjects. 
17. Investigator’s Brochure, the edition clearly identified plus any updates. 
18. Master randomisation list (if appropriate). 
19. Decoding procedures for blinded trials. 


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20. Sample case record form. 
If any of these documents are issued in a language other than English then verified translations are 
required. 
 
11. 
COMPLETION AND RETURN OF CASE RECORD FORMS AND DATA QUERY 
FORMS 
 
11.1 
Recording Data in Case Record Forms (CRF/eCRFs)  
All study data will be recorded on CRFs/e-CRFs provided by BPL or the designated Contract Research 
Organisation.  These must be completed by the Investigator or a duly authorised assistant.   
 
11.2 
Electronic CRF  
In the case of an e-CRF, errors occurring in the e-CRFs will be corrected directly in the data field of the 
e-CRF.  An audit trail capturing the original entry, the new entry, the user ID of the entry personnel, 
and the date and time of each action will be maintained in the data capture system.  Likewise, the 
interchange of queries between the CRO and the site, as well as query replies, will be maintained within 
the audit trail of the data capture system.  Any changes to the data in the data capture system that occur 
after the investigator or authorised co-investigator have electronically signed the e-CRF will require 
that the investigator or authorised co-investigator review and re-sign the e-CRF. 
 
11.3 
Signing off CRF/eCRFs and DQFs and return to BPL or the designated Contract 
Research Organisation 
In the case of e-CRFs for each subject enrolled, e-CRFs will be completed and signed electronically by 
the investigator or an authorised co-investigator.  
 
All paper source documents will be filled out using an indelible pen, and must be legible.  
 
11.4. 
Handling of clinical trial data 
All clinical trial data will be recorded, handled and stored in such a way that it can be accurately 
reported, interpreted and verified, whilst maintaining the confidentiality of the subjects’ records. 
 
11.5 
Source Documents 
Source data are defined as all information related to clinical findings, observations, or other activities 
in the study, written in original records or consisting of certified copies of original records. The 
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Source documents or data to be entered directly into the Case Record Form will be defined prior to 
study start in an appropriate plan e.g. definition of source data document. 
 
12. 
MAINTENANCE AND ARCHIVING OF STUDY RECORDS 
 
12.1 
Investigator Site File 
The Investigator will be supplied with an Investigator Site File by BPL or the designated Contract 
Research Organisation at the start of the study, containing copies of required pre-study essential 
documents.  It is the responsibility of the Investigator and study team members at site to maintain these 
essential documents and ensure their secure storage.  The Investigator Site File will comprise the 
following documentation, although certain sections may be kept in a separate file with certain study 
team members e.g. laboratory or pharmacy staff: 
 
Agreements 
• 
Signed Confidentiality Agreements for study team. 
• 
Signed Clinical Trial Agreement, including any host R&D approval (and submission 
documentation where applicable) detailing versions of the documents approved. 
• 
Other signed financial agreements specific to the site (e.g. laboratory, pharmacy). 
• 
Indemnity Form (if used) signed and dated by both parties, unless indemnity is covered by other 
signed agreements for the study. 
• 
Insurance statement if applicable. 
• 
A completed Investigator Financial Disclosure / Certification Statement and a Statement of 
Investigator (Form FDA 1572), if applicable. 
Protocol 
A signed copy of the protocol and signed amendments approved by the IEC/IRB. 
Product Information 
• 
Investigator’s Brochure, the edition clearly identified plus any updates. 
• 
Supporting publications and information. 
• 
Safety updates from BPL, including any aggregated line listings of SUSARs and summary 
safety reports, in accordance with local regulatory requirements. 
CRF/eCRF and Supporting Information 
• 
Sample case record form. 
• 
Other blank forms used in the study e.g. diary cards. 
• 
Data transmittal forms. 
CVs 
• 
Signed CVs of Investigators and sub-Investigators showing current position and GMC 
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• 
Site Delegation of Duties Log. 
• 
Reference to training records of study site personnel / Site training log. 
Ethics Committee 
• 
IEC / IRB written approval. 
• 
CA Approval. 
• 
ARSAC approval (if applicable). 
• 
Relevant correspondence with IEC/IRB. 
• 
Copies of progress reports to IEC/IRB. 
• 
Copies of annual safety reports to IEC/IRB, in accordance with local regulatory requirements. 
• 
Copies of IEC/IRB approved consent forms. 
• 
Copies of IEC/IRB approved information leaflets. 
• 
Final letter and report to IEC/IRB documenting study completion. 
Laboratory Details 
• 
Central laboratory manual, if applicable. 
• 
Local laboratory normal ranges both current and previous if changed during study, if applicable. 
• 
Local laboratory certification / accreditation both current and any updates. 
• 
Local laboratory validation or SOPs for specialized tests both current and any updates. 
• 
Sample storage log. 
• 
Local sample handling procedures, unless included in a central laboratory manual 
• 
Laboratory parameters 
• 
Medical or technical procedures 
• 
Tests included in the protocol. 
 
Subject Details 
• 
Master randomisation list (if appropriate). 
• 
Subject screening log (if appropriate). 
• 
Subject enrollment log (if appropriate). 
• 
Signed informed consent forms; informed consent checklist, if used. 
• 
Template of letter to primary physician. 
• 
If applicable, completed subject identification code list for randomized studies (at study 
completion). 
Adverse Events 
• 
Reports of Serious Adverse Events and SUSARs. 
• 
Correspondence relating to SAEs and SUSARs. 
• 
Notification of SUSARs to IEC/IRB. 
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Investigational Medicinal Product 
• 
IMP receipt forms. 
• 
Procedure for temperature monitoring. 
• 
Certificates of Analysis, if requested. 
• 
IMP accountability records.  
• 
Instructions for handling IMP. 
• 
Example prescription form (if applicable). 
• 
Documentation of destruction of IMP. 
• 
Randomisation code location (if not kept in Investigator Site File). 
Monitoring 
• 
Pre-study and Initiation Site Visit Report forms. 
• 
Case Record Form correction notes. 
• 
Data query forms.  
Reports 
• 
Any interim clinical study report. 
• 
The final Clinical Study Report.  A synopsis will suffice. 
Completed CRF/eCRFs 
• 
Copies of completed CRF/eCRFs or reference if stored separately. 
• 
Copy of any CRF/eCRF and data query tracking and acknowledgement forms. 
Meetings 
Minutes of meetings, agenda and correspondence relating to meetings. 
Publications 
• 
Any publications of trial results available before site closure. 
• 
If any of these documents are issued in a language other than English then verified translations 
are required. 
 
12.2 
Subject notes 
The Investigator must maintain adequate records of subject participation for the duration of the study.  
These records must be available for inspection upon reasonable request by the sponsor, members of the 
regulatory authorities or other authorised individuals.   The Investigator must detail in the subject notes 
that the subject is eligible for the study prior to enrollment.  The Investigator must also ensure that 
worksheets provided for the study that form part of the source data must always be included in the 
subject notes.  
 
12.3 
Availability of data for inspection 
The Investigator is obliged to provide BPL, or BPL’s representative, with complete test results and all 
data and reports within the timeframe agreed by both parties. 


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After completion of the study, all documents and data relating to the study will be kept in an orderly 
manner by the Investigator in a secure study file.  This file will be available for inspection by the sponsor 
or its representatives.   
 
12.4 
Archiving study documentation 
 
The Investigator must make proper provision for archiving study documentation.  Essential documents 
must be retained in accordance with ICH-GCP.  Essential documents must be retained for two years 
after the last marketing approval in an ICH region or until at least two years have elapsed since the 
discontinuation of clinical development of the IMP.  It is BPL’s responsibility to inform the Investigator 
or Institute as to when these documents no longer need to be retained.  It is the Investigator’s 
responsibility to notify BPL, or BPL’s representative, in writing if they are unable to make suitable 
provisions for archiving study documents at the study centre.  Prior to archive, subject ID codes should 
be kept in a suitable place to enable easy access at the Investigator site.  Subject ID codes must be 
retained for a period of at least 15 years after issue of the final study report.  Subject consent forms and 
other study related documentation must be retained for a maximum period permitted by the hospital, 
institution or private practice 
 
Essential documents from trials which are not to be used in regulatory submissions should be retained 
for at least five years after completion of the trial.  These documents should be retained for a longer 
period if required by the applicable regulatory requirements or by agreement with BPL. 
 
No study document should be destroyed without prior written agreement between the investigator and 
the sponsor. Should the investigator elect to assign the study documents to another party, or move them 
to another location, the sponsor must be notified. 
 
13. 
REPORT AND PUBLICATION 
 
BPL’s standard report and publication policy is detailed below. In the case of the agreement between 
BPL and the Investigator differing from this policy, what is stated in the agreement will override what 
is stated below.  
 
In accordance with relevant guidelines, a final clinical study report will be prepared after the completion 
of the study. 
 


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BPL recognises that the Investigator might wish to publish the results of the study.  The Investigator 
and members of the Investigator’s team engaged in the study shall not be permitted to present at 
symposia and professional meetings or to publish journals, theses or dissertations, or otherwise of their 
choosing, methods and results of the Study (all of which hereinafter referred to as “the Publication”) 
without the consent of BPL. 
 
In the case that the Investigator or members of the Investigator’s team engaged in the study wish to 
pursue the Publication, the Investigator shall furnish BPL with copies of the Publication at least two 
months in advance of the intended date of whichever is the earliest submission of the Publication or 
presentation of the Publication or publication of the Publication or the making of a commitment to do 
any of the foregoing.  The Investigator agrees, if BPL requests a meeting between the Investigator and 
BPL, to discuss in good faith the comments. 
 
BPL shall have two months, after receipt of said copies, to object to such proposed Publication on 
reasonable grounds.  For the avoidance of doubt the grounds that the subject matter is patentable or 
commercially sensitive shall constitute reasonable grounds. 
 
Authorship should reflect work done by the investigators and BPL personnel, in accordance with 
generally recognised principles of scientific collaboration. 
 
14. 
REFERENCES 
 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States relating to 
the implementation of good clinical practice in the conduct of clinical trials on medicinal products for 
human use. 
 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for 
good clinical practice as regards investigational medicinal products for human use, as well as the 
requirements for authorization of the manufacturing or importation of such products. 
 
FDA guidelines CFR 21 (www.fda.gov) which dictates the regulations and principles for conducting 
clinical trials in the USA. 
 
 


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APPENDIX C. - INVESTIGATOR’S RESPONSIBILITIES BASED ON 
THE GUIDELINES FOR GOOD CLINICAL PRACTICE 
1. 
LOCAL INVESTIGATOR 
1.1 
Investigator’s Qualifications and Agreements 
1.1.1 
The investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications specified 
by the applicable regulatory requirement(s), and should provide evidence of such qualifications 
through up-to-date curriculum vitae and/or other relevant documentation requested by the 
sponsor, the IRB/IEC, and/or the Regulatory Authority(ies). 
1.1.2 
The investigator should be thoroughly familiar with the appropriate use of the investigational 
product(s), as described in the protocol, in the current Investigator’s Brochure, in the product 
information and in other information sources provided by the sponsor. 
1.1.3 
The investigator should be aware of, and should comply with, ICH GCP and the applicable 
regulatory requirements. 
1.1.4 
The investigator/institution should permit monitoring and auditing by the sponsor, and 
inspection by the appropriate Regulatory Authority(ies). 
1.1.5 
The investigator should maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related duties. 
1.2 
Adequate Resources 
1.2.1 
The investigator should be able to demonstrate (e.g. based on retrospective data) a potential for 
recruiting the required number of suitable subjects within the agreed recruitment period. 
1.2.2 
The investigator should have sufficient time to properly conduct and complete the study within 
the agreed study period. 
1.2.3 
The investigator should have available an adequate number of qualified staff and adequate 
facilities for the foreseen duration of the study to conduct the study properly and safely. 
1.2.4 
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, the investigational product(s), and their study-related duties and functions. 
1.3 
Medical Care of Study Subjects 
1.3.1 
A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator 
for the study, should be responsible for all study-related medical (or dental) decisions. 
1.3.2 
During and following a subject’s participation in a study, the investigator/institution should 
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significant laboratory values, related to the study.  The investigator/institution should inform a 
subject when medical care is needed for intercurrent illness(es) of which the investigator 
becomes aware. 
1.3.3 
It is recommended that the investigator inform the subject’s primary physician about the 
subject’s participation in the study if the subject has a primary physician and if the subject 
agrees to the primary physician being informed. 
1.3.4 
Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a 
study, the investigator should make a reasonable effort to ascertain the reason(s), while fully 
respecting the subject’s rights. 
1.4 
Communication with IRB/IEC 
1.4.1 
Before initiating a study, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol, written informed consent 
form, consent form updates, subject recruitment procedures (e.g. advertisements), and any other 
written information to be provided to subjects. 
1.4.2 
As part of the investigator’s/institution’s written application to the IRB/IEC, the 
investigator/institution should provide the IRB/IEC with a current copy of the Investigator’s 
Brochure.  If the Investigator’s Brochure is updated during the study, the investigator/institution 
should supply a copy of the updated Investigator’s Brochure to the IRB/IEC. 
1.4.3 
During the study the investigator/institution should provide to the IRB/IEC all documents 
subject to review. 
1.5 
Compliance with Protocol 
1.5.1 
The investigator/institution should conduct the study in compliance with the protocol agreed to 
by the sponsor and, if required, by the Regulatory Authority(ies) and which was given 
approval/favorable opinion by the IRB/IEC.  The investigator/institution and the sponsor should 
sign the protocol, or an alternative contract, to confirm agreement. 
1.5.2 
The investigator should not implement any deviation from, or changes of the protocol without 
agreement by the sponsor and prior review and documented approval/favorable opinion from 
the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to 
study subjects, or when the change(s) involves only logistical or administrative aspects of the 
study (e.g. change in monitor(s), change of telephone number(s)). 
1.5.3 
The investigator, or person designated by the investigator, should document and explain any 
deviation from the approved protocol. 
1.5.4 
The investigator may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to study subjects without prior IRB/IEC approval/favorable opinion.  As 


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soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, 
the proposed protocol amendment(s) should be submitted; 
 
a) 
to the IRB/IEC for review and approval/favorable opinion, 
b) 
to the sponsor for agreement and, if required  
c) 
to the Regulatory Authority(ies). 
1.6 
Investigational Product(s) 
1.6.1 
Responsibility for investigational product(s) accountability at the study site(s) rests with the 
investigator/institution. 
1.6.2 
Where allowed/required, the investigator/institution may/should assign some or all the 
investigator’s/institution’s duties for investigational product(s) accountability at the study 
site(s) to an appropriate pharmacist or another appropriate individual who is under the 
supervision of the investigator/institution. 
1.6.3 
The investigator/institution and/or a pharmacist or other appropriate individual, who is 
designated by the investigator/institution, should maintain records of the product’s delivery to 
the study site, the inventory at the site, the use by each subject, and the return to the sponsor or 
alternative disposition of unused product(s).  These records should include dates, quantities, 
batch/serial numbers expiration dates (if applicable), and the unique code numbers assigned to 
the investigational product(s) and study subjects.  Investigators should maintain records that 
document adequately that the subjects were provided the doses specified by the protocol and 
reconcile all investigational product(s) received from the sponsor. 
1.6.4 
The investigational product(s) should be stored as specified by the sponsor and in accordance 
with applicable regulatory requirement(s). 
1.6.5 
The investigator should ensure that the investigational product(s) are used only in accordance 
with the approved protocol. 
1.6.6 
The investigator, or a person designated by the investigator/institution, should explain the 
correct use of the investigational product(s) to each subject and should check, at intervals 
appropriate for the study, that each subject is following the instructions properly. 
1.7 
Randomization Procedures and Unblinding 
The investigator should follow the study’s randomization procedures, if any, and should ensure 
that the code is broken only in accordance with the protocol.  If the study is blinded, the 
investigator should promptly document and explain to the sponsor any premature Unblinding 
(e.g. accidental Unblinding, Unblinding due to a SAE) of the investigational product(s). 
1.8 
Informed Consent of Study Subjects 


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1.8.1 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to ICH GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki.  Prior to the beginning of the 
study, the investigator should have the IRB/IEC’s written approval/favorable opinion of the 
written informed consent form and any other written information to be provided to subjects. 
1.8.2 
The written informed consent form and any other written information to be provided to subjects 
should be revised whenever important new information becomes available that may be relevant 
to the subject’s consent.  Any revised written informed consent form, and written information 
should receive the IRB/IEC’s approval/favorable opinion in advance of use.  The subject or the 
subject’s legally acceptable representative should be informed in a timely manner if new 
information becomes available that may be relevant to the subject’s willingness to continue 
participation in the study.  The communication of this information should be documented. 
1.8.3 
Neither the investigator, nor the study staff, should coerce or unduly influence a subject to 
participate or to continue to participate in a study. 
1.8.4 
None of the oral and written information concerning the study, including the written informed 
consent form, should contain any language that causes the subject or the subject’s legally 
acceptable representative to waive or to appear to waive any legal rights, or that releases or 
appears to release the investigator, the institution, the sponsor, or their agents from liability for 
negligence. 
1.8.5 
The investigator, or a person designated by the investigator, should fully inform the subject or, 
if the subject is unable to provide informed consent, the subject’s legally acceptable 
representative, of all pertinent aspects of the study including the written information given 
approval/favorable opinion by the IRB/IEC. 
1.8.6 
The language used in the oral and written information about the study, including the written 
informed consent form, should be as non-technical as practical and should be understandable 
to the subject or the subject’s legally acceptable representative and the impartial witness, where 
applicable. 
1.8.7 
Before informed consent may be obtained, the investigator, or a person designated by the 
investigator, should provide the subject or the subject’s legally acceptable representative ample 
time and opportunity to inquire about details of the study and to decide whether or not to 
participate in the study.  All questions about the study should be answered to the satisfaction of 
the subject or the subject’s legally acceptable representative. 
1.8.8 
Prior to a subject’s participation in the study, the written informed consent form should be 
signed and personally dated by the subject or by the subject’s legally acceptable representative, 
and by the person who conducted the informed consent discussion. 


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1.8.9 
If a subject is unable to read or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
written informed consent form and any other written information to be provided to subjects, is 
read and explained to the subject or the subject’s legally acceptable representative, and after 
the subject’s legally acceptable representative has orally consented to the subject’s participation 
in the study and, if capable of doing so, has signed and personally dated the informed consent 
form, the witness should sign and personally date the consent form.  By signing the consent 
form, the witness attests that the information in the consent form and any other written 
information was accurately explained to, and apparently understood by, the subject or the 
subject’s legally acceptable representative, and that informed consent was freely given by the 
subject or the subject’s legally acceptable representative. 
1.8.10 Both the informed consent discussion and the written informed consent form and any other 
written information to be provided to subjects should include explanations of the following: 
 
a) 
That the study involves research. 
 
b) 
The purpose of the study. 
 
c) 
The study treatment(s) and the probability for random assignment to each treatment. 
 
d) 
The study procedures to be followed, including all invasive procedures. 
 
e) 
The subject’s responsibilities. 
 
f) 
Those aspects of the study that are experimental. 
 
g) 
The reasonably foreseeable risks or inconveniences to the subject and, when applicable, 
to an embryo, fetus, or nursing infant. 
 
h) 
The reasonably expected benefits.  When there is no intended clinical benefit to the 
subject, the subject should be made aware of this. 
 
i) 
The alternative procedure(s) or course(s) of treatment that may be available to the 
subject, and their important potential benefits and risks. 
 
j) 
The compensation and/or treatment available to the subject in the event of study-related 
injury. 
 
k) 
The anticipated prorated payment, if any, to the subject for participating in the study. 
l) 
The anticipated expenses, if any, to the subject for participating in the study. 
m) 
That the subject’s participation in the study is voluntary and that the subject may refuse 
to participate or withdraw from the study, at any time, without penalty or loss of 
benefits to which the subject is otherwise entitled. 


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n) 
That the CRA(s), the auditor(s), the IRB/IEC, and the Regulatory Authority(ies) will 
be granted direct access to the subject’s original medical records for verification of 
clinical study procedures and/or data, without violating the confidentiality of the 
subject, to the extent permitted by the applicable laws and regulations and that, by 
signing a written informed consent form, the subject or the subject’s legally acceptable 
representative is authorizing such access 
 
o) 
That records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available.  If the results of the study are published, the subject’s identity will remain 
confidential. 
 
p) 
That the subject or the subject’s legally acceptable representative will be informed in a 
timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. 
 
q) 
The person(s) to contact for further information regarding the study and the rights of 
study subjects, and whom to contact in the event of study-related injury. 
 
r) 
The foreseeable circumstances and/or reasons under which the subject’s participation 
in the study may be terminated. 
 
s) 
The expected duration of the subject’s participation in the study. 
 
t) 
The approximate number of subjects involved in the study. 
1.8.11 Prior to participation in the study, the subject or the subject’s legally acceptable representative 
should receive a copy of the signed and dated written informed consent form and any other 
written information provided to the subjects.  During a subject’s participation in the study, the 
subject or the subject’s legally acceptable representative should receive a copy of the signed 
and dated consent form updates and a copy of any amendments to the written information 
provided to subjects. 
1.8.12 When a clinical study (therapeutic or non-therapeutic) includes subjects who can only be 
enrolled in the study with the consent of the subject’s legally acceptable representative (e.g. 
minors, or patients with severe dementia), the subject should be informed about the study to the 
extent compatible with the subject’s understanding and, if capable, the subject should sign and 
personally date the written informed consent. 
1.8.13 Except as described in 1.8.14, a non-therapeutic study (i.e. a study in which there is not 
anticipated direct clinical benefit to the subject), should be conducted in subjects who 
personally give consent and who sign and date the written informed consent form. 


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1.8.14 Non-therapeutic studies may be conducted in subjects with consent of a legally acceptable 
representative provided the following conditions are fulfilled: 
 
a) 
The objectives of the study cannot be met by means of a study in subjects who can give 
informed consent personally. 
 
b) 
The foreseeable risks to the subjects are low. 
d) 
The negative impact on the subject’s well-being is minimized and low. 
e) 
The study is not prohibited by law. 
f) 
The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of 
such subjects, and the written approval/favorable opinion covers this aspect. 
Such studies, unless an exception is justified, should be conducted in patients having a disease 
or condition for which the investigational product is intended.  Subjects in these studies should 
be particularly closely monitored and should be withdrawn if they appear to be unduly 
distressed. 
1.8.15    In emergency situations, when prior consent of the subject is not possible, the consent of the 
subject’s legally acceptable representative, if present, should be requested.  When prior consent 
of the subject is not possible, and the subject’s legally acceptable representative is not available, 
enrollment of the subject should require measures described in the protocol and/or elsewhere, 
with documented approval/favorable opinion by the IRB/IEC, to protect the rights, safety and 
well-being of the subject and to ensure compliance with applicable regulatory requirements.  
The subject or the subject’s legally acceptable representative should be informed about the 
study as soon as possible and consent to continue and other consent as appropriate (see 1.8.10) 
should be requested. 
1.9 
Records and Reports 
1.9.1 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the CRFs and in all required reports. 
1.9.2 
Data reported on the CRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained. 
1.9.3 
Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and 
should not obscure the original entry (i.e. an audit study should be maintained): this applies to 
both written and electronic changes or corrections (see 1.18.4 (n)).  Sponsors should provide 
guidance to investigators and/or the investigators’ designated representatives on making such 
corrections.  Sponsors should have written procedures to assure that changes or corrections in 
CRFs made by sponsor’s designated representatives are documented, are necessary, and are 


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endorsed by the investigator.  The investigator should retain records of the changes and 
corrections. 
1.9.4 
The investigator/institution should maintain the study documents as specified in Essential 
Documents for the Conduct of a Clinical Study and as required by the applicable regulatory 
requirement(s).  The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents. 
1.9.5 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the sponsor.  It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
1.9.6 
The financial aspects of the study should be documented in an agreement between the sponsor 
and the investigator/institution. 
1.9.7 
Upon request of the monitor, auditor, IRB/IEC, or Regulatory Authority, the 
investigator/institution should make available for direct access all requested study-related 
records. 
1.10 
Progress Reports 
1.10.1 The investigator should submit written summaries of the study status to the IRB/IEC annually, 
or more frequently, if requested by the IRB/IEC. 
1.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC and, 
where applicable, the institution on any changes significantly affecting the conduct of the study, 
and/or increasing the risk to subjects. 
1.11 
Safety Reporting 
1.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for 
those SAEs that the protocol or other document (e.g. Investigator’s Brochure) identifies as not 
needing immediate reporting.  The immediate reports should be followed promptly by detailed, 
written reports.  The immediate and follow-up reports should identify subjects by unique code 
numbers assigned to the study subjects rather than by the subjects’ names, personal 
identification numbers, and/or addresses. The investigator should also comply with the 
applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug 
reactions to the Regulatory Authority(ies) and the IRB/IEC. 


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1.11.2 AE’s and/or laboratory abnormalities identified in the protocol as critical to safety evaluations 
should be reported to the sponsor according to the reporting requirements and within the time 
periods specified by the sponsor in the protocol. 
1.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any 
additional requested information (e.g. autopsy reports and terminal medical reports). 
1.12 
Premature Termination or Suspension of a Study 
If the study is prematurely terminated or suspended for any reason, the investigator/institution 
should promptly inform the study subjects, should assure appropriate therapy and follow-up for 
the subjects, and, where required by the applicable regulatory requirement(s), should inform 
the Regulatory Authority(ies).  In addition: 
1.12.1 If the investigator terminates or suspends a study without prior agreement of the sponsor, the 
investigator should inform the institution where applicable, and the investigator/institution 
should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the 
IRB/IEC a detailed written explanation of the termination or suspension. 
1.12.2 If the sponsor terminates or suspends a study, the investigator should promptly inform the 
institution where applicable and the investigator/institution should promptly inform the 
IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or 
suspension. 
1.12.3 If the IRB/IEC terminates or suspends its approval/favorable opinion of a study, the investigator 
should inform the institution where applicable and the investigator/institution should promptly 
notify the sponsor and provide the sponsor with a detailed written explanation of the termination 
or suspension. 
1.13 
Final Report(s) by Investigator 
Upon completion of the study, the investigator, where applicable, should inform the institution: 
the investigator/institution should provide the IRB/IEC with a summary of the study’s outcome, 
and the Regulatory Authority(ies) with any reports required.  
 
 
 


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APPENDIX D. – COMPARATOR HRIG PRESCRIBING 
INFORMATION (2012 VERSION) 
Adobe Acrobat 
Document
 


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APPENDIX E. – ACTIVE RABIES VACCINE PRESCRIBING 
INFORMATION (2015 VERSION) 
Adobe Acrobat 
Document
 


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APPENDIX F. – HRIG DOSING FOR CLINICAL TRIAL 
The concentration of specific IgG to Rabies virus is nominally 150 IU/mL solution for injection in 
nominal 500 IU vials. 
The recommended dose of rabies immunoglobulin is 20IU/kg of body weight 
Dosing for the trial will be calculated using the actual potency versus the nominal potency. 
The potency of each lot of BPL HRIG and comparator HRIG will be provided. 
To calculate the Day 0 dose; used the subject’s body weight to calculate the total IUs per body weight. 
Then use the potency per vial to calculate the volume to be administered. 
Example: 
The subject weighs 75 kg, the recommended dose is 20 IU/mL, so based on subject weight the total 
IUs to be administered is 1500 IU. Actual potency on the vial is 230 IU/mL, [1500 IU ÷ 230 IU/mL] 
=6.5 mL of product to be administered.  Volume per vial is 3.4 mL, [6.5 ÷ 2.17] = 2 vials are 
required. ** 
**REFER TO THE PHARMACY MANUAL FOR DETAILED DOSING INSTRUCTIONS 
 


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APPENDIX G. –TRIAL PLAN FLOW CHART 
Visit Number 
1 
2 
 
 
3 
4 
5 
6 
7 
8 
9 
Visit Assessment 
Screening 
Baseline 
 
 
 
 
 
 
 
 
End-of-
Study 
Assessment 
Visit Timing 
up to Day 
-28 
Day 0 
 
 
Day 3 
Day 5 
Day 7 
 
Day 14 
 
Day 28 
(±2 days) 
Day 49 
(±4 days) 
Day 140  
(±7 days) 
 
 
pre-dose 
dosing 
30 
min 
post-
dose 
 
 
 
 
 
 
 
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
Demography/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
Xb 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Vital Signs 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Body Temperature (oral) 
 
X 
 
 
X 
 
X 
X 
X 
 
 
Pregnancy Testc 
X 
X 
 
 
 
 
 
 
 
 
X 
Hematology, Serum Biochemistry, 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
Virology: HBsAg, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
X 
Markers of Hemolysis: Direct 
Coomb’s Test, LDH, Plasma Free 
Hemoglobin, Serum Haptoglobin, 
Serum bilirubin, Urine 
Hemosiderin 
 
X 
 
 
Xd,k 
 
 
Xd,k 
Xd,k 
Xe,k 
 
 
 
Archive Serum Sample* 
 
X 
 
 
 
 
 
 
 
 
X 
Randomizationf 
 
X 
 
 
 
 
 
 
 
 
 


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Visit Number 
1 
2 
 
 
3 
4 
5 
6 
7 
8 
9 
Visit Assessment 
Screening 
Baseline 
 
 
 
 
 
 
 
 
End-of-
Study 
Assessment 
Visit Timing 
up to Day 
-28 
Day 0 
 
 
Day 3 
Day 5 
Day 7 
 
Day 14 
 
Day 28 
(±2 days) 
Day 49 
(±4 days) 
Day 140  
(±7 days) 
 
 
pre-dose 
dosing 
30 
min 
post-
dose 
 
 
 
 
 
 
 
Administration of BPL HRIG / 
Competitor HRIG  
 
 
X 
 
 
 
 
 
 
 
 
Administration of Active Rabies 
Vaccine  
 
 
X 
 
X 
 
X 
X 
X 
 
 
Rabies Virus Neutralizing 
Antibody Titer  
 
X 
 
 
Xg 
XJ 
Xg 
Xg 
Xg 
X 
X 
Reserve Sample Collectionh 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Observationsi 
 
X 
 
X  
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
a  informed consent prior to screening procedures 
b  for re-assessment of eligibility and calculation of volume to be administered 
c  females of childbearing potential only: serum at screening and End-of-Study Assessment, urine dipstick pre-dose on Day 0 
d   if the  Day 3 Direct Coomb’s test is positive or not available by Day 5, all markers including CBC will be tested at Day 5. Subsequent testing at Day 7 and Day 14 will only be 
performed if results at the previous visit are suggestive of hemolysis 
e   if hemolysis is indicated at Day 7, all markers, including CBC will be tested at Day 14 
f   after all screening and baseline procedures have been completed and the subject is confirmed as eligible 
g   prior to dose of active rabies vaccine 
h   2 samples will be collected at each timepoint, except for the Baseline Visit (Day 0) and the End-of-Study (EOS) Assessment (Day 140) at which 3 samples will be taken.   
    The additional plasma reserve   samples will be taken in case viral nucleic acid testing is required to confirm viral serology results  
i    to be assessed at each subsequent visit until no symptoms are observed 
j. bloods draw only NO vaccine at this visit 
*archive serum sample-pre-dose, Day 0 and EOS, to be archive for approximately 15 years 
k   routine hematology, chemistry or urinalysis can be repeated if clinically indicated or at the request of the medical monitor 

SAP_001.pdf: 
CONFIDENTIAL 
Bio Products Laboratory 
Final Version 1.0 Study RIG01 
Statistical Analysis Plan 
Protocol V 1.0 
1 | Page 
A Prospective, Randomized, Blinded, Parallel-group, Non-
inferiority Phase II/III Study of the Safety and Effectiveness of 
BPL HRIG With Co-administration of Active Rabies Vaccine in 
Healthy Subjects  
Study Code: RIG01 
NCT03264157
Statistical Analysis Plan 
Based on Protocol Version 1.0, 26 October 2017 
Version 1.0 
10/31/2017 
Prepared by: 
CCI


CONFIDENTIAL 
Bio Products Laboratory 
 
Final Version 1.0 Study RIG01 
Statistical Analysis Plan 
Protocol V 1.0 
 
2 | Page 
 
1. 
Synopsis 
5 
2. 
Study Objectives 
5 
3. 
Sample Size and Power Computation 
6 
4. 
Study Design 
6 
5. 
Schedule of assessments 
7 
6. 
Study Endpoints 
9 
7. 
General Analysis Conventions 
11 
a. 
Definition of Statistical Significance 
11 
b. 
Analytic Populations 
12 
8. 
Analyses and Summaries 
13 
a. 
Descriptive Statistics 
13 
b. 
Demographic and Baseline Characteristics 
13 
c. 
Medical History 
13 
d. 
Efficacy Analyses 
13 
e. 
Primary Efficacy Analysis 
14 
Hypothesis 
14 
Derivation of Primary Endpoint 
14 
f. 
Secondary Efficacy Analyses 
15 
g. 
Exploratory PK Analyses 
17 
h. 
Adverse Event Reporting 
18 
Summary of AEs 
19 
Summary of AEs by Severity of Event 
19 
Summary of AEs by Causality 
19 
i. 
Sensitivity Analyses 
19 
Potential Interaction 
19 
Non-Compliers and Missing Data 
20 
j. 
Subgroup Analyses 
20 
k. 
Missing Values 
21 
l. 
Injection Site Observations 
21 
Summary by Product 
21 
Summary by Number of Injections 
21 


CONFIDENTIAL 
Bio Products Laboratory 
 
Final Version 1.0 Study RIG01 
Statistical Analysis Plan 
Protocol V 1.0 
 
3 | Page 
 
m. 
Viral Serology Variables 
21 
n. 
Hematology, Serum Biochemistry, Urinalysis 
21 
o. 
Markers of Hemolysis 
21 
p. 
Vital Signs and Body Temperature 
22 
q. 
Physical Examination 
22 
r. 
Other Safety Parameters 
22 
s. 
Interim Analysis 
22 
 
 
 
 


CONFIDENTIAL 
Bio Products Laboratory 
 
Final Version 1.0 Study RIG01 
Statistical Analysis Plan 
Protocol V 1.0 
 
4 | Page 
 
APPROVAL SIGNATURES 
 
Title: 
A Prospective, Randomized, Blinded, Parallel-group, Non-
inferiority Phase II/III Study of the Safety and Effectiveness of 
BPL HRIG With Co-administration of Active Rabies Vaccine in 
Healthy Subjects  
 
Protocol: RIG01 
 
 
Date 
 
  
 
 
Date 
Vice President, Global Medical 
Bio Products Laboratory, Ltd 
 
 
 
Date 
Senior Clinical Project Leader 
Bio Products Laboratory, Ltd  
 
Oct 31, 2017
Nov 1, 2017
Nov 1, 2017
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
Bio Products Laboratory 
 
Final Version 1.0 Study RIG01 
Statistical Analysis Plan 
Protocol V 1.0 
 
5 | Page 
 
1. 
SYNOPSIS 
RIG01 is a randomized, blinded, parallel group study intended to obtain data required for 
a license application in the US and other regions.  This will be achieved by comparing 
the safety and effectiveness of BPL HRIG, administered in conjunction with rabies 
vaccine in accordance with the licensed dosing schedule for post-exposure prophylaxis, 
with the safety and effectiveness of a licensed comparator HRIG, also given in 
conjunction with rabies vaccine. 
The doses of BPL HRIG and comparator HRIG to be administered in this study, of 20 
IU/kg, are consistent with the licensed doses.  Unlike the licensed method of 
administration, which requires the vaccine to be administered in and around the wound, 
in this study HRIG will be administered to the lateral thigh muscles and, if required by the 
volume to be administered, to the deltoid muscle.  This will result in a more consistent 
absorption of antibody from the intramuscular compartment between subjects and 
therefore allow an accurate analysis of the PK of HRIG. 
It is unethical to investigate the efficacy of BPL HRIG in patients exposed to rabies virus 
due to the almost invariable fatal nature of the disease.  Therefore, in this study, PK of 
HRIG when given in conjunction with active rabies vaccine to healthy volunteers will be 
used as a surrogate marker of HRIG efficacy.  The pharmacokinetic goal of rabies post-
exposure prophylaxis is to achieve a serum rabies antibody titer of ≥0.5 IU/mL on study 
Day 14. 
2. 
STUDY OBJECTIVES 
The objectives of this study are:  
1. To demonstrate non-inferiority of BPL HRIG compared to an FDA-licensed 
HRIG product, in terms of the proportion of subjects achieving anti-rabies 
antibody titer of ≥0.5 IU/mL at Day 14 following treatment with HRIG in 
conjunction with active rabies vaccine.  


CONFIDENTIAL 
Bio Products Laboratory 
 
Final Version 1.0 Study RIG01 
Statistical Analysis Plan 
Protocol V 1.0 
 
6 | Page 
 
2. To compare the PK of BPL HRIG in conjunction with active rabies vaccine, 
with FDA-licensed HRIG product in conjunction with active rabies vaccine. 
3. To assess whether BPL HRIG interferes with the development of the host-
immune response when given simultaneously with active rabies vaccine, 
relative to an FDA-licensed HRIG product. 
4. To evaluate the safety and tolerability of BPL HRIG in comparison with FDA-
licensed HRIG product.  
3. 
SAMPLE SIZE AND POWER COMPUTATION 
Statistical calculations indicate a minimum of 
 subjects per group is necessary.  To 
allow for a 
 rate of subject withdrawal or unevaluable data, approximately 81 
subjects will be enrolled per group.  
This study is powered based on a 
 test with an overall study 𝞪 of 
.  A total 
of 162 subjects will be randomized to achieve 
 power with a one-sided significance 
level of 
.  This computation accounts for an expected 10% dropout rate resulting in 
146 evaluable subjects. The following table outlines the underlying assumptions. 
 
Day 14 > 0.5 IU/mL 
Non-inferiority Margin 
 
Difference 
 
% Success 
98% 
 
4. 
STUDY DESIGN 
This will be a prospective, randomized, double-blind, parallel-group, non-inferiority, 
phase II/III study of the safety and effectiveness of simulated post-exposure prophylaxis 
with BPL HRIG with co-administration of active rabies vaccine in healthy subjects.  This 
is intended to be a multi-center study.  Treatment assignment is blinded until post 
database lock. 
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Subjects will be randomized 1:1 to one of the 2 treatment groups, as follows: 
HRIG treatment 
Rabies vaccine treatment 
# of Subjects 
BPL HRIG 
active rabies vaccine 
81 
comparator HRIG 
active rabies vaccine 
81 
 
Prior to randomizing a participant, all screening and baseline evaluations must be 
completed and the participant determined to be eligible for inclusion in the study. 
Randomization and the baseline visit (Day 0) should occur no later than 28 days after 
the completion of the screening visit.  
All medicinal product preparation will be performed by the site pharmacist using aseptic 
techniques and according to a standardized procedure on Day 0, and administration of 
HRIGs + vaccine will be administered an unblinded nurse administrator. All study 
assessments and Post Day 0 treatment administration will be performed by blinded 
study personnel. Investigators and subjects will be blinded to treatment assignment. 
Subjects will be identified by a unique five-digit number as follows:  each site will be 
allocated a two-digit site number (e.g. Site 01, etc) and each subject will be allocated a 
three-digit subject number (e.g. 001) at the Screening Visit.  Each subject will be 
identified by the unique site and subject number combination (e.g. 01001).   
5. 
SCHEDULE OF ASSESSMENTS 
Each subject will undergo a total of 8 visits. Subjects’ eligibility will be assessed at 
Screening, which can occur up to 28 days prior to dosing.  Following a repeat eligibility 
check at Day 0, eligible subjects will be randomized and dosed with the randomized 
treatment (HRIG/vaccine or Comparator HRIG/vaccine on Day 0.  Further administration 
of rabies vaccine, PK sampling and safety assessments will be conducted on Days 3, 5 
(PK sampling only), 7, 14 and 28.   An additional visit for PK sampling and safety 
assessment will take place on Day 49 (7 weeks) and Day 140 (20 weeks).  The last visit 
will be the End-of-Study Assessment which will take place on Day 140 (20 weeks).  This 
visit will comprise the final PK sample and safety assessments.  The end of the trial is 


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defined as the last subject’s last End-of-Study Assessment (or the date of their last data 
collected, if the subject has an AE at the End-of-Study Assessment that needs to be 
followed). 
Visit Number 
1 
2 
 
 
3 
4 
5 
6 
7 
8 
9 
Visit Assessment 
Screeni
ng 
Baselin
e 
 
 
 
 
 
 
 
 
End-of-
Study 
Assessment 
Visit Timing 
up to 
Day -28 
Day 0 
 
 
Day 3 
Day 5 
Day 7 
 
Day 14 
 
Day 28 
(±2 days) 
Day 49 
(±4 days) 
Day 140  
(±7 days) 
 
 
pre-dose 
dosing 
30 
min 
post-
dose 
 
 
 
 
 
 
 
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
Demography/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
Xb 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Vital Signs 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Body Temperature (oral) 
 
X 
 
 
X 
 
X 
X 
X 
 
 
Pregnancy Testc 
X 
X 
 
 
 
 
 
 
 
 
X 
Hematology, Serum 
Biochemistry, Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
Virology: HBsAg, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
X 
Markers of Hemolysis: Direct 
Coomb’s Test, LDH, Plasma Free 
Hemoglobin, Serum Haptoglobin, 
Serum bilirubin, Urine 
Hemosiderin 
 
X 
 
 
Xd,k 
Xd,k 
Xd,k 
Xe,k 
 
 
 
Archive Serum Sample* 
 
X 
 
 
 
 
 
 
 
 
X 
Randomizationf 
 
X 
 
 
 
 
 
 
 
 
 
Administration of BPL HRIG / 
Competitor HRIG  
 
 
X 
 
 
 
 
 
 
 
 
Administration of Active Rabies 
Vaccine  
 
 
X 
 
X 
 
X 
X 
X 
 
 
Rabies Virus Neutralizing 
Antibody 
 
X 
 
 
Xg 
XJ 
Xg 
Xg 
Xg 
X 
X 
Reserve Sample Collectionh 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Observationsi 
 
X 
 
X  
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
a  informed consent prior to screening procedures 
b  for re-assessment of eligibility and calculation of volume to be administered 
c  females of childbearing potential only: serum at screening and End-of-Study Assessment, urine dipstick pre-dose on Day 0 
d   if the  Day 3 Direct Coomb’s test is positive or not available by Day 5, all markers will be tested at Day 5. Subsequent testing at Day 7 and Day 14 will 
only be performed if results at the previous visit are suggestive of hemolysis 
e   if hemolysis is indicated at Day 7, all markers will be tested at Day 14 
f   after all screening and baseline procedures have been completed and the subject is confirmed as eligible 
g   prior to dose of active rabies vaccine 


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h   2 samples will be collected at each timepoint, except for the Baseline Visit (Day 0) and the End-of-Study (EOS) Assessment (Day 140) at which 3 
samples will be taken.   
    The additional plasma reserve   samples will be taken in case viral nucleic acid testing is required to confirm viral serology results (see Section 8.2.3) 
i    to be assessed at each subsequent visit until no symptoms are observed 
j. bloods draw only NO vaccine at this visit 
*archive serum sample-pre-dose, Day 0 and EOS, to be archive for approximately 15 years 
k  routine hematology, chemistry or urinalysis can be repeated if clinically indicated or at the request of the medical monitor 
 
6. 
STUDY ENDPOINTS 
The PRIMARY efficacy endpoint is to demonstrate non-inferiority of BPL HRIG 
compared to a FDA-licensed HRIG product, in terms of: 
● the proportion of subjects with anti-rabies antibody titer of > 0.5 IU/mL on day 14 
after administration of BPL HRIG and vaccine versus comparator HRIG and 
vaccine, using a non-inferiority margin of 10%. 
  
The SECONDARY efficacy endpoints are as follows: 
1. Assessment of AUC 0-7days for BPL HRIG+vaccine vs. comparator HRIG+vaccine 
using a non-inferiority margin of 20%. 
2. Comparison of the geometric mean titers (GMTs) for anti-rabies antibody titer at 
Days 3, 5, 7, 14, and 28 after administration of BPL HRIG and vaccine versus 
comparator HRIG and vaccine. 
3. The proportion of subjects reaching anti-rabies antibody titer of ≥0.5 IU/mL at 
Days 3, 5, 7, 14, 28, 49, and 140 after administration of BPL HRIG and vaccine 
versus comparator HRIG and vaccine. 
4. The proportion of subjects reaching anti-rabies antibody titer of ≥ the lower limit 
of quantitation of the assay at Days 3, 5, 7, 14, 28, 49 and 140 after 
administration of BPL HRIG and vaccine versus comparator HRIG and vaccine.   
5. Comparison of the geometric mean titers (GMTs) for anti-rabies antibody titer at 
Days 14, 28, 49, and 140 after administration of BPL HRIG and vaccine versus 
comparator HRIG and vaccine to assess the inhibitory effects of BPL HRIG on 
active immunization relative to that of the comparator HRIG. 


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An EXPLORATORY efficacy endpoint is as follows: 
The following PK parameters for anti-rabies antibody concentrations for both treatment 
groups:  
• 
Cmax [IU/mL] 
• 
Tmax [day] 
• 
area under the concentration vs time curve to the last measurable 
concentration (AUC0-t) [day*IU/mL] 
• 
apparent terminal rate constant (λz) [day-1] 
• 
AUC0-7 days [day*IU/mL] 
• 
area under the concentration vs time curve to infinity (AUC0-∞), if 
appropriate 
• 
Cmax/AUC0-∞ [or Cmax/AUC0-t if AUC0-∞ cannot be estimated] 
• 
half-life (t½), if appropriate 
 
The following will be used to assess the SAFETY of BPL HRIG and vaccine, versus 
comparator HRIG and vaccine: 
• 
Adverse events 
• 
Injection site observations 
• 
Viral serology 
• 
Serum biochemistry, hematology and urinalysis 
• 
Markers of hemolysis 
• 
Physical examination 
• 
Vital signs 
The following additional tests will additionally be performed: 
• 
pregnancy tests (for females of childbearing potential). 


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7. 
GENERAL ANALYSIS CONVENTIONS 
All tables, figures and listings will be produced using SAS (v9.4 or a more recent 
version). 
Unless otherwise stated, categorical data will be presented using counts and 
percentages, whilst continuous variables will be presented using the mean, 95% 
confidence interval for the mean, standard deviation (SD), median, minimum, maximum, 
number of subjects (n) and number of missing subjects or data points.  Minima and 
maxima will be quoted to the number of decimal places as recorded in the CRF; means, 
SDs and medians will be quoted to one further decimal place.  Percentages will be 
rounded to one decimal place. 
Subjects who withdraw from the analysis will have their data analyzed to the point of 
withdrawal.  Subjects who complete all required assessments up to and including Day 
14 will be eligible for the primary PK population.  Other subjects who withdraw from the 
study will be eligible for the ITT population.  Unblinded subjects will continue in study 
after being unblinded unless noted otherwise.   
For the purpose of the statistical analyses visit labels may be used interchangeably as 
Visit and Day as in the table below regardless of actual timing of study visit.  Sensitivity 
analyses will be performed to address any potential visit timing issues. 
Visit 
Label 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Intended 
Day 
Day -28 
Baseline, 
Day 0 
Day 3 
Day 5 
Day 7 
Day 14 
Day 28 
Day 49 
Day 
140 
 
a. DEFINITION OF STATISTICAL SIGNIFICANCE 
• 
Primary Efficacy Endpoint 
The BPL HRIG treatment effect will be considered non-inferior to the active comparator 
HRIG treatment when the resultant p-value from the one-sided Farrington-Manning 


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Score Test for proportion difference is 
.   
• 
Secondary Efficacy Endpoints 
The secondary efficacy endpoint analyses will be considered statistically significant 
using a two-sided significance level of 0.05. 
b. ANALYTIC POPULATIONS 
The following analysis populations will be defined for this study. 
• 
Intent-to-Treat [ITT] Population 
The intent-to-treat (ITT) population will include all randomized subjects.  All analyses will 
be performed using the ITT population. 
• 
Safety Population 
The safety population will be defined as all subjects who receive at least one dose of 
BPL HRIG / comparator HRIG. Safety data will be analyzed up to the point of withdrawal 
for applicable subjects.  The safety population will be used for all safety analyses. 
• 
Per Protocol [PP] Population 
The per protocol population will be split into the primary and secondary PK 
populations. 
 
The primary PK population will be defined as all subjects who receive the full dose of 
BPL HRIG / comparator HRIG and the first 3 doses of active rabies vaccine on Visits 2, 
3, and 5, and for whom the PK sample at Visit 6 is taken.  This population will be used 
for the primary PK analysis and selected secondary PK analyses. The secondary PK 
population will be defined as all subjects who receive the full dose of BPL HRIG / 
comparator HRIG and all 5 doses of active rabies vaccine and for whom all required PK 
samples are taken.  This population will be used for selected secondary PK analysis and 
the exploratory analysis. 
Subjects with a pre-dose RVNA of ≥ the LLOQ will be excluded from the all 
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analyses. 
 
 
    
8. 
ANALYSES AND SUMMARIES  
a. DESCRIPTIVE STATISTICS 
For continuous and pseudo-continuous variables, the number of observations, number 
of missing values, mean, standard deviation, median, twenty-fifth percentile, and 
seventy-fifth percentile will be given.  For yes/no, categorical, and/or ordinal variables a 
simple count and percent or frequency will be given.  Other statistics may be considered 
if necessary. 
b. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristic data will include age (based on date of 
informed consent), sex, race, ethnicity, height, weight, and body mass index (BMI).  All 
demographic and baseline characteristic data will be summarized. An analysis of 
variance [ANOVA] will be used to assess homogeneity regarding demographic 
characteristics between treatment groups. 
c. MEDICAL HISTORY 
Medical history is collected at screening and will be summarized by treatment group. 
d. EFFICACY ANALYSES 
PK is a surrogate for efficacy, since a titer of ≥ 0.5 IU/mL is well-established as 
protective against the rabies virus.  RVNA titers will be listed for each subject, and 
summary statistics for each timepoint presented by treatment group. 
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e. PRIMARY EFFICACY ANALYSIS 
The primary efficacy analysis will be based on the primary PK population.  
The primary hypothesis is that the proportion of subjects receiving BPL HRIG + active 
vaccine with an anti-rabies antibody of ≥ 0.5 IU/mL will not be less than the 
corresponding proportion for subjects receiving comparator HRIG + active vaccine, by 
more than 0.1 at Visit 6.  The Farrington and Manning test statistic will be used to assess 
the statistical comparison of the proportions at a one-sided significance level of 
  It 
will be concluded that the BPL HRIG is non-inferior to the comparator HRIG if the lower 
limit of an exact binomial 95% confidence interval is greater than the a priori set 
 
non-inferiority margin. 
HYPOTHESIS 
The null hypothesis is p-p0 ≤ -0.1; 
The alternative hypothesis is p-p0 > -0.1,  
where p is the proportion of subjects with RVNA titer of  >0.5 IU/mL at Visit 6 in subjects 
receiving BPL HRIG + vaccine and p0 is the proportion receiving comparator HRIG + 
vaccine 
We reject the null hypothesis at the one-sided 
 significance level, and conclude 
that p-p0 > -0.1, if the lower bound of an exact 95% binomial confidence interval 
exceeds -0.1. 
DERIVATION OF PRIMARY ENDPOINT 
 will be performing the RFFIT test and providing the results for 
data analysis.  Subject serum will be tested in duplicates.  If either individual test in 
duplicated set 1 fails QC, a second duplicate set of RFFIT tests will be run.  The 
arithmetic mean value of the appropriate duplicate set, (set 1 if QC passed, set 2 if QC 
failed), will be used for the final reported rabies antibody titer [IU] for primary endpoint 
derivation.  If the final arithmetic mean value is >0.5 IU/mL that subject-specific time 
point will be coded as 1 (success); otherwise if the final arithmetic mean value is < 0.5 
IU/ml the time point will be coded as 0 (failure).  If both duplicate sets fail the QC test, 
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the subject data is deemed non-evaluable.  The proportion of subjects with RVNA titer 
>0.5 IU/mL is calculated as follows: 
∑(𝑠𝑢𝑐𝑐𝑒𝑠𝑠𝑒𝑠, 1)
∑𝑎𝑙𝑙 𝑒𝑣𝑎𝑙𝑢𝑎𝑏𝑙𝑒 𝑠𝑢𝑏𝑗𝑒𝑐𝑡⁞, 𝑛 
Sensitivity analyses will be performed to assess impact of missing data, see section 8j. 
f. SECONDARY EFFICACY ANALYSES 
Secondary efficacy analyses 2 and 5 will be based on the secondary PK population.  
Secondary efficacy analyses 1, 3, and 4 will be based on the primary PK population, 
since timepoints post-Visit 6 are not included in these analyses. 
The second secondary analyses will be performed using an appropriate mixed model 
repeated measures [MMRM] analysis to assess for differences of the slope and the 
change in GMT of the titers at the days described below.  The correlation structure 
involves multiple pieces, including measurement errors, random variation, and inter-
individual variability.  For the longitudinal data analysis, an unstructured correlation 
matrix for within-subject error will be assumed.  Other correlation structures, including 
compound symmetry, will be examined as needed. The validity of this model will be 
assessed 
via 
standard 
modeling 
diagnostics 
and 
goodness-of-fit 
measures. 
Comparisons of geometric mean titers [GMTs] between the treatment group at each 
timepoint and across all timepoints will be reported. The final output will include one row 
indicating the mean change [95% confidence intervals] in titer across all PK 
assessments from Visit 2 [baseline] through Visit 7 by treatment group and one row for 
every specific timepoint thereafter. Additionally, the difference in the means [or the ratio 
of the GMT] between treatment groups, the corresponding 95% confidence intervals, 
associated chi-square test statistic, and p-value will be reported. A p-value of <0.05 will 
signal a statistically significant difference in titers.  See table below for example output: 


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1. a one-sided t-test will be used to assess non-inferiority of the mean of the 
AUC0-7 d of the BPL HRIG + vaccine group to the comparator HRIG + vaccine 
group.  The pre-specified non-inferiority margin is 20%.  It will be concluded the 
mean AUC0-7d in the BPL HRIG + vaccine group is non-inferior to that in the 
comparator group if the lower limit of the 95% confidence interval for the mean 
AUC0-7d is greater than -20% of comparator mean AUC0-7d.  Log-transformation of 
the AUC0-7d data will be performed as necessary during statistical testing to meet 
assumptions for normality. 
The null hypothesis is (𝜇T-𝜇C)/𝜇T  < -0.2 ; 
The alternative hypothesis is  (𝜇T-𝜇C)/𝜇T > -0.2; 
Where 𝜇T=the geometric mean of the AUC0-7d in the BPL HRIG + vaccine 
group, 
𝜇C=the geometric mean of the AUC0-7d in the comparator HRIG + vaccine 
group. 
2. The geometric mean titers (GMTs) for RVNA titer up to peak serum level after 
administration of BPL HRIG and vaccine versus comparator HRIG and vaccine.  
Due to the observed change in relationship between time and titer level, only PK 
timepoints up to peak serum level will be included in this analysis. 
A generalized estimating equation [GEE] for a repeated measures analysis will be 
used to assess the difference in proportions between the treatment groups for the 
third and fourth secondary efficacy analyses.  Standard model building methods, 
diagnostics, and goodness-of-fit measures will be performed as appropriate.  
Proportions of subjects reaching set anti-rabies antibody titer will be compared at 
each timepoint as well as throughout all timepoints.    


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3. The proportion of subjects reaching anti-rabies antibody titer of ≥0.5 IU/mL at 
Visits 3-6 after administration of BPL HRIG and vaccine versus comparator HRIG 
and vaccine. 
4. The proportion of subjects reaching anti-rabies antibody titer of ≥ the lower limit 
of quantitation of the assay at Visit 3-6 after administration of BPL HRIG and 
vaccine versus comparator HRIG and vaccine.  This titer threshold corresponds 
to the lower limit of quantitation of the assay. 
The GEE analysis will include timepoints through Visit 6 for endpoints 3 and 4, at 
which point all or nearly all subjects are expected to have reached the stated 
thresholds.  There is no clinical benefit of including subsequent timepoints in this 
analysis. 
5. The geometric mean titers (GMTs) for anti-rabies antibody titer at Visit 6-9 will be 
compared between treatment groups.  Descriptive statistics and visual 
inspections will be reported as appropriate.  No formal hypotheses testing will be 
performed.  
g. EXPLORATORY PK ANALYSES 
The following PK parameters for anti-rabies antibody concentrations will be summarized 
for both treatment groups:  
• 
Cmax [IU/mL] 
• 
Tmax [day] 
• 
area under the concentration vs time curve to the last measurable 
concentration (AUC0-t) [day*IU/mL] 
• 
apparent terminal rate constant (λz) [day-1] 
• 
AUC0-7 d [day*IU/mL] 
• 
area under the concentration vs time curve to infinity (AUC0-∞), if 
appropriate 


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• 
Cmax/AUC0-∞ [or Cmax/AUC0-t if AUC0-∞ cannot be estimated] 
● half-life (t½), if appropriate 
Non-compartmental PK methods will be utilized to calculate the subject level PK 
parameters.  Cmax, AUC0-t, AUC0-7d\, AUC0-∞, apparent terminal rate constant (λz), and t1/2 
will be dose normalized by dividing the raw PK parameters by the actual dose the 
subject received.  A t-test will compare the PK and dose-normalized PK parameters 
between treatment groups.  Log-transformations will be performed as necessary during 
statistical analysis when appropriate.   
h. ADVERSE EVENT REPORTING 
Adverse events (AEs) will be reported by the MedDRA system organ class and preferred 
term. Only treatment emergent AEs (i.e. beginning after dosing with BPL HRIG / vaccine 
or comparator HRIG / vaccine) will be included in the summary tables.  All AEs will be 
included in the data listings.   
Treatment-related AEs will be defined as events recorded as having a possible, probable 
or very likely/certain causality to treatment.  AEs leading to withdrawal will be defined as 
events where the subject’s participation in the study was discontinued as a result of the 
AE. 
AEs will be summarized descriptively for all subjects and by treatment group.  The 
denominator used for the calculation of percentages will be the number of subjects in the 
safety population per treatment group.  For all AE summaries described below, counting 
will be performed by subject and event.  For counts by subject, subjects experiencing the 
same event more than once will have that event counted only once within each system 
organ class and once within each preferred term. 
 
 


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The following summaries of treatment-emergent AEs will be provided: 
SUMMARY OF AES 
• 
The number and percentage of subjects reporting AEs, serious AEs, study 
medication-related AEs, AEs leading to withdrawal and AEs leading to death. 
• 
The number of AEs, serious AEs, study medication-related AEs, AEs leading to 
withdrawal and AEs leading to death. 
SUMMARY OF AES BY SEVERITY OF EVENT 
The number and percentage of subjects reporting AEs, and study medication-related 
AEs, will be summarized by the system organ class and by the preferred term. The 
severity of event will be recorded once per subject for each term as the maximum 
severity experienced by each subject (i.e. where the order of most severe to least severe 
is given by: severe, moderate and then mild). 
SUMMARY OF AES BY CAUSALITY 
The number and percentage of subjects reporting AEs will be summarized by the system 
organ class and by the preferred term. The causality will be recorded once per subject 
for each term giving the most likely relationship to study medication (i.e. in the order: 
very likely/certain, probable, possible, unlikely and then unrelated). 
i. SENSITIVITY ANALYSES 
Sensitivity analyses will be performed to assess the impact on the primary PK analysis 
of non-compliers within the ITT population, missing primary endpoints, and timing of 
vaccine dosing.   
POTENTIAL INTERACTION 
Before treatment unblinding, timing of vaccine dosing and PK sampling, if not performed 
on the designated day, will be assessed as potential effect modifiers on the association 
between RVNA levels and treatment group in the primary and secondary PK analysis.  A 
chi-square or fisher’s exact test, as appropriate, will be used to measure the association 
between the dichotomous indicator of receiving dose/PK sampling on the intended day 


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[yes/no] and target level of RVNA titer reached [yes/no].  If the association is significant 
at the 0.05 level, a subgroup analysis including only subjects who were dosed/sampled 
on the target day will be reported in addition to the full analysis.   
 
NON-COMPLIERS AND MISSING DATA 
Non-compliers will be defined as subjects who meet one of the following:  
• 
subjects who did not receive the full dose of BPL HRIG/comparator HRIG [not 
eligible for primary PK population]; 
• 
all 3 doses of active rabies vaccine at the time specified [not eligible for primary 
PK population];  
• 
randomized without meeting all eligibility criteria [
 
; 
• 
subjects with any major protocol deviations reported [
 
]. 
Specifically, the following two analyses will be performed to assess impact on primary 
PK analysis: 
• 
The primary PK analysis will be repeated assuming that non-compliant subjects 
did not attain an RVNA titer of > 0.5 IU/mL at Visit 6.  [worst case scenario] 
• 
The primary PK analysis will be repeated assuming that non-compliant subjects 
successfully attain an RVNA titer of > 0.5 IU/mL at Visit 6. [best case scenario] 
j. SUBGROUP ANALYSES 
Subgroup analyses will be performed as appropriate, due to either imbalance 
randomization in baseline subject demographics and/or clinical relevance to primary and 
secondary PK analyses and safety analysis.  Factors including, but not limited to, age, 
race, BMI, and sex will be considered.  Subgroups will be defined based on population 
median.   
 
 
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k. MISSING VALUES 
No missing value imputation methods will be applied, e.g. the analyses are based on a 
valid case basis. 
l. INJECTION SITE OBSERVATIONS 
 
Injection site observations data will be summarized as appropriate.   
 SUMMARY BY PRODUCT 
The number and percentage of subjects reporting injection site reactions will be 
summarized by preferred term and product (HRIG or vaccine). 
SUMMARY BY NUMBER OF INJECTIONS 
The number and percentage of subjects reporting injection site reactions will be 
summarized by preferred term, product (HRIG or vaccine) and number of injections.    
m. VIRAL SEROLOGY VARIABLES 
Viral serology variables will be summarized. Shift tables for virology will present the 
number of subjects with positive and negative results and those for whom the results 
change during the study. 
n. HEMATOLOGY, SERUM BIOCHEMISTRY, URINALYSIS 
Hematology, serum biochemistry and urinalysis variables will be summarized, including 
changes from baseline.  Shift tables for hematology and biochemistry variables will be 
provided for the number and percentage of subjects with values below, within and above 
the reference range.  
o. MARKERS OF HEMOLYSIS 
Markers of hemolysis will be summarized, including changes from baseline. 


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p. VITAL SIGNS AND BODY TEMPERATURE 
Sitting diastolic and systolic blood pressure, pulse rate, body temperature and 
respiration rate will be summarized, including changes from baseline (i.e. pre-dose on 
Visit 2 for body temperature, Screening for all other parameters).  In addition, the 
number of subjects with “substantial” increases or decreases from baseline in blood 
pressure (>20 mmHg) and pulse (>15 b.p.m.) will be summarized. 
q. PHYSICAL EXAMINATION  
Physical Examination and ECG findings will be summarized. The shift from Screening to 
Visit 8 and Screening to the End-Study Assessment will be summarized. Body weight 
data will be fully listed.   
r. OTHER SAFETY PARAMETERS  
Pregnancy test results will be listed. 
s. INTERIM ANALYSIS 
No interim analysis is planned.