Effect of Antimalarial Drugs on the Immune Response to Rabies Vaccine for Post-exposure Prophylaxis. A Randomized, Open Label, Trial in Healthy US Adults Age 18-60 Years
Phase: PHASE4
Conditions: Rabies
Sponsor: State University of New York - Upstate Medical University

 
STUDY TITLE: Effect of Antimalarial Drugs on the Immune Response to Rabies Vaccine for 
Post-exposure Prophylaxis. A Randomized, Open Label, Trial in Healthy US Adults Age 18-60 
Years  
 
NCT#: 02564471 
 
DOCUMENT DATE: 14 May 2018 
 

Effect of Antimalarial Drugs on the Immune Response to Rabies 
Vaccine for Post-exposure Prophylaxis. A Randomized, Open Label, 
Trial in Healthy US Adults Age 18-60 Years  
Short Title: MALRAB 
 
Principal Investigator: 
 
Timothy P. Endy, MD, MPH 
 
 
 
 
 
Upstate Medical University 
 
 
 
 
 
766 Irving Avenue  
 
 
 
 
 
Weiskotten Hall, Room 2204 
Syracuse, NY 13210 
 
Funder: 
 
 
 
Defense Health Program 
COL Paul Keiser 
 
 
 
 
 
Walter Reed Army Institute or Research 
 
 
 
 
 
503 Robert Grant Ave. 
 
 
 
 
 
Silver Spring, MD 20910 
 
 
 
 
 
301-319-3347 
Research Monitor:  
 
Tasaduq Fazili, MD 
 
 
 
 
 
Upstate Medical University 
 
 
 
 
 
725 Irving Ave, Suite 311 
 
 
 
 
 
Syracuse, NY 13210 
 
Study Location: 
 
 
Center for Global Health and Translational Science 
 
 
 
 
 
Upstate Medical University 
 
 
 
 
 
505 Irving Ave, Suite 4200 
 
 
 
 
 
Syracuse, NY 13210 
 
Licensed Products:  
RabAvert® Rabies Vaccine 
 
 
 
 
 
Chloroquine 
 
 
 
 
 
Malarone 
 
 
 
 
 
Doxycycline 
 
Version Number:  11.0 
09 May 2018 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US Federal 
regulations and ICH guidelines. 
Principal Investigator: 
Signed: 
 
Date:  
 
Name: Timothy P. Endy, MD, MPH 
 
Title: Principal Investigator 
 

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TABLE OF CONTENTS 
PAGE 
SIGNATURE PAGE .................................................................................................................... 2 
TABLE OF CONTENTS .............................................................................................................. 3 
LIST OF ABBREVIATIONS ......................................................................................................... 6 
SYNOPSIS ................................................................................................................................. 8 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................. 12 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....... 14 
2.1 
Background Information ........................................................................................ 14 
2.2 
Rationale .............................................................................................................. 14 
2.3 
Potential Risks and Benefits ................................................................................. 15 
2.3.1 
Potential Risks .......................................................................................... 15 
2.3.2 
Potential Benefits ...................................................................................... 16 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................... 17 
3.1 
Study Objectives ................................................................................................... 17 
3.1.1 
Primary Study Objective ............................................................................ 17 
3.1.2 
Secondary Study Objective ....................................................................... 17 
3.1.3 
Exploratory Study Objective ...................................................................... 17 
3.2 
Study Endpoints .................................................................................................... 17 
3.2.1 
Primary Endpoint (Immunogenicity) ........................................................... 17 
3.2.2 
Secondary Endpoint (Immunogenicity) ...................................................... 17 
3.2.3 
Exploratory ................................................................................................ 17 
4 
STUDY DESIGN .............................................................................................................. 18 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 19 
5.1 
Subject Inclusion Criteria ...................................................................................... 19 
5.2 
Subject Exclusion Criteria ..................................................................................... 19 
5.3 
Strategies for Recruitment and Retention ............................................................. 20 
5.4 
Treatment Assignment Procedures ....................................................................... 20 
5.4.1 
Randomization Procedures ....................................................................... 20 
5.5 
Subject Withdrawal ............................................................................................... 21 
5.5.1 
Contraindications for Subsequent Vaccinations ......................................... 21 
5.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ............................................................................................... 21 
5.5.3 
Classification of Subjects Who Discontinue the Study ............................... 22 
5.6 
Premature Termination or Suspension of Study .................................................... 22 
6 
STUDY INTERVENTION .................................................................................................. 24 
6.1 
Study Product Description .................................................................................... 24 
6.1.1 
Acquisition ................................................................................................. 25 
6.1.2 
Packaging ................................................................................................. 25 
6.1.3 
Product Storage and Stability .................................................................... 26 
6.2 
Accountability Procedures for the Study Product .................................................. 26 
6.3 
Assessment of Subject Compliance with Study Product Administration ................ 26 
6.4 
Concomitant Medications ...................................................................................... 26 

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6.5 
Preparation and Administration of Product(s) ........................................................ 27 
7 
STUDY SCHEDULE AND PROCEDURES ...................................................................... 28 
7.1 
Informed Consent Procedures .............................................................................. 28 
7.2 
Medical History ..................................................................................................... 28 
7.3 
Screening ............................................................................................................. 29 
7.4 
Day 0 Visit - ALL SUBJECTS ................................................................................ 29 
7.5 
Group 1 (Chloroquine), Group 2 (Malarone), Group 3 (Doxycycline) ..................... 30 
7.6 
Group 4 (Controls) ................................................................................................ 34 
8 
SAMPLE COLLECTION ................................................................................................... 37 
8.1 
Sample Preparation .............................................................................................. 37 
8.2 
Laboratory Assays ................................................................................................ 37 
8.2.1 
Rapid Fluorescent Foci Inhibition Test (RFFIT) ......................................... 37 
8.2.2 
Proteomics ................................................................................................ 37 
8.2.3 
Cellular Assays ......................................................................................... 38 
8.2.4 
Sample Storage and Shipment .................................................................. 38 
9 
ASSESSMENT OF SAFETY ............................................................................................ 39 
9.1 
Specification of Safety Parameters ....................................................................... 39 
9.1.1 
Unanticipated Problems ............................................................................ 39 
9.1.2 
Adverse Events ......................................................................................... 39 
9.1.3 
Serious Adverse Events ............................................................................ 40 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 40 
9.3 
Characteristics of an Adverse Event ..................................................................... 40 
9.3.1 
Relationship to Study Intervention ............................................................. 40 
9.3.2 
Severity of Event ....................................................................................... 41 
9.4 
Reporting Procedures ........................................................................................... 41 
9.4.1 
Unanticipated Problem Reporting to IRB ................................................... 41 
9.4.2 
Serious Adverse Event Reporting to HRPO .............................................. 41 
9.4.3 
Reporting of Pregnancy ............................................................................. 42 
10 
STUDY OVERSIGHT ....................................................................................................... 43 
10.1 
Research Monitor ................................................................................................. 43 
11 
CLINICAL SITE MONITORING ........................................................................................ 44 
12 
STATISTICAL CONSIDERATIONS .................................................................................. 45 
12.1 
Study Hypotheses ................................................................................................. 45 
12.2 
Sample Size Considerations ................................................................................. 45 
12.2.1 Safety Review ........................................................................................... 45 
12.3 
Final Analysis Plan ............................................................................................... 45 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 48 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 49 
14.1 
Quality Control in Data .......................................................................................... 49 
14.2 
Quality Assurance in Clinical Study ....................................................................... 49 
15 
PROTECTION OF HUMAN SUBJECTS .......................................................................... 50 
15.1 
Ethical Standard ................................................................................................... 50 
15.2 
Institutional Review Board .................................................................................... 50 

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15.3 
Informed Consent Process ................................................................................... 50 
15.4 
Subject Confidentiality .......................................................................................... 51 
15.5 
Future Use of Stored Specimens and Other Identifiable Data ............................... 51 
16 
DATA HANDLING AND RECORD KEEPING ................................................................... 52 
16.1 
Data Management Responsibilities ....................................................................... 52 
16.2 
Data Capture Methods .......................................................................................... 52 
16.3 
Study Records Retention ...................................................................................... 53 
16.4 
Protocol Deviations ............................................................................................... 53 
17 
LITERATURE REFERENCES .......................................................................................... 54 
APPENDIX A: SCHEDULE OF EVENTS .................................................................................. 55 
D – 15 MINUTE OBSERVATION ON DAY 7 & DAY 35 APPLIES TO GROUP 1 ONLY ........... 56 
APPENDIX B: SCHEDULE OF EVENTS .................................................................................. 57 
GROUP 4 (CONTROL) ............................................................................................................. 57 
APPENDIX C: BLOOD DRAW SCHEDULE .............................................................................. 58 
 

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LIST OF ABBREVIATIONS 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CGHATS 
Center for Global Health and Translational Science 
CRU 
Clinical Research Unit 
DHHS 
Department of Health and Human Services 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data collection 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GMT 
Geometric Mean Titer 
HDCV 
Human diploid cell vaccine 
HIV 
Human Immunodeficiency virus 
HRIG 
Human Rabies Immunoglobulin 
HRPO 
Human Research Protection Office 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Intradermal 
IM 
Intramuscular 
IRB 
Institutional Review Board 
mL 
milliliter 
NIH 
National Institute of Health 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral Blood Mononuclear Cell 
PCECV 
Purified chick embryo cell vaccine 
PEP 
Post exposure prophylaxis 
PO 
per os (oral) 
PP 
Per protocol 
PI 
Principal Investigator 
QA 
Quality Assurance 
QAIP 
Quality Assessment and Improvement Programs 

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QC 
Quality Control 
RFFIT 
Rapid fluorescent foci inhibition test 
RVNA 
Rabies virus neutralization assay 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
SSP 
Study Specific Procedure 
SUNY 
State University of New York 
UMU 
Upstate Medical University 
US 
United States 
USAMRMC 
United States Army Medical Research and Materiel Command 
WFI 
Water For Injection 
WHO 
World Health Organization 
 

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SYNOPSIS 
Trial Title 
Effect of Antimalarial Drugs on the Immune Response to Rabies 
Vaccine for Post-exposure Prophylaxis. A Randomized, Open Label, 
Trial in US Adults Age 18-60 Years 
Short title 
MALRAB 
Clinical Phase  
Investigational 
Trial Site 
State University of New York, Upstate Medical University, Center for 
Global Health and Translational Science 
Principal 
Investigator 
Timothy P. Endy, MD, MPH 
Licensed 
Products 
RabAvert® Rabies Vaccine 
Chloroquine Tablets 
Malarone Tablets 
Doxycycline Tablets 
Planned Trial 
Period 
September 2016 – August 2018 
Trial Participants 
18-60 year old adults living in the US 
Planned Sample 
Size 
100 vaccinated, 25 vaccinated subjects in each group 
Treatment 
duration 
1 month 
Follow up 
duration 
1 month 
Trial Design 
Randomized, open-label study with 100 vaccinated adults age ≥ 18 and 
≤ 60 years at time of enrollment. 
After screening, eligible subjects will be enrolled and randomized into 
one of four groups and assigned a unique subject ID number. 
Each subject will be scheduled to receive four doses of rabies vaccine 
intramuscularly. Groups 1, 2 and 3 will receive 14 days of malaria 
chemoprophylaxis prior to first immunization. Group 4 will not receive 
malaria chemoprophylaxis and will receive first immunization on day 0.  
 
Blood and urine samples for research assays will be drawn at different 
time points throughout the study, depending on group assignment. As of 
April 30 2018, urine will not be collected and saved for transport to 
Syracuse University for those in group 1. This portion of the study is 
complete. 
 
Additional blood samples may be drawn if required to assess AEs and 
SAEs. 

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Schedule of Vaccine Administration  
Day 
0 
3 
7 
14 
17 
21 
28 
Group 1 
 
 
 
IM 
IM 
IM 
IM 
Group 2 
 
 
 
IM 
IM 
IM 
IM 
Group 3 
 
 
 
IM 
IM 
IM 
IM 
Group 4 
IM 
IM 
IM 
IM 
 
 
 
Inclusion 
Criteria: 
Subjects must meet all of the following criteria in order to be eligible for 
trial enrollment: 
1. Provide signed and dated informed consent form 
2. Willing to comply with all study procedures and be available for the 
duration of the study  
3. Male or female, aged ≥ 18 to ≤ 60 years on day of inclusion 
4. In good general health based on medical history and physical exam 
Exclusion 
Criteria: 
A subject fulfilling any of the following criteria will be excluded from trial 
enrollment: 
1. Subject is pregnant, or lactating, or of childbearing potential (to be 
considered of non-childbearing potential, a female must be post- 
menopausal for at least 1 year, surgically sterile, or using an 
effective method of contraception or abstinence from at least 4 
weeks prior to the first vaccination and until at least 4 weeks after the 
last vaccination. 
2. Participation in the 4 weeks preceding the first trial vaccination, or 
planned participation during the present trial period, in another 
clinical trial investigating a vaccine, drug, medical device, or medical 
procedure. 
3. Previous history of receiving the rabies vaccine. 
4. Previous history of receiving rabies immune globulin. 
5. Any major psychiatric disorder, such as severe depression, severe 
anxiety disorder, psychosis, schizophrenia, other major psychiatric 
disorders, or seizures. History of mild depression or anxiety disorder 
that are well controlled are not exclusion criteria. 
6. Use of any immunosuppressive drug at the time of the study or 30 
days previously. Topical steroids will not be considered an 
immunosuppressive drug and their use will not be considered an 
exclusion criteria. 
7. Any immunosuppressive disorder, such as HIV infection, common 
variable immunodeficiency, active cancers or chemotherapy. 
8. History of renal insufficiency or requiring dialysis.  
9. Have any condition that would, in the opinion of the site investigator, 

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place the subject at an unacceptable risk of injury or render the 
subject unable to meet the requirements of the protocol. 
10. Previous adverse reaction to any of the antimalarial drugs used in 
this study. 
 
Temporary Exclusion Criteria: Moderate or severe acute illness/infection 
(according to investigator judgment) or febrile illness (temperature ≥ 
38.0°C [≥ 100.4°F) on the day 0. A prospective subject should not be 
included in the study until the condition has resolved or the febrile event 
has subsided.  If the delay for the febrile illness exceeds the window 
between screening and Day 0, or if deemed necessary by the 
investigator, a prospective subject may be re-screened once the fever 
has resolved. 
Recent or scheduled receipt of any vaccine 4 weeks prior to day 0.  
Randomization: 
Randomization will be performed through a computer generated 
process. A standard permuted-block design will be used for 
randomization/allocation in order to avoid undesirable differences in the 
numbers of patients assigned to each group. The randomization 
schedule will be generated by our statistician using SAS 9.3 PROC 
PLAN. Variable block sizes will be kept confidential from the protocol to 
reduce the predictability of the treatment assignments. Subjects who 
withdraw prior to first vaccination will be replaced. 
Licensed 
Product, 
Formulation, 
Dose, Route of 
Administration 
RabAvert® rabies vaccine (Novartis): 1.0 mL reconstituted freeze dried 
vaccine containing ≥ 2.5 international units of rabies antigen 
administered intramuscularly (IM). 
 
Chloroquine: Chloroquine phosphate two 250 mg tablets containing 150 
mg base administered weekly, orally. 
 
Malarone: 250 mg Malarone tablet containing 250 mg atovaquone and 
100 mg proquanil hydrochloride administered daily, orally. 
 
Doxycycline: 100 mg tablet administered daily, orally. 
Objectives: 
Primary: Compare GMT at 14 days post completion of four dose PEP 
with PCECV in each of the malaria prophylaxis groups with control to 
determine if a fifth dose of PEP at that point would be of any added 
value. 
Secondary: To evaluate GMT over protective titer prior to third dose, 
fourth dose and 28 days post fourth dose of PCECV. 
Exploratory: Cell Mediated Immunity, Proteomics if differences in the 
immune responses are seen, Urine analysis in chloroquine group. 
Endpoints: 
Primary: GMT by RFFIT at 14 days post completion of four doses PEP 

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in prophylaxis groups vs. control group 
Secondary: GMT by RFFIT prior to third or fourth dose of rabies 
vaccine and 28 days post fourth vaccine in prophylaxis groups vs control 
group. 
Exploratory: Cell Mediated Immunity, Proteomics if differences in the 
immune response are seen, Urine analysis in chloroquine group. 
Statistical 
Methods: 
This will be a descriptive study to assess immunogenicity of a licensed 
rabies vaccine using recommended dosage schedules in the presence 
of malaria chemoprophylaxis. No formal statistical hypothesis tests will 
be conducted. Descriptive analyses will be based on the per-protocol 
analysis sets. 
Exploratory statistical analyses of final data may be conducted, if 
indicated by the descriptive results. Parametric, non-parametric and 
resampling (bootstrapping) methods for statistical inference may be 
used in exploratory analyses, based on data compliance with 
assumptions of methods.  P -values ≤ 0.05 will be considered significant 
and p-values ≤ 0.10 will be considered a trend. Confidence intervals will 
be constructed at α=0.05 and α=0.10.  When necessary, p-value 
corrections for multiple comparisons will be applied. 
Descriptive and any inferential analyses will be carried out using SAS 
Version 9.2 (or higher), which is licensed and supplied by SAS Institute, 
Cary, NC, USA. 
 
 

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1 KEY ROLES AND CONTACT INFORMATION 
 
Principal 
Investigator:   
 
Timothy P. Endy, MD, MPH 
SUNY Upstate Medical University 
766 Irving Avenue 
Weiskotten Hall, Room 2204 
Syracuse, NY 13210 
315-464-7692 
endyt@upstate.edu 
 
Research Monitor: 
 
Tasaduq Fazili, MD 
SUNY Upstate Medical University 
725 Irving Ave, Suite 311 
Syracuse, NY 13210 
315-464-9630 
fazilit@upstate.edu 
Statistician: 
Donald Cibula 
Center for Research Evaluation 
SUNY Upstate Medical University 
766 Irving Ave, Suite 2260 
Syracuse, NY 13210 
cibulad@upstate.edu 
Clinical Trial Site: 
Clinical Research Unit 
SUNY Upstate Medical University 
505 Irving Ave. 
Syracuse, NY 13210 
 
 
Review Boards 
SUNY Upstate Medical University 
766 Irving Ave. 
Weiskotten Hall, Room 1109 
Telephone: 315-464-4317 
Fax: 315-464-4318 
FWA#: 00005967; IRB#: 00000391 
 
 
 
 
 
 
 

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Data Management: 
Frontier Science (oversight) 
Amherst, NY 
 
 
SUNY Upstate Medical University 
505 Irving Ave. 
Syracuse, NY 13210 
 
 
Research 
Laboratories: 
SUNY Upstate Medical University 
Department of Medicine 
766 Irving Ave. 
Syracuse, NY 13210 
 
Walter Reed Army Institute of Research 
Division of Viral Disease 
503 Robert Grant Ave. 
Silver Spring, MD 20910 
 
Kansas State Veterinary Diagnostic Laboratory 
Rabies Laboratory 
Kansas State University 
2005 Research Park Circle 
Manhattan, KS 66502 
 
Syracuse University 
Department of Chemistry 
1-014 Center for Science and Technology 
Syracuse, NY 13244 

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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
Rabies is present on all continents and enzootic in most African and Asian countries 
where U.S. military personnel deploy, including countries where malaria is also endemic 
and where U.S. military personnel are required to take malaria prophylaxis. (1). The 
incubation period for rabies can be as long as 10 years following infection, placing 
soldiers who have been exposed, but not rabies vaccinated, at risk for a prolonged 
period of time. Current DOD policy does not require routine vaccination prior to 
deployment in rabies enzootic countries. The death of a U.S. soldier in 2011 prompted a 
survey of other soldiers deployed at the same time. It was determined that 140 out of 
8,600 screened had exposures for which post-exposure prophylaxis was indicated but 
did not seek medical attention (2).  
Antimalarial drugs, chloroquine in particular, have previously been shown to impair the 
immune response to intradermal (ID) rabies vaccination. A randomized controlled trial 
was performed in veterinary students to evaluate the antibody response to ID HDCV 
pre-exposure prophylaxis administered with and without chloroquine (3).  The study 
consisted of 51 students not previously vaccinated against rabies, of which 26 received 
300mg chloroquine base per week and 25 did not. All received 0.1 mL of rabies vaccine 
ID on days 0, 7, and 28. Chloroquine was given weekly to the treatment group starting 9 
days before the first dose of vaccine and continued until day 48. Rabies-neutralizing 
antibody titers for the chloroquine group were significantly lower than for the control 
group on days 28, 49, and 105 post-vaccination, indicating that chloroquine taken in 
pre-exposure prophylaxis doses reduces the antibody response to primary 
immunization with ID HDCV. This observation was also reflected in a Peace Corp 
population in Thailand who had received chloroquine and had reduced immune 
responses to rabies vaccine (4).  As a result, current ACIP guidelines recommend that 
exposed persons who are taking malaria prophylaxis should receive a fifth dose of 
rabies vaccine 28 days after the exposure.  These guidelines do not differentiate 
between drugs used for malaria prophylaxis (5).   
Obtaining rabies vaccine and rabies immune globulin in a deployed setting can be 
challenging (6).  A full understanding of the requirements for protecting exposed 
individuals is necessary for appropriate decision making in a resource-constrained 
environment. 
2.2 
Rationale 
This is an exploratory trial to evaluate the effect of antimalarial drugs on the immune 
response generated by rabies vaccine when administered for post-exposure 
prophylaxis.  This study will use the FDA approved post-exposure prophylaxis vaccine 
regimen (without rabies immune globulin) in the presence or absence of an FDA-
approved malaria chemoprophylaxis regimen.  

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Rabies post-exposure prophylaxis in unvaccinated individuals who are not on malaria 
prophylaxis consists of four, 1.0-mL IM injections of the human diploid cell vaccine 
(HDCV) or purified chick embryo cell (PCECV) rabies vaccine on days 0, 3, 7,  and 14 
(5). In the event of an exposure, human rabies immunoglobulin (HRIG) would also be 
administered on day 0, at 20 units per kg of body weight, IM, preferably at the site of 
exposure and not in the same location as the first vaccine dose. In previously 
vaccinated individuals, HRIG is not administered, and two doses of vaccine are given, 
one at day 0 and one at day 3.  Current ACIP guidelines recommend that because 
“corticosteroids, other immunosuppressive agents, antimalarials, and 
immunosuppressive illnesses might reduce immune responses to rabies vaccines 
substantially,” exposed persons on antimalarials should receive a fifth dose of rabies 
vaccine on day 28.  The guidelines do not differentiate between malaria prophylaxis 
regimens (5), therefore this fifth dose is indicated in all compliant soldiers serving in 
malaria-endemic areas.   
This study will administer the post-exposure regimen to volunteers from a US population 
of military age who are taking one of three malaria prophylaxis regimens or no malaria 
prophylaxis.  The primary endpoint is the rabies titer 28 days after the first dose or 14 
days after completion of the 4-dose regimen given to individuals not on malaria 
prophylaxis (ie, the time point at which the fifth dose would be given) to determine if 
there is any added value in administering this fifth dose.   
Malarone and doxycycline were chosen because they are the drugs most commonly 
prescribed to deploying soldiers for malaria prophylaxis.  Chloroquine was chosen 
because this was the drug previously shown to affect the immune response to 
intradermal rabies vaccination given for pre-exposure prophylaxis (3).  Its effect on the 
immune response to intramuscular rabies vaccines given in the regimen for post-
exposure prophylaxis has not previously been studied. 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
Subjects receiving Rabies Vaccine 
Reactions to the current rabies vaccine are mild with local pain, erythema and swelling 
at the injection site. Systemic reactions are less frequent and include headache and 
malaise (1). Guillain-Barré syndrome has been reported as a rare event following 
vaccination but its association with vaccination is uncertain (1).     
Subjects receiving Chloroquine 
Reactions to chloroquine include gastrointestinal upset, headache and pruritus, which 
may be intolerable, is common among Africans. 
 

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Subjects receiving Malarone 
Reactions to malarone are nausea, vomiting, abdominal pain, headache, diarrhea, 
weakness, loss of appetite, and dizziness. 
Subjects receiving Doxycycline 
Reactions to doxycycline are mild nausea, mild diarrhea, gastrointestinal upset, mild 
skin rash, photosensitivity and itching and for females, vaginal itching or discharge. This 
medication may also have more severe symptoms such as headaches, fever, chills, 
severe diarrhea, and decreased urination. 
All subjects 
 
Potential risks of blood sampling include tenderness or bruising at the spot where 
blood was drawn. Fainting or dizziness can occur after a blood draw, but this is 
uncommon. 
2.3.2 
Potential Benefits 
Potential benefits to subjects receiving the rabies vaccine include potentially developing 
protective antibody levels to rabies. 
There are no potential benefits to malaria chemoprophylaxis for this study.  

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3 OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary Study Objective 
 
To compare Geometric Mean Titer (GMT) at 14 days post completion of four dose post 
exposure prophylaxis (PEP) with PCECV in each of the malaria prophylaxis groups with 
control to determine if a fifth dose of PEP at that point would be of any added value. 
3.1.2 
Secondary Study Objective 
To evaluate GMT over protective titer prior to third dose and fourth dose and 28 days 
post fourth dose of PCECV. 
3.1.3 
Exploratory Study Objective 
To explore Cell Mediated Immunity and Proteomics if differences in the immune 
responses are seen. To explore the hypothesis that a lysosomal protein saposin B may 
play a role in mitigating chloroquine toxicity and/or may be a source of toxicity 
associated with long term chloroquine use.  
3.2 
Study Endpoints 
3.2.1 
Primary Endpoint (Immunogenicity) 
GMT by RFFIT at 14 days post completion of four doses PEP in prophylaxis groups vs. 
control group. 
3.2.2 
Secondary Endpoint (Immunogenicity) 
GMT by RFFIT prior to third or fourth dose of rabies vaccine and 28 days post fourth 
vaccine in prophylaxis groups vs control group. 
3.2.3 
Exploratory 
To explore Cell Mediated Immunity and Proteomics if differences in the immune 
responses are seen. Urine analysis to explore the hypothesis that a lysosomal protein 
saposin B may play a role in mitigating chloroquine toxicity and/or may be a source of 
toxicity associated with long term chloroquine use.  

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4 STUDY DESIGN 
This is a randomized, open-label, single site study conducted in 100 vaccinated healthy 
adults age ≥ 18 to ≤ 60 years old in the US. 
Subjects meeting inclusion/exclusion criteria will be randomly assigned to one of the four 
groups through a computer generated process. 
Rabies vaccine will be administered to subjects who have been randomized into four 
groups. Group 1 will receive Chloroquine (po) for 14 days prior to first rabies 
vaccination. Group 2 will receive Malarone (po) for 14 days prior to first rabies 
vaccination. Group 3 will receive Doxycycline (po) for 14 days prior to first rabies 
vaccination. Group 4 (control) will begin rabies vaccination without antimalarial 
prophylaxis. See Table 1 for group allocation and number of subjects per group 
Table 1. Schedule of vaccine administration and subjects per group 
Day 
0 
3 
7 
14 
17 
21 
28 
Number of 
subjects 
Group 1 
Chloroquine 
 
 
 
IM 
IM 
IM 
IM 
25 
Group 2 
Malarone 
 
 
 
IM 
IM 
IM 
IM 
25 
Group 3 
Doxycycline 
 
 
 
IM 
IM 
IM 
IM 
25 
Group 4 
Controls 
IM 
IM 
IM 
IM 
 
 
 
25 
Blood samples will be taken at most visits for RFFIT assays. Samples will also be taken 
or exploratory proteomic and cellular assays.  
In all groups additional blood samples may be taken if required to assess AEs. 
Additional biological samples (e.g., body fluid, tissue samples) may be collected in the 
event of an AE, or SAE. 
Clinical site personnel will record immediate unsolicited AEs that occur within 30 
minutes after receiving the rabies vaccine. The occurrence of SAEs will be collected 
throughout the study.  
Expected study duration for Groups 1-3 once enrolled in the study is approximately 2 
months. Expected study duration for Groups 4 once enrolled in the study is 
approximately 1 month.  

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5 STUDY ENROLLMENT AND WITHDRAWAL 
Healthy subjects will be recruited from Syracuse and the surrounding area for 
participation in this clinical trial.  
Enrollment will continue until 25 subjects are vaccinated in each group. Any subject 
withdrawing prior to first vaccination will be replaced. Any subject withdrawing after first 
vaccination will not be replaced. 
Subjects will be compensated at each study visit. Specifics of compensation is included 
in the informed consent and approved by the Upstate IRB.  
5.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria: 
1. Provide signed and dated informed consent form. 
2. Willing to comply with all study procedures and be available for the duration of the 
study.  
3. Male or female, aged ≥ 18 to ≤ 60 years on day of inclusion. 
4. In good general health based on medical history and physical exam. 
5.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation 
in this study: 
1. Subject is pregnant, or lactating, or of childbearing potential (to be considered of 
non-childbearing potential, a female must be post-menopausal for at least 1 year, 
surgically sterile, or using an effective method of contraception or abstinence from at 
least 4 weeks prior to the first vaccination and until at least 4 weeks after the last 
vaccination. 
2. Participation in the 4 weeks preceding the first trial vaccination, or planned 
participation during the present trial period, in another clinical trial investigating a 
vaccine, drug, medical device, or medical procedure. 
3. Previous history of receiving the rabies vaccine. 
4. Previous history of receiving rabies immune globulin. 
5. Any major psychiatric disorder, such as severe depression, severe anxiety disorder, 
psychosis, schizophrenia, other major psychiatric disorders, or seizures. History of 
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6. Use of any immunosuppressive drug at the time of the study or 30 days previously. 
Topical steroids will not be considered an immunosuppressive drug and their use will 
not be considered an exclusion criteria. 
7. Any immunosuppressive disorder, such as HIV infection, common variable 
immunodeficiency, active cancers or chemotherapy. 
8. History of renal insufficiency or requiring dialysis.  
9. Have any condition that would, in the opinion of the site investigator, place the 
subject at an unacceptable risk of injury or render the subject unable to meet the 
requirements of the protocol. 
10. Previous adverse reaction to any of the antimalarial drugs used in this study. 
Temporary Exclusion Criteria: Moderate or severe acute illness/infection (according to 
investigator judgment) or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]) on day 0.. A 
prospective subject should not be included in the study until the condition has resolved 
or the febrile event has subsided.  If the delay for the febrile illness exceeds the window 
between screening and vaccination, or if deemed necessary by the investigator, a 
prospective subject may be re-screened once the fever has resolved.  
Recent or scheduled receipt of any vaccine 4 weeks prior to day 0. 
5.3 
Strategies for Recruitment and Retention 
Subjects will be recruited via IRB approved posters, email, radio advertisements, social 
media outlets, word of mouth, or recruiting agency. 
5.4 
Treatment Assignment Procedures 
Randomization and analysis will be performed by Upstate Medical University. 
Randomization will be performed through a computer generated process. A standard 
permuted-block design will be used for randomization/allocation in order to avoid 
undesirable differences in the numbers of patients assigned to each group. 
5.4.1 
Randomization Procedures 
The randomization schedule will be generated by the statistician using SAS 9.3 PROC 
PLAN. Variable block sizes will be kept confidential from the clinical staff to reduce the 
predictability of the treatment assignments. Subjects who withdraw prior to first 
vaccination will be replaced by the next enrolled subject who will be assigned to the 
same group as the withdrawn subject. 
The first 39 subjects would be randomized to malarone, doxycycline and control group 
(1:1:1).  Subjects 40-100 would be randomized to chloroquine, malarone, doxycycline 
and control groups (2:1:1:1). This would ensure that upon completion of enrollment 

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subjects would be randomly allocated 1:1:1:1 across all four groups - three treatment 
groups and one control group. 
5.5 
Subject Withdrawal 
Subjects are free to withdraw from participation in the study at any time upon request. 
5.5.1 
Contraindications for Subsequent Vaccinations 
5.5.1.1 Temporary Contraindications 
An investigator may temporarily postpone a subject’s further vaccination until the 
following are resolved: 
• Ongoing clinical AE or biological abnormality related to the trial vaccination 
• Febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]) or moderate or severe acute 
illness/infection on the day of vaccination, according to Investigator judgment. 
• Acute illness on day of vaccination that the investigator determines the subject to 
be ineligible for vaccine that day. 
5.5.1.2 Definitive Contraindications 
An investigator may terminate a study subject’s participation in the study if the following 
contraindications are met: 
• Any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the subject. 
• The subject meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
• Significant noncompliance with the protocol, based on the Investigator’s 
judgment. 
5.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
Subjects who withdraw or are withdrawn from the study will have the reason clearly 
documented in their source records and on the corresponding eCRF.  
In the case of subjects who fail to return for a follow-up examination, documented 
reasonable effort (i.e., documented telephone calls) should be undertaken to locate or 
recall them, or at least to determine their health status while fully respecting their rights. 
These efforts should be documented in the source documents. 

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Subjects who have received at least one dose of vaccine will not be replaced. If a 
subject has already received at least one dose of the study vaccine and experiences a 
safety related contraindication to further participation in the trial, they will continue to be 
followed for safety evaluation for two weeks after the last vaccination was given or the 
time of withdrawal, whichever is later.  This safety evaluation will include targeted 
physical exam if deemed necessary by the physician, injection site assessment (if within 
2 weeks of last vaccination), and blood draw (if within two weeks of last vaccination). 
5.5.3 
Classification of Subjects Who Discontinue the Study 
 
For any subject who discontinues the trial prior to completion, the most serious reason 
for early termination will be checked in the eCRF. Reasons will be listed from the most 
serious to the least serious as follows: 
 
• Serious adverse event: To be used when a subject drops out of or is withdrawn 
from the study by the Investigator because of the occurrence of an SAE, as 
defined in Section 9.1.3. 
• Other adverse event: To be used when a subject drops out of or is withdrawn 
from the study by the Investigator because of the occurrence of an AE other 
than an SAE, as defined in Section 9.4.1.5. 
• Non-compliance with protocol: To be used when the Investigator withdraws a 
subject from the study because of failure to follow protocol guidelines (e.g., not 
attending visits, not being available for telephone calls, not providing blood 
samples). This termination category may also be used if it is retrospectively 
discovered that a subject did not fulfill the eligibility criteria. The Investigator 
will provide a comment as to the specific cause of non-compliance. 
• Lost to follow-up: To be used when the Investigator withdraws a subject from 
the study because of failure to establish contact, as outlined in Section 5.2.9. 
The Investigator will provide documentation that contact was attempted (i.e., 
return of unsigned certified letter receipt). 
• Voluntary withdrawal not due to an adverse event: To be used when a 
subject drops out of the study for any reason other than those listed above. 
5.6 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to principal 
investigator or funding agency. If the study is prematurely terminated or suspended, the 
principal investigator will promptly inform the IRB and will provide the reason(s) for the 
termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects. 

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• Insufficient adherence to protocol requirements. 
• Data are not sufficiently complete and/or evaluable.  

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6 STUDY INTERVENTION 
6.1 
Study Product Description 
There are four (4) products used for this study: RabAvert® (rabies vaccine) produced by 
Novartis Vaccines and Diagnostics GmbH, chloroquine phosphate, malarone and 
doxycycline hyclate.  
RabAvert® (Rabies Vaccine) 
RabAvert® (rabies vaccine) produced by Novartis Vaccines and Diagnostics GmbH is a 
sterile freeze-dried vaccine obtained by growing the fixed-virus strain Flury LEP in 
primary cultures of chicken fibroblasts. The strain Flury LEP was obtained from 
American Type Culture Collection as the 59th egg passage. The growth medium for 
propagation of the virus is a synthetic cell culture medium with the addition of human 
albumin, polygeline (processed bovine gelatin) and antibiotics. The virus is inactivated 
with β-propiolactone, and further processed by zonal centrifugation in sucrose density-
gradient. The vaccine is lyophilized after addition of a stabilizer solution that consists of 
buffered polygeline and potassium glutamate. One dose of reconstituted vaccine 
contains less than 12 mg polygeline (processed bovine gelatin), less than 0.3 mg 
human serum albumin, 1 mg potassium glutamate and 0.3 mg sodium EDTA.  Small 
quantities of bovine serum are used in the cell culture process. Bovine components 
originate only from the United States, Australia and New Zealand. Minimal amounts of 
chicken protein may be present in the final product; ovalbumin content is less than 3 
ng/dose (1 mL), based on ELISA. In the final vaccine, neomycin is present at < 1 μg, 
chlortetracycline at < 20 ng, and amphotericin B at < 2 ng per dose. RabAvert® is 
intended for intramuscular (IM) injection. The vaccine contains no preservative and 
should be used immediately after reconstitution with the supplied Sterile Diluent for 
RabAvert® (Water for Injection). The potency of the final product is determined by the 
US National Institute of Health (NIH) mouse potency test using the US reference 
standard. The potency of one dose (1.0 mL) RabAvert® is at least 2.5 IU of rabies 
antigen. 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 opaque, 
colorless solution.    
Form: Powder and solvent for suspension for injection 
Dose: 1.0 mL of the reconstituted vaccine 
Route: IM 
Lot number: 532011A  
Chloroquine Phosphate Tablets 
Chloroquine Phosphate Tablets are an antimalarial and amebicidal drug. Each tablet, 
for oral administration, contains 250 mg chloroquine phosphate (equivalent to 150 mg 
base). Inactive ingredients 125 mg: Calcium Stearate, Colloidal Silicon Dioxide, Dibasic 
Calcium Phosphate, Microcrystalline Cellulose, and Talc. Inactive ingredients 250 mg: 

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Colloidal Silicon Dioxide, Corn Starch, Lactose Monohydrate, Magnesium Stearate, 
Microcrystalline Cellulose, Polyvinylpyrrolidone, Sodium Starch Glycolate, and Titanium 
Dioxide. Film Coating and Polishing Solution contains: D&C Red #27 Aluminum Lake, 
D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, Hypromellose, 
Polyethylene Glycol, Polysorbate 80 and Titanium Dioxide. 
Malarone 
Malarone is an antimalarial drug.  Each tablet, for oral administration, contains 250 mg 
atovaquone and 100 mg proguanil hydrochloride. The inactive ingredients are low-
substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, 
poloxamer 188, povidone K30, and sodium starch glycolate. The tablet coating contains 
hypromellose, polyethylene glycol 400, polyethylene glycol 8000, red iron oxide, and 
titanium dioxide. 
Doxycycline hyclate 
Doxycycline hyclate is a tetracycline antibiotic.  Each tablet, for oral administration, 
contains specially coated pellets of doxycycline hyclate equivalent to 100 mg of 
doxycycline.  Doxycycline hyclate is a yellow crystalline powder soluble in water and in 
solutions of alkali hydroxides and carbonates. Doxycycline has a high degree of lipid 
solubility and a low affinity for calcium binding. It is highly stable in normal human 
serum. Doxycycline will not degrade into an epianhydro form.  Inert ingredients in the 
tablet formulation are: lactose monohydrate; microcrystalline cellulose; sodium lauryl 
sulfate; sodium chloride; talc; anhydrous lactose; corn starch; crospovidone; 
magnesium stearate; cellulosic polymer coating. 
6.1.1 
Acquisition 
Medication will be purchased by the study team through approved vendors and shipped 
directly to Upstate University Hospital Pharmacy.  
6.1.2 
Packaging 
 
RabAvert® comes in individually packaged unit doses for IM administration. 
Chloroquine USP 250 mg is a pink, round tablet. 
Malarone is a pink, film-coated, round, biconvex tablet. 
Doxycycline is a white, oval, scored tablet. 
 Subjects in the chloroquine group will be dispensed a 1 day supply of antimalarial. All 
doses will be taken weekly during the weekly study visit. Subjects in the malarone and 
doxycycline groups will be dispensed a 42 day supply of antimalarial. The first dose will 
be taken during the first study visit, the remaining doses will be taken daily by the 
subject.  

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6.1.3 
Product Storage and Stability 
 
The Investigator is responsible for product management or will designate a staff 
member to assume this responsibility. 
Vaccine will be stored at SUNY-UMU Clinical Research Unit in a secure location with 
restricted access. Vaccine will be stored in a refrigerator at a temperature ranging from 
+2°C to +8°C. The vaccine must not be frozen. The temperature must be monitored and 
documented for the entire time that the vaccine is at the trial site. In case of accidental 
freezing or disruption of the cold chain, vaccine must not be administered and must be 
quarantined, and the Investigator or authorized designee should contact the Novartis 
representative for further instructions. Medication in the form of tablets will be stored at 
room temperature in a secure location within Upstate University Hospital Pharmacy.  
6.2 
Accountability Procedures for the Study Product 
Vaccine and medication accountability will be the responsibility of the Investigator or 
designee, who will receive and distribute product and maintain accountability logs for all 
products. 
As all products used in this study are licensed products, any undispensed product may 
be used as directed by the PI for other studies. 
6.3 
Assessment of Subject Compliance with Study Product Administration 
All subjects will be administered RabAvert® by study staff. Chloroquine will be 
administered to subjects by direct observation by study staff.  
Subjects receiving malarone or doxycycline will be asked to return any unused portion 
of the product at the next study visit. Any unused doses will be documented by the site 
staff and destroyed by the monitor after accountability. Any dispensed doses that are 
lost by subjects will be thoroughly documented and replaced. 
6.4 
Concomitant Medications 
Use of any immunosuppressive drug at the time of the study or 30 days previously.  
 
 

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6.5 
Preparation and Administration of Product(s) 
RabAvert® rabies vaccine is reconstituted with 1 mL Water for Injection (WFI) and 1 mL 
is administered by IM injection in the deltoid muscle by CRU nurses. All subjects will 
receive four vaccinations. Schedule will be determined by group assignment. 
Chloroquine, Malarone and Doxycycline are oral administration tablets. 
The dose for chloroquine will be 500 mg po for once weekly administration for 6 weeks. 
The dose for malarone will be 250/100 mg po once daily administration for 42 days. 
The dose for doxycycline will be 100 mg po for once daily administration for 42 days.  
See Appendix A and Appendix B for Study Events and Appendix C for Blood Draw 
Schedule. 

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7 STUDY SCHEDULE AND PROCEDURES 
7.1 
Informed Consent Procedures 
Informed consent is the process by which a subject voluntarily confirms his or her 
willingness to participate in a particular trial. Informed consent must be obtained before 
any study procedures are performed. The process is documented by means of a 
written, signed, and dated ICF.  In accordance with GCP, prior to signing and dating the 
consent form, the subject must be informed by appropriate study personnel about all 
aspects of the trial that are relevant to making the decision to participate, and must have 
sufficient time and opportunity to ask any questions. 
Any change to the content of the ICF must be approved by the IRB prior to the form 
being used. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial, this will be communicated to him/her in a timely 
manner. Such information will be provided via a revised ICF or an addendum to the 
original ICF. 
Informed consent forms will be photocopied. The original will be kept by the 
Investigator, and the copy will be kept by the subject. 
Documentation of the consent process will be recorded in the source documents. 
7.2 
Medical History 
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, 
both past and ongoing. This assessment will include a physical examination that will 
include, but not be limited to, the following body systems: neurological, heart, head, 
respiratory, and abdomen. Any pre-existing conditions and illnesses will be documented 
in the source document.  A signed medical records release will be requested.  
Significant medical history (reported as diagnosis) including conditions for which the 
subject is or has been followed by a physician or conditions that could resume during 
the course of the study or lead to an SAE or to a repetitive outpatient care will be 
collected in the electronic case report form (eCRF). 
Dates, medications, and body systems will be recorded; the information collected will 
not be coded. 
For each condition, the data collected will be limited to: 
• Diagnosis with dates (this is preferable to reporting signs and symptoms). 
• Presence or absence of the condition at enrollment. 

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Vital signs will include temperature, blood pressure, and pulse taken while the subject is 
in a resting position. 
At subsequent visits, a history-driven (targeted) physical examination will focus on areas 
of complaint by the subject at the discretion of the physician. This may include, but not 
be limited to, the following body systems: neurological, heart, head, respiratory, and 
abdomen. The necessity of this physical examination is determined through 
conversation between the study staff and the subject about the subject’s current 
medical status. 
7.3 
Screening 
Potential subjects will be recruited from the Syracuse, NY area and scheduled for a 
screening visit. Once a subject signs the informed consent document (see below), they 
will be assigned a screening number beginning with XXX, XXX+1, etc. When a subject 
has completed screening and is eligible for participation and they are willing to continue, 
they will be scheduled for a Day 0 visit. Screen failures will not be entered into the data 
management system for the study.   
Screening Visit (Day -60 to -1)  
• Obtain and document consent from potential subject. 
• Obtain signed medical records release. 
• Collect medical history. 
• Assess inclusion and exclusion criteria. 
• Perform physical examination, including collection of vital signs and temperature. 
• Concomitant medications will be recorded. 
• Collect demographics. 
• Perform urine pregnancy test. 
• Schedule subject for Day 0 visit, if eligible.  
7.4 
Day 0 Visit - ALL SUBJECTS 
 
• Review consent with subject. 
• Review inclusion/exclusion criteria to confirm eligibility.   
• Review medical history and note any changes since screening.  
• Conduct targeted physical exam, including collection of vital signs and 
temperature. 

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• Review concomitant medications. 
• Perform urine pregnancy test 
Randomize subject. Schedule will vary depending on group assignment. See 
Section 7.5 (Groups 1, 2, 3) and 7.6 (Group 4) for detailed schedule. 
  
7.5 
Group 1 (Chloroquine), Group 2 (Malarone), Group 3 (Doxycycline) 
Day 0 
• Collect blood for Research Assays 
• Confirm group assignment 
• Group 1: Collect urine specimen 
• Group 1: Administer chloroquine 500 mg po OR  
Group 2: Administer malarone 250/100 mg po and dispense 41 days with 
instruction OR 
Group 3: Administer doxycycline 100 mg po and dispense 41 days with 
instruction 
• Observe subject for 15 minutes and record any adverse reaction(s). 
 
Day 7 (+/- 1 day) 
• Conduct targeted physical exam, including collection of vital signs and 
temperature. 
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Group 1: Collect urine specimen 
• Group 1: Confirm group assignment. 
• Group 1: Administer chloroquine 500 mg po.  
• Group 1: Observe subject for 15 minutes and record any adverse reaction(s). 
• Groups 2 and 3: Review drug accountability. 
 
 

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Day 14 (+/- 1 day) Vaccination #1 
• Review contraindications to confirm eligibility.  
• Perform urine pregnancy test 
• Review medical history and note any changes.  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Group 1: Collect urine specimen 
• Group 1: Administer chloroquine 500 mg po OR  
Groups 2 and 3: Review drug accountability 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 
 
Day 17 (+/- 1 day) Vaccination #2 
• Review contraindications to confirm eligibility.  
• Perform urine pregnancy test 
• Review medical history and note any changes.  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 

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Day 21 (+/- 1 day) Vaccination #3 
• Review contraindications to confirm eligibility.  
• Perform urine pregnancy test 
• Review medical history and note any changes.  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Group 1: Collect urine specimen 
• Group 1: Administer chloroquine 500 mg po OR  
Groups 2 and 3: Review drug accountability. 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 
 
Day 28 (+/- 2 days) Vaccination #4 
• Review contraindications to confirm eligibility.  
• Perform urine pregnancy test 
• Review medical history and note any changes.  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Group 1: Collect urine specimen 

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• Group 1: Administer chloroquine 500 mg po OR  
Groups 2 and 3: Review drug accountability. 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 
 
Day 31 (+/- 2 days)  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Collect blood for Research Assays 
• Record any adverse reaction(s). 
 
Day 35 (+/- 2 days)  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Group 1: Confirm group assignment. 
• Group 1: Collect urine specimen 
• Group 1: Administer chloroquine 500 mg po.  
• Group 1: Observe subject for 15 minutes and record any adverse reaction(s). 
• 
Groups 2 and 3: Review drug accountability. 
 
 
 
 
 
 

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Day 42 (+/- 3 days)  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Collect blood for Research Assays 
• Record any adverse reaction(s). 
• Group 1: Collect urine specimen 
• Groups 2 and 3: Perform final drug accountability and collect any unused drug. 
 
Day 56 (+/- 7 days)  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Collect blood for Research Assays 
• Group 1: Collect urine specimen 
• Record any adverse reaction(s). 
 
7.6 
Group 4 (Controls) 
Day 0 Vaccination #1 
• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 
 
Day 3 (+/- 1 day) Vaccination #2 
• Review contraindications to confirm eligibility.  
• Perform urine pregnancy test 
• Review medical history and note any changes.  

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• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 
Day 7 (+/- 1 day) Vaccination #3 
• Review contraindications to confirm eligibility.  
• Perform urine pregnancy test 
• Review medical history and note any changes.  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 
• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 
 
Day 14 (+/- 1 day) Vaccination #4 
• Review contraindications to confirm eligibility.  
• Perform urine pregnancy test 
• Review medical history and note any changes.  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Record any adverse reaction(s). 

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• Collect blood for Research Assays (must be completed prior to vaccination) 
• Confirm group assignment 
• Inject RabAvert® vaccine 1.0 mL IM in deltoid. 
• Observe subject for 30 minutes and record any adverse reaction(s). 
 
Day 17 (+/- 2 days)  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Collect blood for Research Assays 
• Record any adverse reaction(s). 
 
Day 28 (+/- 3 days)  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Collect blood for Research Assays 
• Record any adverse reaction(s). 
 
Day 42 (+/- 7 days)  
• Conduct targeted physical exam, including collection of vital signs and 
temperature  
• Review concomitant medications. 
• Collect blood for Research Assays 
• Record any adverse reaction(s). 
 

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8 SAMPLE COLLECTION 
Blood samples will be collected for Research Laboratory Assays according to the Blood 
Draw Schedule in Appendix A. Immediately prior to the blood draw; the staff member 
performing the procedure will remove the collection tubes from the supplied kit and 
verify the subject’s ID number on the labels. Blood will be taken prior to vaccination(s).  
In the event of an AE or SAE, additional biological samples (e.g., additional blood, body 
fluids, tissue samples) may be collected. 
8.1 
Sample Preparation 
Blood samples will be retrieved and processed according to Center for Global Health 
and Translational Science (CGHATS) Standard Operating Procedures (SOP) or Study 
Specific Procedures (SSP). Briefly, serum samples will be maintained at room 
temperature for the allotted time, centrifuged, aliquoted and frozen at -80°C for long 
term storage. Peripheral Blood Mononuclear Cell (PBMC) samples will be centrifuged, 
plasma will be removed and retained, cells will be washed, resuspended in freezing 
media, aliquoted and frozen in liquid nitrogen vapor phase for long term storage.  
8.2 
Laboratory Assays 
8.2.1 
Rapid Fluorescent Foci Inhibition Test (RFFIT) 
RFFIT is a serum neutralization (inhibition) test, which means it measures the ability of 
rabies specific antibodies to neutralize rabies virus and prevent the virus from infecting 
cells. These antibodies are called rabies virus neutralizing antibodies (RVNA).  
The World Health Organization (WHO) guideline of 0.5 International Units per milliliter 
(IU/mL) is used as an adequate response to rabies vaccination, as well as the ACIP 
level of “complete neutralization at a serum dilution of 1:5 in the RFFIT test” as evidence 
of adequate response in a person. 
RFFIT analysis will be performed on samples taken from Day 0, prior to vaccination 3, 
prior to vaccination 4, 14 and 28 days post 4th vaccination. 
8.2.2 
Proteomics 
Proteomics is the analysis of the expression, localization, function, and interactions of a 
set of proteins expressed by the genetic material of an organism under a given set of 
environmental conditions, using iTRAQ or equivalent method. This technique offers a 
novel method to evaluate clinical samples from experimental inoculation for 
identification of novel biomarkers and correlates of immunogenicity. Proteomics may 
help elucidate the mechanisms by which antimalarials alter the immune response to 
rabies vaccination.  Proteomics analysis can be performed on either serum or plasma 
samples. Proteomics is an exploratory assay and may or may not be done based on 

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whether a statistically significant difference in GMT is detected between study groups 
and on data collected from other ongoing studies.  
8.2.3 
Cellular Assays 
The cellular response to rabies vaccination is an exploratory assay and may or may not 
be done  based on whether or not a difference in GMT is detected between study 
groups and data collected from other ongoing studies. 
8.2.4 
Urine Analysis 
Urine will be analyzed to determine if chloroquine is excreted in part, bound to saposin 
B. Saposin B may play a role in mitigating chloroquine toxicity and/or may be a source 
of toxicity associated with long term chloroquine use. 
8.2.5 
Sample Storage and Shipment 
Samples will be stored in temperature controlled units, -80°C ± 10°C for serum and 
plasma samples, vapor phase liquid nitrogen for PBMCs. These units are monitored 24 
hours per day and documentation of the temperature will be maintained throughout the 
trial. Any temperature deviations resulting in an alarm condition will be noted on the 
shipping manifest. 
At mutually agreed upon times, samples will be shipped for testing according to 
CGHATS SOP. Sera will be shipped frozen, using dry ice to maintain a frozen state. 
PBMCs will be shipped using dry shippers. Shipments must be compliant with the 
International Air Transport Association (IATA) 602 regulations and temperature will be 
monitored while in transit.  

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9 ASSESSMENT OF SAFETY 
Although using only licensed products for this study, subjects will be kept under 
observation for 15 minutes after the first dose of antimalarial and 30 minutes after each 
rabies vaccination to ensure their safety. Any AE that occurs during this period will be 
noted on the source document and identified as an immediate event / reaction; and will 
additionally be recorded in the eCRF.  
9.1 
Specification of Safety Parameters 
9.1.1 
Unanticipated Problems 
Federal regulations require that unanticipated problems involving risks to subjects or 
others be promptly reported to the IRB. These events encompass a broader category of 
events than SAEs and may include issues such as problems with loss of control of 
subject data or the investigational product, adverse psychological reactions, or breach 
of confidentiality. Risks to others (eg, program personnel) must also be reported.  
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to subjects or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
The IRB and the HRPO will evaluate the PI’s and research monitor’s reports to 
determine whether a given incident, experience or outcome constitutes an unanticipated 
problem involving risk to subjects or others and ensure upward reporting of the 
unanticipated problems involving risk to subjects or others to the appropriate regulatory 
offices. 
9.1.2 
Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (for example, abnormal physical exam or 
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participation in the research, whether or not considered related to the subject’s 
participation in the research. 
9.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from the event 
as it occurred) 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect   
• An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
9.2 Time Period and Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the 
study.  
The PI will record all reportable events with start dates occurring any time after informed 
consent until study completion.  At each study visit, the investigator will inquire about 
the occurrence of AE/SAEs since the last visit.  Events will be followed for outcome 
information until resolution or stabilization. 
Any SAE that occurs after a subject has completed the study but that is likely to be 
related to the product or to the experiment must also be reported as soon as possible. 
9.3 Characteristics of an Adverse Event 
9.3.1 
Relationship to Study Intervention 
To assess relationship of an event to study intervention, the following guidelines are 
used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
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c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event 
onset. 
b. An alternate etiology has been established. 
9.3.2 
Severity of Event 
The following scale will be used to grade adverse events: 
1. Mild: does not interfere with routine activities; minimal level of discomfort 
2. Moderate: interference with routine activities; moderate level of discomfort 
3. Severe: unable to perform routine activities; significant level of discomfort  
9.4 
Reporting Procedures 
The PI will report all AEs to the SUNY IRB and the USAMRMC ORP HRPO in the 
appropriate safety, annual, and/or final reports.  
9.4.1 
Unanticipated Problem Reporting to IRB 
Incidents or events that meet the requirements for notifying the SUNY IRB of 
unanticipated problems will be reported to the SUNY IRB using the following timeline:   
• Unanticipated problems that are serious adverse events will be reported to the 
IRB within 1 week of the investigator becoming aware of the event.  
• Any other unanticipated problem will be reported to the IRB within 2 weeks of the 
investigator becoming aware of the problem.  
9.4.2 
Serious Adverse Event Reporting to HRPO 
Any Serious Adverse Event will be submitted to the USAMRMC ORP HRPO and the 
research monitor. 
Initial reports of SAEs should be sent by the PI within 72 hours of the Investigator 
becoming aware of an SAE. Any new relevant information concerning the SAE (e.g., 
outcome, precise description of medical history, results of the investigation) should be 
sent as soon as possible. Copies of documents (e.g., medical records, discharge 
summary, autopsy) may be requested. 

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Notification of an SAE to the Research Monitor for the study, email: fazilit@upstate.edu 
and the Human Research Protection Office (HRPO) email: usarmy.detrick.medcom-
usamrmc.other.hrpo@mail.mil  Human Research Protection Office (HRPO), U.S. Army 
Medical Research and Materiel Command, ATTN: MCMR-RPH, 504 Scott Street, 
Frederick, MD 21702-5012 will be done in parallel. 
All SAEs will be followed until resolution or stabilization.  
9.4.3 
Reporting of Pregnancy 
If the Investigator becomes aware of pregnancy of study participant, paper pregnancy 
reporting form should be completed and sent within 72 hours. The investigator will notify 
the research monitor, email: fazilit@upstate.edu and the Human Research Protection 
Office (HRPO) email: usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil. 
Study staff must then maintain contact with the subject to obtain information about the 
outcome, i.e., details about the delivery and the newborn, or about pregnancy 
termination. Pregnancy itself is not considered an AE, but any complications during 
pregnancy are to be considered as AEs, and in some cases could be considered SAEs. 
Spontaneous abortions, fetal death, stillbirth, and congenital anomalies reported in the 
baby are always considered as SAEs, and the information should be provided using an 
SAE form. 

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10 STUDY OVERSIGHT 
10.1 
Research Monitor 
In addition to the PI’s responsibility for oversight, study oversight will be under the 
direction of a Research Monitor.  The research monitor is independent of the study and 
will be available in real time to review and recommend appropriate action regarding 
adverse events and other safety issues. 
Per requirements of Department of Defense Instructions 3216.02, research funded with 
Department of Defense funds requires a research monitor to be appointed.  Dr. 
Tasaduq Fazili will be the research monitor for this trial.  His duties will include 
reviewing and providing and unbiased assessment and written report of all: SAEs, 
Subject deaths, Unexpected AEs, Protocol deviations that are related to an adverse 
event impacting the subject, Annual reports and Unanticipated problems involving risks 
to subject and others involved in the trial.  The research monitor may observe 
recruitment and enrollment procedures and the consent process for individuals, groups 
or units, review monitoring plans and data collection. 
The research monitor may discuss the research protocol with the investigators, 
interview human subjects, and consult with others outside of the study about the 
research.  He shall have authority to stop a research protocol in progress, remove 
individual human subjects from a research protocol, and take whatever steps are 
necessary to protect the safety and well-being of human subjects until the IRB can 
assess the monitor's report.  He shall have the responsibility to promptly report his 
observations and findings to the IRB or other designated official and the Human 
Research Protection Office. 

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11 CLINICAL SITE MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human subjects are 
protected, that the study is implemented in accordance with the protocol and/or other 
operating procedures, and that the quality and integrity of study data and data collection 
methods are maintained.  The monitor will evaluate study processes and documentation 
based on International Conference on Harmonisation (ICH), E6: Good Clinical Practice 
guidelines (GCP). 
Before the start of the trial (i.e., before the inclusion of the first subject), the 
Investigators and the Monitoring representative will meet at the site-initiation visit to 
discuss the trial protocol and the detailed trial procedures. Emphasis will be placed on 
inclusion and exclusion criteria, visit timing, informed consent procedures, eCRF 
completion, and the handling of samples and products. 
The monitoring staff will ensure and document that all material to be used during the 
trial has been received at the site; and that the study investigator team and local 
monitoring staff have been properly informed about the trial, GCP and regulatory 
requirements. 
After the start of the trial, the monitoring staff or a representative will be in regular 
contact with the investigational team through telephone calls and regular follow-up 
visits. The Investigator or delegate must be available for these visits, and must allow the 
monitoring staff direct access to subject medical files and eCRFs. During these visits, 
the monitoring staff will: 
• Evaluate the quality of the trial progress (adherence to protocol and any study-
specific guidelines, quality of data collection and document completion, signature 
of consent forms, occurrence of SAEs, sample and product management, cold-
chain monitoring, archiving, and direct observation of study procedures during 
the trial). 
• Source-verify completed eCRFs and any corresponding answered queries. 
• Determine the number of complete or ongoing issues identified at monitoring 
visits (e.g., protocol violations, SAEs). Any identified problems will be discussed 
with the Investigator, and corrective or preventive actions will be determined, as 
appropriate. 
• Review that all protocol procedures have been completed and the data have 
been entered into the eCRF. All data-related queries must be completed prior to 
database lock. 
At the end of the trial, a close-out visit will be performed to ensure that: 
• CGHATS has all the documents necessary for archiving. 
• All samples have been shipped to the appropriate laboratories. 
• All unused products have been either destroyed or accounted for. 

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12 STATISTICAL CONSIDERATIONS 
12.1 
Study Hypotheses 
 
This will be a descriptive study to assess immunogenicity of a licensed rabies vaccine 
using test dosage schedules in the presence of malaria chemoprophylaxis. No formal 
statistical hypothesis tests will be conducted. Descriptive analyses will be based on the 
per-protocol analysis sets.  
 
Exploratory statistical analyses of final data may be conducted, if indicated by the 
descriptive results. Parametric, non-parametric and resampling (bootstrapping) methods 
for statistical inference may be used in exploratory analyses, based on data compliance 
with assumptions of methods.  P -values ≤ 0.05 will be considered significant and p-
values ≤ 0.10 will be considered a trend. Confidence intervals will be constructed at 
α=0.05 and α=0.10.  When necessary, p-value corrections for multiple comparisons will 
be applied. 
 
Descriptive and any inferential analyses will be carried out using SAS Version 9.2 (or 
higher), which is licensed and supplied by SAS Institute, Cary, NC, USA. 
12.2 
Sample Size Considerations 
The planned sample size is 100 subjects, who will be randomly allocated (1:1:1:1) into 
three treatment groups and one control group.  The sample size was chosen 
empirically, based on sample sizes of other exploratory studies of this general type.  
This exploratory study is not powered to formally test equivalency or non-inferiority in 
immunogenicity among groups according to malaria prophylaxis. Subjects who withdraw 
prior to first vaccination will be replaced by the next enrolled subject who will be 
assigned to the same group as the withdrawn subject. Replacement subjects will not be 
randomized.   
12.2.1 Safety Review 
A descriptive summary of adverse events that were reported throughout the trial will be 
produced. 
12.3 
Final Analysis Plan 
Primary Objective Analysis 
Descriptive analyses for the primary endpoints will be based on per-protocol analysis 
data sets using the RFFIT data from blood samples taken 14 days post completion of all 
four vaccine doses. Separate descriptive analyses will be conducted for each per-
protocol data set and group. 

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Secondary Objective Analysis 
Descriptive analyses for the secondary endpoints will be based on per-protocol analysis 
data sets using the RFFIT data from blood samples taken prior to third and fourth dose 
of rabies vaccine and 28 days post fourth vaccine dose. 
Per Protocol Analysis Set 
The Per-Protocol (PP) analysis set will include all subjects who had no protocol 
deviations at the time that the data was collected. Two PP analysis sets will be 
produced for the primary objective that will contain separate data from blood drawn on 
day 0 and 14 days post 4th vaccination. Descriptive analysis of the secondary endpoint 
will require three additional per protocol analysis sets for blood drawn prior to 3rd and 
prior to 4th vaccination and on day 28 post 4th vaccination.   
Subjects will be excluded from the PPAS for the following reasons: 
1. Subject did not meet all protocol-specified inclusion/exclusion criteria or 
experienced a definitive contraindication 
2. Administration of vaccine was not done per protocol 
3. Subject did not receive vaccine in the proper time window as defined in the study 
procedures 
4. Subject did not provide a post-dose serology sample in the proper time window 
as defined in the study procedures* 
5. For the malarone and doxycycline groups, subject missed the three or more of 
the daily dose of antimalarial in any one week. 
6. For the chloroquine group, subject missed their weekly dose by three or more 
days  
*Subjects whose serology sample is outside the defined window for the secondary 
endpoint will still be included in the primary endpoint analysis. 
For the computation of GMTs, a titer reported as < LLOQ will be converted to a value of 
0.5 LLOQ. 
For calculating fold-rise and titer ratio (GMTR), < LLOQ will be converted to 0.5 LLOQ 
for a numerator and < LLOQ will be converted to LLOQ for a denominator 
Any titer reported as > ULOQ (upper limit of quantization) will be converted to ULOQ.  
Missing data will not be imputed.  

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Potential outliers will be identified using histograms and modified box plots or normal 
probability plots, when appropriate.  Choice of subsequent tests for outliers (e.g. 
Grubbs, Tietjen-Moore and ESD) will depend on the number and nature of suspected 
outliers and may require data transformation.  Bootstrapped estimates of standard 
errors may also be reported. Sensitivity analysis of effect of outliers on descriptive 
statistics will be conducted, and if necessary descriptive statistics that include and 
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13 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Source documents are original documents or certified copies, and include, but are not 
limited to medical and hospital records, screening logs, informed consent forms, 
telephone contact logs, and worksheets. The purpose of trial source documents is to 
document the existence of subjects and to substantiate the integrity of the trial data 
collected. Investigators must maintain source documents so that they are accurate, 
complete, legible, and up to date. 
The subject screening and enrollment log should list all individuals contacted by the 
Investigators to participate in the trial, regardless of the outcome. 
Source documents will be stored in a secure location with access restricted to study 
personnel for the protection of confidentiality of subjects. 
Study staff will permit authorized representatives of Upstate Medical University and 
regulatory agencies to examine (and when required by applicable law, to copy) research 
records for the purposes of quality assurance reviews, audits, and evaluation of the 
study safety, progress and data validity.   

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14 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Quality Control in Data 
Accuracy of data in the database is reviewed on numerous levels. Every attempt is 
made by the CRC to review source documentation prior to the subject leaving the site. 
Data is reviewed during data entry, usually completed within 24 hours of the subject 
visit. Source document to database entry is monitored 100% by the clinical monitor. Any 
discrepancies between the source and database will be corrected by the CRC. 
Product accountability is the responsibility of the principal investigator or designee. 
Documentation pertaining to product accountability are monitored by the clinical monitor 
and SUNY-UMU Pharmacy. 
14.2 
Quality Assurance in Clinical Study 
During review of a clinical protocol, the SUNY IRB ensures that staff, who will be part of 
the clinical study, are properly trained to perform the tasks assigned. Additionally, 
training records are reviewed by the clinical monitor. 
The SUNY IRB works very closely with the SUNY Quality Assessment and 
Improvement Programs (QAIP) which is a post (IRB) approval monitoring program 
aimed at providing subjects with an extra level of protection by reviewing the conduct of 
the study in real time. In the event a quality issue arises, the QAIP office will make 
recommendations for a corrective action and it is the responsibility of the principal 
investigator to ensure the corrective action has been implemented. 

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15 PROTECTION OF HUMAN SUBJECTS 
15.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in the Declaration of Helsinki (2008) as far as adopted by the 
concerned regulatory authorities as well as in accordance with 45 CFR Part 46 and/or 
the ICH E6. The investigator will ensure that this study is conducted in full conformity 
with the applicable national and local requirements regarding ethical committee review, 
informed consent, and other statutes or regulations regarding the protection of the rights 
and welfare of human subjects participating in biomedical research. 
15.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any subject is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are 
implemented in the study.   
Copies of these approvals, along with information on the type, version number, and date 
of document, and the date of approval, must be forwarded by the Investigator HRPO.  
15.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation.  Extensive 
discussion of risks and possible benefits of study participation will be provided to 
subjects and their families, if applicable.  A consent form describing in detail the study 
procedures and risks will be given to the subject.  Consent forms will be IRB-approved, 
and the subject is required to read and review the document or have the document read 
to him or her.  The investigator or designee will explain the research study to the subject 
and answer any questions that may arise.  The subject will sign the informed consent 
document prior to any study-related assessments or procedures.  Subjects will be given 
the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate.  They may withdraw consent at any time throughout the course 
of the study.  A copy of the signed informed consent document will be given to subjects 
for their records.  The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if 
they decline to participate in this study. 
The consent process will be documented in the clinical or research record.   

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15.4 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents.  This confidentiality is extended to cover testing of 
biological samples in addition to any study information relating to subjects. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence.  No information concerning the study or the data will be 
released to any unauthorized party without prior approval of the Principal Investigator. 
The study monitor may inspect all study documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) for the study subjects.  The clinical study site will permit access to 
such records. 
The IRBs, and regulatory agencies, including the FDA, require direct access to all study 
records, and will treat these documents in a confidential manner. 
15.5 
Future Use of Stored Specimens and Other Identifiable Data 
Any unused part of the research samples will be securely stored at WRAIR or Upstate 
Medical University for at least 5 years.  
Subjects will be asked to indicate on the ICF whether they will permit the future use of 
any unused samples for other tests. If they refuse permission, the samples will not be 
used for any testing other than that directly related to this study. If they agree to this 
use, they will not be paid for giving permission. (Anonymity of samples will be ensured.) 
The aim of any possible future research is unknown today, and may not be related to 
this particular study. It may be to improve the knowledge of vaccines or infectious 
diseases, or to improve laboratory methods. Genetic tests will never be performed on 
these samples without individual informed consent. 
 

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16 DATA HANDLING AND RECORD KEEPING 
The investigators are responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported.  All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data.  
At specified intervals, the Investigator or an authorized designee will interview the 
subjects to collect information, and will attempt to clarify anything that is incomplete or 
unclear. All clinical trial information gathered by the study site will be reported 
electronically by the Investigator or authorized designee using a web-based eCRF held 
at Frontier Science in Amherst, NY. The eCRF has been designed specifically for this 
trial using a validated Electronic Records / Electronic Signature-compliant platform 
(21CFR Part 11). 
16.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff 
under the supervision of the investigator.  All source documents and laboratory reports 
must be reviewed by the study team and data entry staff, who will ensure that they are 
accurate and complete.  Unanticipated problems and adverse events must be reviewed 
by the investigator or designee.   
Data monitoring at the sites and quality control in the form of computerized logic and / or 
consistency checks will be systematically applied in order to detect errors or omissions. 
Any questions pertaining to the reported clinical data will be submitted to the 
Investigator for resolution using the Electronic Data Capture (EDC) system. Each step 
of this process will be monitored through the implementation of individual passwords to 
maintain appropriate database access and to ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the 
information in the eCRFs; must provide explanations for all missing information; and 
must sign the eCRF using an e-signature.  
16.2 
Data Capture Methods 
Clinical source data will be captured on paper and entered into electronic database by 
study staff. 
Upon completion of training, each user requiring access to the EDC system will be 
issued a unique username and password. In the event of a change in trial personnel, 
each newly assigned individual will receive a unique username and password; the 
username and password of a previous user may not be reissued. 
Immunogenicity data will be performed at the laboratory level following the laboratory’s 
procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical database. 

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After integration of all corrections in the complete set of data, the database will be 
released for statistical analysis. 
16.3 
Study Records Retention 
The Investigator will retain all source documents, consent forms, for at least 2 years 
after the investigation is discontinued. 
The Investigator will retain all documentation pertaining to the trial. The protocol, 
documentation, approvals, and all other documents related to the trial, including 
certificates attesting that satisfactory audit and inspection procedures have been carried 
out will be kept by Upstate in the Investigator’s File. Data on AEs are included in the 
Investigator’s file. Archived data may be held on microfiche or electronic records, 
provided that a back-up exists and that a hard copy can be obtained if required. All data 
and documents will be made available if requested by relevant authorities. 
16.4 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements.  The noncompliance may be on the 
part of the subject, the investigator, or study staff.  As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. 
These practices are consistent with investigator and sponsor obligations in ICH E6: 
• Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4. 
• Quality Assurance and Quality Control, Section 5.1.1 
• Noncompliance, Sections 5.20.1 and 5.20.2. 
All deviations from the protocol must be addressed in study subject source documents 
and reported to the IRB according to their requirements.   
 
 

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17 LITERATURE REFERENCES 
(1) World Health Organization (WHO): Rabies Fact Sheet No 99. Available at 
http://www.who.int/mediacentre/factsheets/fs099/en/ ; accessed 25 July 2015. 
 
(2) Montgomery N: Confusion, anger surround report of soldier’s rabies death, Stars and 
Stripes 2012. Available at http://www.stripes.com/news/confusion-anger-surround-report-of- 
soldier-s-rabies-death-1.166967; accessed 25 July 2015. 
 
(3) Pappaioanou M, Fishbein DB, Dreesen DW, Schwartz IK, Campbell GH, Sumner JW, 
Patchen LC, Brown WJ.  Antibody response to preexposure human diploid-cell rabies vaccine 
given concurrently with chloroquine. N Engl J Med. 1986 Jan 30;314(5):280-4. 
 
(4) Taylor DN, Wasi C, Bernard K. Chloroquine prophylaxis associated with a poor antibody 
response to human diploid cell rabies vaccine. Lancet. 1984 Jun 23;1(8391):1405. 
 
(5) Rupprecht CE, Briggs D, Brown CM, et al, Use of a Reduced (4-Dose) Vaccine Schedule for 
Postexposure Prophylaxis to Prevent Human Rabies: Recommendations of the Advisory 
Committee on Immunization Practices, MMWR March 19, 2010 / 59(RR02);1-9. 
 
(6)  Moe CD, Keiser PB, Should U.S. troops routinely get rabies pre-exposure prophylaxis? Mil 
Med. 2014 Jul;179(7):702-3. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: SCHEDULE OF EVENTS 
GROUP 1 (Chloroquine), GROUP 2 (Malarone), GROUP 3 (Doxycycline) 
Study Day 
-60 to 
0 
0 
7 
14 
17 
21 
28 
31 
35 
42 
56 
Visit Type 
SCR 
BL 
  
BL 
BL 
BL 
BL 
BL 
  
BL 
BL 
VAC 
VAC 
VAC 
VAC 
Time Windows 
(days) 
-60 to 
0 
0 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+/- 2 
+/- 2 
+/- 2 
+/- 3 
+/- 7 
Informed Consent 
IC Review 
X 
X 
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion 
Criteria 
X 
X 
  
  
  
  
  
  
  
  
  
Medical Records 
Release 
X 
  
  
  
  
  
  
  
  
  
  
Contraindications  
  
  
  
X 
X 
X 
X 
  
  
  
  
Medical History 
X 
X 
  
X 
X 
X 
X 
  
  
  
  
Physical Exam 
X 
  
  
  
  
  
  
  
  
  
  
Targeted Physical 
Exam a 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy 
Test b 
X 
X 
  
X 
X 
X 
X 
  
  
  
  
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
Confirm Group 
Assignment c 
  
  
X  
X 
  X  
X 
X 
  
X 
  
  
Blood Draw for 
Research  
  
X 
  
X 
X 
X 
X 
X 
  
X 
X 
Collect Urine  
Group 1 
 
X 
X 
X 
 
Xe 
Xe 
 
Xe 
Xe 
Xe 
Dispense 
Medication 
  
X 
X 
X 
  
X 
X 
  
X 
  
  
Group 1 
Dispense 
Medication 
  
X 
  
  
  
  
  
  
  
  
  
Groups 2 and 3 
Review Medication 
  
  
X 
X 
  
X 
X 
  
X 
  
  
Groups 2 and 3 

MALRAB 
Version 11.0 
 
09 May 2018 
 ________________________________________________________________________________________________________  
 
56 
 
Vaccination 
  
  
  
X 
X 
X 
X 
  
  
  
  
Study Day 
-60 to 
0 
0 
7 
14 
17 
21 
28 
31 
35 
42 
56 
Final Drug 
Accountability 
Groups 2 and 3 
  
  
  
  
  
  
  
  
  
X 
  
AE/SAE  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
15 min post dose 
observation d 
  
X 
X 
  
  
  
  
  
X 
  
  
30 min post 
vaccine 
observation 
  
  
  
X 
X 
X 
X 
  
  
  
  
 
 
a – At Investigator’s discretion 
b – Female subjects only 
c – Confirm group assignment on Day 7 & Day 35 applies to Group 1 only 
d – 15 minute observation on Day 7 & Day 35 applies to Group 1 only 
e – Urine samples may not be collected at later dates pending results from early samples  
 
 
 
 
 
 
 
 
 
 
 
 
 

MALRAB 
Version 11.0 
 
09 May 2018 
 ________________________________________________________________________________________________________  
 
57 
 
 
APPENDIX B: SCHEDULE OF EVENTS 
 GROUP 4 (Control)   
 
 
a – At Investigator’s discretion 
b – Female subjects only 
 
 
Study Day 
-60 to 0 
0 
3 
7 
14 
17 
28 
42 
Visit Type 
Screening 
BL 
VAC 
BL 
VAC 
BL 
VAC 
BL 
VAC 
BL 
BL 
BL 
Time Windows (days) 
-60 to 0 
0 
+/- 1 
+/- 1 
+/- 1 
+/- 2 
+/- 3 
+/- 7 
Informed Consent/IC 
Review 
X 
X 
 
 
 
 
 
 
Medical Records Release 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Contraindications 
 
X 
X 
X 
X 
 
 
 
Medical History 
X 
X 
X 
X 
X 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
Targeted Physical Exam a 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test b 
X 
X 
X 
X 
X 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Blood Draw for Research  
 
X 
X 
X 
X 
X 
X 
X 
Confirm Group Assignment 
 
X 
X 
X 
X 
 
 
 
Vaccination 
 
X 
X 
X 
X 
 
 
 
AE/SAE  
 
X 
X 
X 
X 
X 
X 
X 
30 minute post vaccine 
observation  
 
X 
X 
X 
X 
 
 
 

MALRAB 
Version 11.0 
 
09 May 2018 
 ________________________________________________________________________________________________________  
 
58 
 
APPENDIX C: Blood Draw Schedule 
 
GROUP 1 (Chloroquine), GROUP 2 (Malarone), GROUP 3 (Doxycycline) 
 
Study Day 
0 
7 
14 
17 
21 
28 
31 
35  
42 
56 
Serum (8.5 mL) 1 
 
1 
1 
1 
1 
1 
 
1 
1 
PBMC (8.0 mL)  
 
5 
 
3 
3 
 
 
5 
5 
Daily BV (mL) 
8.5 0 
48.5 8.5 
32.5 32.5 
8.5 
 0 
48.5 
48.5 
CBV (Total) 
8.5 8.5 57 
65.5 98 
130.5 139 139 187.5 236 
Total (56 Days) 
 
 
 
 
 
 
 
 
 
236 
 
 
GROUP 4 (Control) 
 
Study Day 
0 
3 
7 
14 
17 
28 
42 
Serum (8.5 mL) 1 
1 
1 
1 
1 
1 
1 
PBMC (8.0) 
5 
 
3 
3 
 
5 
5 
Daily BV (mL) 
48.5 8.5 32.5 32.5 8.5 
48.5 48.5 
CBV (Total) 
48.5 57 
89.5 122 
130.5 179 
227.5 
Total (56 Days) 
 
 
 
 
 
 
227.5