A Phase 4 Comparative Trial of Benzathine Penicillin G 2.4 Million Units Administered as a Single Dose Versus Three Successive Weekly Doses for Treatment of Early Syphilis in Subjects With or Without HIV Infection
Phase: PHASE4
Conditions: Syphilis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 17-0101 
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A Phase 4 Comparative Trial of Benzathine Penicillin G 2.4 
Million Units Administered as a Single Dose versus Three 
Successive Weekly Doses for Treatment of Early Syphilis in 
Subjects with or without HIV Infection 
DMID Protocol Number: 17-0101 
 
DMID Funding Mechanism: HHSN272201300012I; HHSN27200014 
Principal Investigator: Edward W. Hook, III, MD 
DMID Clinical Project Manager: Delmyra Turpin, RN, MPH, CCRP 
DMID Medical Monitor: Jorge Mejia-Galvis, MD 
DMID Medical Officer: Lori Newman, MD 
DMID Scientific Lead: Carolyn Deal, PhD 
Version Number: 4.0 
22 June 2020 

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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
International Conference on Harmonisation: Good Clinical Practice (ICH) E6; 62 Federal 
Register 25691 (1997); and future revisions  
• 
National Institutes of Health (NIH) Clinical Terms of Award 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 
 
 
 
 
 

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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:  
 
Edward W. Hook, III, MD 
University of Alabama at Birmingham 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Teresa A. Batteiger, MD 
Indiana University 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Jodie A. Dionne-Odom, MD 
University of Alabama at Birmingham 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Julia C. Dombrowski, MD, MPH 
University of Washington 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Kenneth H. Mayer, MD 
Fenway Health 
 
 
 
 
 
 

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Site Investigator: 
 
Signed:  
Date:  
 
Candice J. McNeil, MD, MPH 
Wake Forest University Health Sciences  
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Arlene C. Seña, MD, MPH 
University of North Carolina at Chapel Hill 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Stephanie N. Taylor, MD 
Louisiana State University Health Sciences Center 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Harold C. Wiesenfeld, MD, CM 
University of Pittsburgh 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Kimberly A. Workowski, MD 
Emory University 
 
 
 
Site Investigator: 
 
Signed:  
Date:  
 
Jonathan M. Zenilman, MD 
Johns Hopkins University 
 
 
 
 

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TABLE OF CONTENTS 
Page 
Statement of Compliance 
2 
Signature Page 
3 
Table of Contents 
5 
List of Abbreviations 
8 
Protocol Summary 
10 
1 
Key Roles 
13 
2 
Background Information and Scientific Rationale 
16 
2.1 
Background Information ........................................................................................ 16 
2.2 
Rationale .............................................................................................................. 17 
2.3 
Potential Risks and Benefits ................................................................................. 17 
2.3.1 
Potential Risks .......................................................................................... 17 
2.3.2 
Known Potential Benefits........................................................................... 18 
3 
Objectives 
19 
3.1 
Study Objectives ................................................................................................... 19 
3.1.1 
Primary Objective ...................................................................................... 19 
3.1.2 
Secondary Objectives ............................................................................... 19 
3.2 
Study Outcome Measures .................................................................................... 19 
3.2.1 
Primary Outcome Measure ........................................................................ 19 
3.2.2 
Secondary Outcome Measures ................................................................. 19 
4 
Study Design 
20 
5 
Study Enrollment and Withdrawal 
22 
5.1 
Subject Inclusion Criteria ...................................................................................... 22 
5.2 
Subject Exclusion Criteria ..................................................................................... 23 
5.3 
Treatment Assignment Procedures ....................................................................... 24 
5.3.1 
Randomization Procedures ....................................................................... 24 
5.3.2 
Masking Procedures .................................................................................. 24 
5.3.3 
Reasons for Withdrawal from Study Participation/Discontinuation of 
Study Treatment ........................................................................................ 24 
5.3.4 
Handling of Withdrawals from Study Participation/Discontinuations of 
Study Treatment ........................................................................................ 25 
5.3.5 
Termination of Study ................................................................................. 26 
6 
Study Intervention/Investigational Product 
27 
6.1 
Study Product Description .................................................................................... 27 
6.1.1 
Acquisition ................................................................................................. 27 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 27 
6.1.3 
Product Storage and Stability .................................................................... 27 
6.2 
Dosage, Preparation, and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 27 
6.3 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 28 

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6.4 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ................................................................................................................. 28 
6.5 
Concomitant Medications/Treatments ................................................................... 29 
7 
Study Schedule 
30 
7.1 
Visit 1 – Screening and Enrollment/Baseline Visit (Day 1) .................................... 30 
7.2 
Follow-up .............................................................................................................. 31 
7.2.1 
Visit 2 – Week 1 (Day 7 to 13) ................................................................... 31 
7.2.2 
Visit 3 – Week 2 (6 to 12 days after Visit 2) ............................................... 32 
7.2.3 
Visit 4 – Month 1 (Day 30 ± 7 days) ........................................................... 33 
7.2.4 
Visit 5 – Month 3 (Day 90 ± 21 days) ......................................................... 33 
7.2.5 
Visit 6 – Month 6 (Day 180 ± 21 days) ....................................................... 34 
7.2.6 
Visit 7 – Month 9 (Day 270 ± 28 days) ....................................................... 35 
7.2.7 
Visit 8 – Month 12 (Day 360 ± 28 days) (Final Study Visit) ........................ 35 
7.3 
Early Termination Visit .......................................................................................... 36 
7.4 
Unscheduled Visit ................................................................................................. 36 
8 
Study Procedures/Evaluations 
38 
8.1 
Clinical Evaluations ............................................................................................... 38 
8.2 
Laboratory Evaluations ......................................................................................... 39 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 39 
8.2.2 
Special Assays or Procedures ................................................................... 39 
8.2.3 
Specimen Preparation, Handling, and Shipping ........................................ 39 
9 
Assessment of Safety 
40 
9.1 
Specification of Safety Parameters ....................................................................... 40 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 40 
9.2.1 
Adverse Events ......................................................................................... 40 
9.2.2 
Reactogenicity ........................................................................................... 41 
9.2.3 
Serious Adverse Events ............................................................................ 41 
9.3 
Reporting Procedures ........................................................................................... 42 
9.3.1 
Serious Adverse Events ............................................................................ 42 
9.3.2 
Regulatory Reporting for Studies Not Conducted Under DMID-
Sponsored IND .......................................................................................... 43 
9.3.3 
Reporting of Pregnancy ............................................................................. 43 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 44 
9.5 
Halting Rules ........................................................................................................ 44 
9.6 
Safety Oversight (ISM plus DSMB) ....................................................................... 45 
10 
Clinical Monitoring 
46 
10.1 
Site Monitoring Plan .............................................................................................. 46 
11 
Statistical Considerations 
47 
11.1 
Study Hypotheses ................................................................................................. 47 
11.2 
Sample Size Considerations ................................................................................. 47 
11.3 
Planned Interim Analyses ..................................................................................... 48 
11.3.1 Safety Review ........................................................................................... 48 

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11.3.2 Immunogenicity or Efficacy Review ........................................................... 48 
11.4 
Final Analysis Plan ............................................................................................... 49 
11.4.1 Analysis Populations ................................................................................. 49 
11.4.2 Baseline Characteristics ............................................................................ 49 
11.4.3 Safety Analysis Plan .................................................................................. 50 
11.4.4 Efficacy Analysis Plan ............................................................................... 50 
12 
Source Documents and Access to Source Data/Documents 
53 
13 
Quality Control and Quality Assurance 
54 
14 
Ethics/Protection of Human Subjects 
55 
14.1 
Ethical Standard ................................................................................................... 55 
14.2 
Institutional Review Board .................................................................................... 55 
14.3 
Informed Consent Process ................................................................................... 55 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 56 
14.5 
Subject Confidentiality .......................................................................................... 56 
14.6 
Study Discontinuation ........................................................................................... 57 
14.7 
Future Use of Stored Specimens .......................................................................... 58 
15 
Data Handling and Record Keeping 
59 
15.1 
Data Management Responsibilities ....................................................................... 59 
15.2 
Data Capture Methods .......................................................................................... 59 
15.3 
Types of Data ....................................................................................................... 60 
15.4 
Timing/Reports ..................................................................................................... 60 
15.5 
Study Records Retention ...................................................................................... 60 
15.6 
Protocol Deviations ............................................................................................... 60 
16 
Publication Policy 
62 
17 
Literature References 
63 
Appendix A: Schedule of Events 
64 
Appendix B: Table for Grading the Severity of Adverse Events 
66 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
BPG 
Benzathine Penicillin G 
CFR 
Code of Federal Regulations 
CMS 
Clinical Material Services 
CoC 
Certificate of Confidentiality 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
DFA-TP 
Direct Fluorescence Antibody-Treponema pallidum 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICON 
ICON Clinical Research, Inc. 
IDES 
Internet Data Entry System 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intent-to-Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSM 
Men who have Sex with Men 
MU 
Million Units 
N 
Number (typically refers to subjects) 
NAT 
Nucleic Acid Test 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OER 
Office of Extramural Research, NIH, DHHS 
OHRP 
Office for Human Research Protections 
P&S 
Primary and Secondary 
PASS 
Power Analysis and Sample Size Software 
PCR 
Polymerase Chain Reaction 

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PI 
Principal Investigator 
RCT 
Randomized Controlled Trial 
RPR 
Rapid Plasma Reagin 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAS 
Statistical Analysis System 
SDCC 
Statistical and Data Coordinating Center 
SOP 
Standard Operating Procedure 
STI 
Sexually Transmitted Infection 
STI CTG 
Sexually Transmitted Infections Clinical Trials Group 
STS 
Serological Test for Syphilis 
TRI 
Technical Resources International, Inc. 
US 
United States 
 
 
 

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PROTOCOL SUMMARY 
Title: 
A Phase 4 Comparative Trial of Benzathine Penicillin G 2.4 
Million Units Administered as a Single Dose versus Three 
Successive Weekly Doses for Treatment of Early Syphilis in 
Subjects with or without HIV Infection 
Phase: 
4 
Population: 
Approximately 560 adults aged 18 years or older with 
untreated early (primary, secondary, or early latent) syphilis (to 
achieve 420 evaluable subjects) 
Number of Sites: 
Ten 
Study Duration: 
48 months 
Subject Participation 
Duration: 
12 months 
Description of Agent or 
Intervention: 
Benzathine penicillin G (BPG) 2.4 million units (MU) injected 
once (Arm 1) or weekly for three successive weeks (Arm 2) 
Objectives:  
 
Primary: 
• 
To compare the serological response to therapy in 
subjects with early (primary, secondary, or early latent) 
syphilis treated with BPG 2.4 MU once or weekly for 
three successive weeks 
Secondary: 
• 
To determine if the difference in response to therapy 
between treatment arms by Month 6 differs among 
subjects with or without HIV infection  
• 
To determine the impact of multiple BPG injected 
doses on subject compliance with study product and 
adherence to the corresponding scheduled visits  
• 
To determine the incidence and manifestations of the 
Jarisch-Herxheimer reaction among subjects treated 
for early syphilis with BPG 
• 
To collect prospective data up to Month 12 on the 
serological response to therapy in subjects treated for 
early syphilis with either BPG regimen  
• 
To compare epidemiological characteristics of early 
syphilis among subjects with or without HIV infection 

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Description of Study 
Design: 
BPG 2.4 MU injected either once (Arm 1) or weekly for three 
successive weeks (Arm 2) as determined by randomization, 
with follow-up visits at Months 1, 3, 6, 9, and 12 for safety, 
clinical, and laboratory assessments 
Estimated Time to 
Complete Enrollment: 
36 months 

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Schematic of Study Design 
 
Total N: Approximately 560 to achieve 420 evaluable 
Study Visit 1 
Screening/ 
Enrollment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Visit 2 
Week 1 
 
Study Visit 3 
Week 2 
 
Study Visit 4 
Month 1 
 
Study Visit 5 
Month 3 
 
Study Visit 6 
Month 6 
 
 
Study Visit 7 
Month 9 
 
 
Study Visit 8 
Month 12 
 
 
Prior to enrollment: obtain informed consent; perform screening; collect history; perform 
physical examination and pregnancy test; collect blood for assays (syphilis and HIV); obtain 
CD4 counts on persons with known HIV infection if needed; collect specimens for 
screening/diagnosis of chlamydia, gonorrhea, and other STIs as indicated per Section 7 
Randomize (1:1) 
Administer BPG (both Arms) 
Approximately 24 hours after Visit 1: contact subject to assess Jarisch-Herxheimer reaction 
Administer 2nd BPG injected dose for Arm 2; collect interval history, perform targeted 
physical examination, pregnancy test, and AE evaluation; collect specimens for assays; 
assess Jarisch-Herxheimer reaction if subject was not reached after Visit 1 
Administer 3rd BPG injected dose for Arm 2; collect interval history, perform targeted 
physical examination, pregnancy test, and AE evaluation; collect specimens for assays 
Assessment of Final Study Outcome 
Measures 
Collect interval history, perform targeted physical examination, pregnancy test, and AE 
evaluation; collect specimens for assays including CD4 counts on HIV-infected subjects if 
needed 
Perform HIV testing if subject previously noted to be HIV-uninfected; collect interval history, 
perform targeted physical examination and pregnancy test; collect specimens for assays 
Perform HIV testing if subject previously noted to be HIV-uninfected; collect interval history, 
perform targeted physical examination and pregnancy test; collect specimens for assays 
including CD4 counts on HIV-infected subjects if needed 
Perform HIV testing if subject previously noted to be HIV-uninfected; collect interval history, 
perform targeted physical examination and pregnancy test; collect specimens for assays  
~280 subjects Arm 1 
(to achieve 210 evaluable: 
~140 HIV+/~70 HIV-) 
~280 subjects Arm 2 
(to achieve 210 evaluable: 
~140 HIV+/~70 HIV-) 

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1 
KEY ROLES 
Individuals: 
 
 
Principal Investigator:   
Edward W. Hook, III, MD 
The University of Alabama at Birmingham 
 
Site Investigator: 
Teresa A. Batteiger, MD 
Indiana University  
 
Site Investigator: 
Jodie A. Dionne-Odom, MD  
University of Alabama at Birmingham  
 
Site Investigator: 
Julia C. Dombrowski, MD, MPH 
University of Washington  
 
Site Investigator: 
Kenneth H. Mayer, MD 
Fenway Health  
 
Site Investigator: 
Candice J. McNeil, MD, MPH 
Wake Forest University Health Sciences  
 
Site Investigator: 
Arlene C. Seña, MD, MPH 
University of North Carolina at Chapel Hill  
 
Site Investigator: 
Stephanie N. Taylor, MD 
Louisiana State University Health Sciences Center 
 
Site Investigator: 
Harold C. Wiesenfeld, MD 
University of Pittsburgh, Magee-Women’s Hospital 
 
Site Investigator: 
Kimberly A. Workowski, MD 
Emory University  

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
 
Despite syphilis being a major public health problem for well over a century, and its treatment 
recommendations being unchanged for nearly 50 years, questions about syphilis and its 
management are amongst the most common questions to arise regarding sexually transmitted 
infections (STIs). The human immunodeficiency virus (HIV) epidemic has compounded these 
problems, as syphilis is now appreciated as both a risk marker and risk factor for HIV 
acquisition, and case reports and uncontrolled case series have led to recurring, unresolved 
questions regarding the optimal management of syphilis with respect to treatment regimens, 
serological follow-up, and risks for treatment failure [1]. Syphilis in the US is resurging, with 
rates of primary and secondary (P&S) syphilis increasing by 74% from 2012 to 2016 and 
disproportionately among HIV-infected persons [2].  Further rising P&S rates in women led to a 
28% increase in congenital syphilis cases in the US between 2015 and 2016 [3]. No large 
prospective studies in the US have provided data on outcomes of recommended single-dose 
penicillin therapy versus widely-used but unstudied multiple-dose therapy for persons with early 
syphilis and HIV co-infection for over 30 years. In addition, there are no contemporary data 
describing serological responses to syphilis therapy at >6 months following therapy, raising 
questions as to how to best follow the ~20% of “serofast” patients who fail to serologically 
respond at >6 months following therapy. These questions represent a pressing public health 
need that is best addressed through a multicenter, randomized clinical trial (RCT). 
 
Infections due to Treponema pallidum are the third most commonly reported infection in the US 
and are a global public health priority. Currently, P&S syphilis rates in the US are increasing 
faster than for any other reportable STI, and over half of P&S syphilis cases in men who have 
sex with men (MSM), the group that accounts for most new cases, are occurring among 
persons with HIV co-infection [3]. Untreated syphilis is a significant cause of morbidity in 
children born to mothers with untreated infection, may cause serious neurological or 
cardiovascular disease, and is both a proven risk factor and risk marker for HIV acquisition. 
Syphilis also remains a glaring example of STI health disparities, with P&S syphilis rates among 
African Americans in the US being more than six times those of non-Hispanic whites [4]. 
 
Penicillin is currently the only recommended treatment for syphilis (alternative therapies may be 
used in persons with penicillin allergy [5]). However, recent studies have shown that ~20% of 
persons treated for early syphilis with recommended, single-dose BPG 2.4 MU are “serofast” 
(do not show the desired 4-fold decline in serological test for syphilis titers 6 months following 
therapy) [5, 6], and concerns have been raised as to whether this regimen adequately treats 
early syphilis in HIV-infected persons. A well-conducted, multicenter RCT in the 1990s showed 
that higher doses of penicillin given in combination with the recommended BPG regimen did not 

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significantly change the serological response to therapy at 3, 6, or 12 months [7], but there are 
no RCTs evaluating whether a longer duration of BPG therapy improves the serological 
response to therapy among persons with or without HIV infection. While this earlier study 
addressed questions regarding daily penicillin doses for early syphilis treatment, the question of 
duration remains unresolved. As a result, there is substantial variation in the treatment of early 
syphilis, with many providers using multiple injected doses of BPG or treating serofast persons 
who have no evidence of active infection. 
2.2 
Rationale 
 
Epidemiologically, syphilis infections tend to shift from one risk group to another. Past syphilis 
epidemics in the US have occurred in heterosexual men and women, or MSM. More recently, 
syphilis rates in the US have more than doubled over the past decade and now occur 
disproportionately among HIV-infected persons [4]. 
 
While penicillin is generally regarded as highly effective for syphilis treatment, whether or not 
currently recommended therapy is equally effective for persons with or without HIV infection 
remains unclear. In addition, recent appreciation of the fact that ~20% of persons treated for 
early syphilis are serofast has raised concerns regarding the significance of this observation [6]. 
Some clinicians believe that the serofast state signifies treatment failure, while others believe it 
represents failure to serologically respond to therapy in successfully treated patients. Each of 
these concerns may lead to inadequate therapy or over treatment in persons with early syphilis, 
as well as much confusion among clinicians about appropriate therapy. 
 
The primary aims of this study are to determine whether subjects with or without HIV infection 
benefit from a longer duration of therapy (BPG 2.4 MU weekly for three successive weeks 
instead of as a single dose), and whether subjects with or without HIV infection differ in their 
response to BPG therapy for early syphilis. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
 
The risks associated with participation in the study are small. Penicillin is widely used to treat 
syphilis and other infections and is relatively well tolerated. All subjects in the trial will receive at 
least the currently recommended therapy. The most common adverse events (AEs) caused by 
penicillin include rash and hypersensitivity reactions. Therapeutic outcome is not a major 
concern, as all subjects will receive at least the Centers for Disease Control and Prevention-
recommended dose of BPG for early syphilis. Subjects randomized to receive two additional 
injected doses of BPG will be at risk for additional discomfort and bruising at injection sites. 
Subjects may feel temporary pain or discomfort during blood draws, and there is a small risk of 

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infection at the site of the blood draw. 
Information concerning subjects’ sexual history is necessarily detailed given the study’s 
objectives and may provoke some minor psychological or emotional stress when requested; 
subjects who receive a new diagnosis of an STI during the study may also experience minor 
psychological or emotional stress. Female subjects will be cautioned about the potential hazard 
of becoming pregnant and advised to use adequate birth control methods for the entire duration 
of their participation in the trial. 
2.3.2 Known Potential Benefits 
Subjects may benefit from this study by finding out more about the specific cause of symptoms 
they may be experiencing. Subjects may benefit from pre- and post-test counseling, treatment, 
and referrals, as necessary. It has previously been observed that subjects are empowered by 
knowing, for example, more about what syphilis is and how it can be prevented. 
 

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3 
OBJECTIVES 
3.1 
Study Objectives 
3.1.1 Primary Objective 
• 
To compare the serological response to therapy in subjects with early (primary, 
secondary, or early latent) syphilis treated with BPG 2.4 MU once or weekly for three 
successive weeks 
3.1.2 Secondary Objectives 
• 
To determine if the difference in response to therapy between treatment arms by Month 
6 differs among subjects with or without HIV infection 
• 
To determine the impact of multiple BPG injected doses on subject compliance with 
study product and adherence to the corresponding scheduled visits  
• 
To determine the incidence and manifestations of the Jarisch-Herxheimer reaction 
among subjects treated for early syphilis with BPG 
• 
To collect prospective data up to Month 12 on the serological response to therapy in 
subjects treated for early syphilis with either BPG regimen  
• 
To compare epidemiological characteristics of early syphilis among subjects with or 
without HIV infection 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measure 
• 
The proportion of subjects in each treatment group with a 4-fold decline in rapid plasma 
reagin (RPR) titers or seroreversion, simultaneously measured in sera collected 
throughout study participation at a single reference laboratory, by Month 6 
3.2.2 Secondary Outcome Measures 
• 
The proportion of subjects in each treatment group with a 4-fold decline in RPR titers or 
seroreversion by Month 6 among subjects with or without HIV infection 
• 
The proportion of subjects in each treatment group with a 4-fold decline in RPR titers or 
seroreversion by Month 12 
• 
The proportion of subjects in each treatment group with a 4-fold decline in RPR titers or 
seroreversion by Month 12 among subjects with or without HIV infection 
• 
The proportion of subjects (overall and in each treatment group) who receive all 
assigned doses within the assigned visit windows 
• 
The proportion of subjects in each treatment group who report Jarisch-Herxheimer 
reaction manifestations (fever, intensification of rash, myalgia, and other systemic 
symptoms) occurring within approximately 24 hours of initial BPG administration 
• 
Demographics, sexual history, and socio-epidemiologic characteristics at baseline and 
sexual history through Months 6 and 12 among subjects with or without HIV infection 
and overall  

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4 
STUDY DESIGN 
This is a Phase 4, open-label, multicenter trial to evaluate the efficacy of a single injected 
dose of BPG 2.4 MU (Arm 1) compared to three successive weekly injected doses of BPG 
2.4 MU (Arm 2) for treatment of early syphilis in HIV-infected and HIV-uninfected subjects. 
Subjects will be aged 18 years or older with untreated early syphilis (primary, secondary, or 
early latent as defined in prior syphilis treatment trials of the Sexually Transmitted Infections 
Clinical Trials Group (STI CTG)). The study will be conducted at 10 sites in the US and will 
enroll approximately 560 subjects to achieve 420 evaluable. 
 
The study will involve a screening/enrollment visit and seven scheduled follow-up visits 
(Weeks 1 and 2, and Months 1, 3, 6, 9, and 12) over a 12-month period. At the enrollment 
visit, after providing informed consent, all subjects will undergo a brief sexual and medical 
history and a directed physical examination; all women of childbearing potential will have a 
urine or serum pregnancy test performed as part of qualification for study participation; all 
subjects will undergo phlebotomy for serological testing for syphilis and HIV according to 
the study and clinic protocols. All subjects who have not been tested for chlamydia and 
gonorrhea since last sexual activity and all subjects who have been sexually active in the 
past 14 days will have specimens collected for chlamydia and gonorrhea testing. Subjects 
will have specimens collected for other STI testing as indicated by local standard of care 
and subject history. All eligible subjects will be randomized to Arm 1 or Arm 2 and will 
receive an injected dose of BPG 2.4 MU. 
 
Study personnel will attempt to contact subjects approximately 24 hours after Visit 1 to 
assess for symptoms of a Jarisch-Herxheimer reaction as described in Section 8.1. At the 
second and third visits (Weeks 1 and 2 of follow-up), subjects randomized to Arm 2 will 
receive injected doses of BPG 2.4 MU.    
 
At all follow-up visits, subjects will have an interval history obtained, undergo a directed 
physical examination, and have repeat specimens collected for STI testing (based on the 
subject history and clinic protocols). At all follow-up visits, subjects will undergo phlebotomy 
for serological testing for syphilis and serum storage. At the Month 3, Month 6, Month 9, 
and Month 12 follow-up visits, consenting HIV-uninfected subjects will be tested for HIV 
infection using a 4th generation serological test for HIV. At Visit 1, study staff will swab 
consenting subjects’ oral cavities and primary or secondary lesions (if lesions are present 
per Section 5.1); see Section 8.2.2. 
 
Safety will be measured by subject report and physical examination (including vital signs: 
temperature, heart rate, respiration rate, and blood pressure; and genital, rectal, oral, skin, 
and lymph node examinations). All AEs (including solicited reactogenicity AEs and other 
unsolicited AEs) will be recorded through Month 1. Safety oversight will be provided by a 

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Data and Safety Monitoring Board (DSMB) and site Independent Safety Monitors (ISMs) as 
described in Section 9.6. 
 
While sites will perform their own serological testing as needed for subject management, 
serological testing to determine study outcomes and serum banking will be performed at the 
Central Laboratory (University of Alabama at Birmingham). 
 
The duration of the study for each subject will be 12 months. Enrollment is expected to be 
completed in 36 months. For additional details on study procedures/evaluations and study 
schedule by study visits, see Sections 7 and 8 and Appendix A. 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
To achieve 420 evaluable subjects, approximately 560 adults aged 18 years or older who meet 
all inclusion criteria and no exclusion criteria will be enrolled. No exemptions are granted on 
inclusion/exclusion criteria in trials sponsored by the Division of Microbiology and Infectious 
Diseases (DMID). Subjects may be recruited from STI clinics, HIV clinics, student health 
centers, and the public via advertising (e.g., flyers, radio, newspaper, social media). To enhance 
recruitment and retention, sites may seek institutional review board (IRB) permission to contact 
subjects by phone, text messaging, and/or email as appropriate. Any communication with 
subjects must be made using devices, methods, and services allowed by the local IRB and must 
be documented appropriately. As noted in Section 7.1, each subject may indicate his/her 
preferred method of contact to the study staff. 
5.1 
Subject Inclusion Criteria 
Subjects eligible to enroll in this study must meet all inclusion criteria: 
 
1. Subject is aged 18 years or older. 
2. Subject has provided informed consent. 
3. Subject has untreated primary*, secondary**, or early latent*** syphilis. 
*Primary syphilis is characterized by the presence of an ulcerative lesion at a 
potential site of inoculation (while classically solitary, shallow, painless and with an 
indurated, clean base, primary lesions may be multiple, may vary considerably in 
appearance, and/or may not be painless) or by darkfield, acceptable polymerase 
chain reaction (PCR), or direct fluorescence antibody-T. pallidum (DFA-TP) positive 
ulcers. 
**Secondary syphilis is characterized by classical palmar/plantar rash, condylomata 
lata, mucous patches, etc. or by darkfield, acceptable PCR, or DFA-TP positive 
lesions. 
***Early latent syphilis is characterized by current reactive serologic tests for syphilis 
(STS) and a documented non-reactive STS, or documented sexual exposure to an 
individual known to have primary, secondary, or early latent syphilis diagnosed within 
the last 12 months. 
4. Subject either has a newly reactive non-treponemal test (such as an RPR test) or a 
history of syphilis and a current increase in RPR titer of two or more dilutions (i.e., four-
fold).   
5. If subject is of childbearing potential, subject has a negative urine or serum pregnancy 
test. 
6. Subject is willing to have an HIV test, participate in HIV counseling, and return to clinic 
for follow-up.  
7. In the opinion of the investigator, subject is able and willing to comply with study 
procedures, including receipt of three BPG injected doses if randomized to Arm 2. 

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8. If female, subject must be of non-childbearing potential* or must be using an acceptable 
method of birth control** to avoid becoming pregnant. 
*Non-childbearing potential is defined as being post-menopausal for at least 1 year, 
status after bilateral tubal ligation, or status after bilateral oophorectomy, or status 
after hysterectomy. 
**Subject must agree to avoid becoming pregnant by using one of the following 
acceptable methods of birth control for the entire duration of participation in the trial: 
• 
Intrauterine contraceptive device; OR 
• 
Oral contraceptives; OR 
• 
Hormonal injections; OR 
• 
Hormonal implants; OR 
• 
Contraceptive patches; OR 
• 
Monogamous relationship with vasectomized partner; OR 
• 
Exclusively same-sex relationships; OR 
• 
Use of condoms by the male partner; OR 
• 
Abstinence 
5.2 
Subject Exclusion Criteria 
Subjects eligible to enroll in this study must not meet any exclusion criteria: 
 
1. Subject previously enrolled in this trial. 
2. Subject has latent syphilis of unknown duration, late latent syphilis, or evidence of 
neurosyphilis, including ocular syphilis.* 
*e.g., eye pain/redness, recent ocular change, and/or changes in visual acuity 
3. Subject has a known or suspected allergy or hypersensitivity to penicillin or other beta-
lactam antibiotics. 
4. Subject has a known or suspected STI other than syphilis requiring treatment with a drug 
active against T. pallidum. 
5. Subject has used antibiotics* active against T. pallidum in the preceding 30 days.  
*Note: the use of antimicrobials known to NOT be effective against T. pallidum (e.g., 
quinolones, sulfonamides, trimethoprim, metronidazole, spectinomycin) will be 
allowed. 
6. Subject has suspected or known ongoing drug use that might interfere with study 
participation and follow-up treatment. 
7. Subject is breastfeeding. 
8. Subject has used an investigational drug in the past 30 days that might interfere with 
safety or efficacy assessment.* 
*If the subject has used any investigational drugs in the past 30 days, contact the 
Principal Investigator, DMID Clinical Project Manager, DMID Medical Officer, and 
FHI 360 to confirm eligibility. 
9. Subject has any other condition that, in the opinion of the investigator, would interfere 
with participation in the study. 

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5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
Enrollment of subjects will be done online using the enrollment module of Emmes Advantage 
eClinical®. Subjects will be randomized at a 1:1 ratio to receive one of the two BPG treatments 
after informed consent is obtained and their eligibility is confirmed. 
The study will use a stratified, permuted block-randomization scheme. Permuted block 
randomization is used to avoid the potential for serious imbalance in the number of subjects 
assigned to each group, an imbalance that can occur in the simple randomization procedures. 
Stratification will be by study site. While HIV status may not be known at the time of 
randomization, subjects will be classified as HIV-infected or HIV-uninfected to assess the 
secondary HIV status subgroup objective, and randomization will be limited as follows: 
• 
If 280 subjects who were HIV-infected at baseline are confirmed evaluable, additional 
subjects who are known to be HIV-infected will not be allowed to enroll thereafter, while 
HIV-uninfected subjects and subjects of unknown HIV status may continue to enroll. 
• 
If 140 subjects who were HIV-uninfected at baseline are confirmed evaluable, only 
subjects who are known to be HIV-infected will be allowed to enroll thereafter. 
The list of randomized treatment assignments will be prepared by statisticians at Emmes 
and included in the enrollment module of its Internet Data Entry System (IDES). IDES will 
assign each subject a treatment code from the list after demographic and eligibility data have 
been entered.  
Instructions for use of the enrollment module are included in the IDES User’s Guide. Manual 
back-up randomization procedures are provided in the Manual of Procedures (MOP) for use in 
case a site temporarily loses access to the Internet or the online enrollment system is 
unavailable. 
5.3.2 Masking Procedures 
Neither subjects nor providers will be masked in this study. The outcome (serological response 
to therapy) is objective—furthermore, laboratory staff will be blinded to subject ID and treatment 
assignment—and it would not be ethical to give subjects placebo injections. 
5.3.3 Reasons for Withdrawal from Study Participation/Discontinuation of Study 
Treatment 
Subjects may voluntarily withdraw their consent for further study participation or may request to 
discontinue study treatment at any time and for any reason without penalty or prejudice to future 

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medical care.  
In addition to voluntarily requesting to discontinue study treatment as noted above, subjects 
randomized to Arm 2 may also be discontinued from additional treatment after discussion with 
the investigator for the following reasons:  
• 
AE(s) judged to be Grade 3 and related to study drug 
• 
SAE(s) judged to be related to study drug  
• 
Investigator’s discretion 
• 
Violation of eligibility criteria 
• 
Significant deviation from the treatment plan specified in the protocol (e.g., incorrect 
administration of BPG, failure to attend study visits) 
• 
Receipt of antibiotic therapy active against T. pallidum for treatment of syphilis infection 
Subjects in either arm who require off-study retreatment for syphilis infection will be withdrawn 
from the study after completing an Early Termination Visit. 
5.3.4 Handling of Withdrawals from Study Participation/Discontinuations of 
Study Treatment 
Subjects who withdraw from study participation, or are excluded from any efficacy endpoint 
analysis, or are lost to follow-up after signing the informed consent form (ICF), randomization, 
and receipt of the first dose of BPG will not be replaced. Subjects who withdraw consent after 
signing the ICF and randomization but before receipt of the first dose of BPG may be replaced. 
If the subject requests to discontinue study treatment at any time after the first dose of BPG, the 
subject will be asked to continue scheduled study procedures including safety and efficacy 
evaluations, if possible, and be given appropriate care under medical supervision if symptoms of 
any AE related to participation in the study are continuing. The subject will be followed until the 
AE is resolved or until the subject’s condition becomes stable. 
Subjects who request to discontinue study treatment at any time after the first dose of BPG will 
be reminded of the importance of continuing in the study for safety evaluations. Subjects will be 
encouraged to complete the Early Termination Visit if they choose not to complete the 
remaining study visits (i.e., if they withdraw from study participation). The Early Termination Visit 
procedures are listed in Section 7.3. Subjects who choose to withdraw from study participation 
will no longer be contacted for follow-up. 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort 
(e.g., three documented contact attempts via phone calls, e-mails, etc., made on separate 
occasions and followed by a certified letter) will be made to locate or recall them, or at least to 
determine their health status. Subjects who cannot be located after extensive effort will no 
longer be contacted for follow-up. These efforts will be documented in the subject’s records.  
If a subject is withdrawn from the study due to an AE that prohibits continued participation in the 
study, s/he will be given appropriate care and treatment under medical supervision until the 
condition has resolved or becomes stable. 

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Safety and efficacy data will be collected on any subject who is excluded from any efficacy 
endpoint analysis. Refer to Section 11 for details on how subjects who are withdrawn will be 
handled during analysis. 
5.3.5 Termination of Study  
Although the study sponsor has every intention of completing the study, the sponsor reserves 
the right to terminate the study at any time for clinical or administrative reasons. Reasons for 
termination include, but are not limited to, study closure due to DSMB review and 
recommendation or at the discretion of DMID. 

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preferred healthcare practitioner to be delegated to perform this activity. If a Research 
Pharmacist is not available, a physician, nurse practitioner, physician assistant, registered 
nurse, or other authorized healthcare practitioner who is a member of the clinical study staff 
may be delegated to dispense BPG. These personnel must be licensed, trained, and qualified to 
prepare an investigational study product and must be authorized to dispense it under state and 
local rules and regulations. 
BPG will be administered as a deep IM injection in the upper, outer quadrant of the buttock. 
Subjects will be randomized to one of two treatment assignments: 
• 
Arm 1: BPG 2.4 MU injected once as two 2-mL injections (one in each buttock) 
• 
Arm 2: BPG 2.4 MU injected weekly as two 2-mL injections (one in each buttock) for 
three successive weeks 
6.3 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
After receiving the BPG, the site principal investigator (PI) is responsible for its distribution and 
disposition and has ultimate responsibility for its accountability. The site PI may delegate to a 
site Research Pharmacist or an appropriately qualified staff member the responsibility for BPG 
accountability. The designee will be responsible for maintaining complete records and 
documentation of BPG receipt, accountability, dispensation, temperature and storage 
conditions, and final disposition. All BPG, whether administered or not, must be documented on 
the appropriate study drug accountability record or dispensing log. The sponsor's monitoring 
staff will verify the participating clinical sites’ study drug accountability records and dispensing 
logs per the study monitoring plan. 
Upon completion or termination of the study and after the final monitoring visit, final disposition 
of the unused BPG will be determined by DMID and communicated to the sites by the DMID 
Clinical Project Manager. 
6.4 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
All BPG injections will be directly observed by the administering clinician. Compliance with study 
product for all subjects will be defined as whether subjects receive all assigned doses within the 
assigned visit windows. 

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6.5 
Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
data collection form. Concomitant medications will include all medications taken 30 days before 
initiating study treatment through Month 12 or early termination, whichever occurs first. 
Prescription and over-the-counter drugs will be included, as well as herbs, vitamins, and 
supplements. Previously recorded medications will be updated as appropriate. 
Subjects who have received BPG and are subsequently diagnosed with a concomitant infection 
that requires systemic antibiotics will receive treatment according to the local clinic’s standard 
protocols. Likewise, subjects who have received BPG through the study and subsequently 
require retreatment for syphilis infection will receive treatment according to the local clinic’s 
standard protocols and will be withdrawn from the study per protocol Section 5.3.3. 
At the discretion of the site PI, use of new medication should prompt evaluation for the presence 
of a new diagnosis of chronic medical disease or condition. 
Medications that might interfere with the evaluation of BPG should not be used unless 
absolutely necessary.  
Refer to Section 5 (Subject Inclusion and Exclusion Criteria) for medications that are prohibited 
for study eligibility and throughout study participation. 

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7 
STUDY SCHEDULE 
Study visit information is listed in this section, Section 8, and the Schedule of Events (Appendix 
A). Further instructions are described in the protocol-specific MOP. 
7.1 
Visit 1 – Screening and Enrollment/Baseline Visit (Day 1) 
• 
The potential subject will be provided with a description of the study (purpose and study 
procedures) and asked to read the ICF or have it read to him/her. The ICF must be 
signed before any screening or study procedures are performed. 
• 
Demographic information will be collected from the subject. 
• 
Eligibility criteria will be reviewed with the subject. 
o Complete medical history will be obtained by interviewing subjects (and 
reviewing medical records for the past 14 days, if available) to assure eligibility. If 
available in the medical record, the most recent viral load result from the past six 
months prior to enrollment should be recorded. 
o Sexual history for the past 60 days will be collected. 
o A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood 
pressure; and genital, rectal, oral, skin, and lymph node examinations). 
o Study staff will swab consenting subjects’ oral cavities and primary or secondary 
lesions (if lesions are present per Section 5.1); see Section 8.2.2. 
o A urine or serum pregnancy test will be performed on all subjects of childbearing 
potential and must be negative prior to randomization. 
o All concomitant medications taken in the last 30 days prior to initiating BPG 
treatment will be recorded on the appropriate data collection form. 
o Blood will be collected for RPR test, storage, and HIV assays (including a CD4 
count for persons with known HIV infection whose medical records do not include 
a CD4 count in the past 30 days, and an HIV test for persons who do not have a 
previously documented positive HIV test result). Specimens will be collected at 
sites of exposure for screening/diagnosis of gonorrhea and chlamydia for all 
subjects who have not been tested since last sexual activity and for all subjects 
who have been sexually active in the past 14 days and for other STIs as 
indicated by local standard of care and subject history. Clinicians will provide pre- 
and post-test counseling, treatment, and referrals per local standard of care. 
At this juncture, if a potential subject is not eligible, the reason for screening failure will be 
recorded and the subject will not be enrolled. 

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• 
Subject will be enrolled in Advantage eClinical® and randomly assigned to Arm 1 or Arm 
2. 
• 
BPG will be administered, and the subject will be observed per clinic standard operating 
procedure (SOP). 
• 
Study personnel will discuss with subjects and assess and record all AEs/SAEs 
(including solicited reactogenicity AEs and other unsolicited AEs).  
• 
Protocol requirements will be reviewed with the subject. 
• 
Contact information will be collected, the subject’s preferred method of contact will be 
noted, and the Week 1 visit will be scheduled. 
• 
The Jarisch-Herxheimer checklist will be distributed and the instructions reviewed with 
the subject. The subject will be asked to have the completed checklist available for 
reference during the non-visit contact approximately 24-48 hours after Visit 1 and to 
bring it to Visit 2. Study personnel will instruct the subject to use a thermometer to take 
temperature reading(s) at home, if possible, and note the highest temperature if s/he 
feels feverish any time before being contacted to assess for symptoms of a Jarisch-
Herxheimer reaction as described in Section 8.1. Study personnel will attempt to contact 
subjects by phone call, text message, or email approximately 24 hours after Visit 1 to 
make this assessment. Note that data will be recorded on the appropriate electronic 
case report forms (eCRFs) based on subject interview; the Jarisch-Herxheimer checklist 
completed by the subject will not be retained. 
7.2 
Follow-up 
7.2.1 Visit 2 – Week 1 (Day 7 to 13) 
• 
Subject will be evaluated for resolution of any clinical signs of infection and will be asked 
specific questions on medication tolerance. If the subject was not contacted following 
Visit 1, s/he will be evaluated for symptoms of a Jarisch-Herxheimer reaction at Visit 2 
as described in Section 8.1. 
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If available in the medical 
record, the most recent viral load result since enrollment should be recorded. If the local 
laboratory results indicate a need for retreatment for syphilis infection, the subject will 
receive treatment according to the local clinic’s standard protocols and will be withdrawn 
from the study per protocol Section 5.3.3. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 
collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 

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• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
Blood will be collected for follow-up RPR tests and storage. 
• 
Arm 2 only: second dose of BPG will be administered, and the subject will be observed 
per clinic SOP. 
• 
Study personnel will discuss with subjects and assess and record all AEs/SAEs 
(including solicited reactogenicity AEs and other unsolicited AEs).  
• 
Contact information will be reviewed, and the Week 2 visit will be scheduled. 
7.2.2 Visit 3 – Week 2 (6 to 12 days after Visit 2) 
• 
Subject will be evaluated for resolution of any clinical signs of infection. 
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If available in the medical 
record, the most recent viral load result since enrollment should be recorded. If the local 
laboratory results indicate a need for retreatment for syphilis infection, the subject will 
receive treatment according to the local clinic’s standard protocols and will be withdrawn 
from the study per protocol Section 5.3.3. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 
collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 
• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
Blood will be collected for follow-up RPR tests and storage. 

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• 
Arm 2 only: third dose of BPG will be administered, and the subject will be observed per 
clinic SOP. 
• 
Study personnel will discuss with subjects and assess and record all AEs/SAEs 
(including solicited reactogenicity AEs and other unsolicited AEs).  
• 
Contact information will be reviewed, and the Month 1 visit will be scheduled. 
7.2.3 Visit 4 – Month 1 (Day 30 ± 7 days) 
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If available in the medical 
record, the most recent viral load result since enrollment should be recorded. If the local 
laboratory results indicate a need for retreatment for syphilis infection, the subject will 
receive treatment according to the local clinic’s standard protocols and will be withdrawn 
from the study per protocol Section 5.3.3. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 
collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 
• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
Study personnel will discuss with subjects and assess and record all AEs/SAEs 
(including solicited reactogenicity AEs and other unsolicited AEs).  
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
Blood will be collected for follow-up RPR tests, storage, and CD4 counts on persons 
newly found to have HIV infection from Visit 1 to Visit 4 (inclusive) whose medical 
records do not include a CD4 count in the past 30 days. Clinicians will provide pre- and 
post-test counseling, treatment, and referrals per local standard of care. 
• 
Contact information will be reviewed, and the Month 3 visit will be scheduled. 
7.2.4 Visit 5 – Month 3 (Day 90 ± 21 days)  
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If the local laboratory results 
indicate a need for retreatment for syphilis infection, the subject will receive treatment 

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according to the local clinic’s standard protocols and will be withdrawn from the study 
per protocol Section 5.3.3. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 
collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 
• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
HIV testing will be performed if the subject was previously noted to be HIV-uninfected. 
Clinicians will provide pre- and post-test counseling, treatment, and referrals per local 
standard of care. 
• 
Blood will be collected for follow-up RPR tests and storage. 
• 
Contact information will be reviewed, and the Month 6 visit will be scheduled. 
7.2.5 Visit 6 – Month 6 (Day 180 ± 21 days) 
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If the local laboratory results 
indicate a need for retreatment for syphilis infection, the subject will receive treatment 
according to the local clinic’s standard protocols and will be withdrawn from the study 
per protocol Section 5.3.3. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 
collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 
• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
HIV testing will be performed if the subject was previously noted to be HIV-uninfected. 

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Clinicians will provide pre- and post-test counseling, treatment, and referrals per local 
standard of care. 
• 
Blood will be collected for follow-up RPR tests, storage, and CD4 counts on persons 
found to have HIV infection whose medical records do not include a CD4 count in the 
past 30 days. 
• 
Contact information will be reviewed, and the Month 9 visit will be scheduled. 
7.2.6 Visit 7 – Month 9 (Day 270 ± 28 days) 
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If the local laboratory results 
indicate a need for retreatment for syphilis infection, the subject will receive treatment 
according to the local clinic’s standard protocols and will be withdrawn from the study 
per protocol Section 5.3.3. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 
collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 
• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
HIV testing will be performed if the subject was previously noted to be HIV-uninfected. 
Clinicians will provide pre- and post-test counseling, treatment, and referrals per local 
standard of care. 
• 
 Blood will be collected for follow-up RPR tests and storage. 
• 
Contact information will be reviewed, and the Month 12 visit will be scheduled. 
7.2.7 Visit 8 – Month 12 (Day 360 ± 28 days) (Final Study Visit) 
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If the local laboratory results 
indicate a need for retreatment for syphilis infection, the subject will receive treatment 
according to the local clinic’s standard protocols. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 

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collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 
• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
HIV testing will be performed if the subject was previously noted to be HIV-uninfected. 
Clinicians will provide pre- and post-test counseling, treatment, and referrals per local 
standard of care. 
• 
Blood will be collected for follow-up RPR tests, storage, and CD4 counts on persons 
found to have HIV infection whose medical records do not include a CD4 count in the 
past 30 days. 
• 
Contact information will be reviewed. 
7.3 
 Early Termination Visit 
The Visit 8 assessments and eCRFs (see Section 7.2.7: Visit 8 – Month 12 (Final Study Visit)) 
must be completed at the end of each subject’s participation in the study if discontinued prior to 
Visit 8. If a subject withdraws between scheduled visits, the subject must come to the clinic to 
perform the Visit 8 assessments. 
7.4 
Unscheduled Visit  
Subjects will be permitted to return for unscheduled visits between scheduled visits as needed 
to address issues related to AEs, continuing or new symptoms, or other problems as they arise. 
Any of the following activities may be performed at the discretion of the site PI (note that some 
items are only relevant to a subset of subjects): 
• 
Medical history will be reviewed (including review of interval medical records and local 
laboratory results, if available) and updated as appropriate. If the local laboratory results 
indicate a need for retreatment for syphilis infection, the subject will receive treatment 
according to the local clinic’s standard protocols and will be withdrawn from the study 
per protocol Section 5.3.3. 
• 
Interim sexual history since the last study visit will be collected. Specimens will be 
collected at sites of exposure for STI screening/diagnosis as indicated by local standard 
of care and subject history. 

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• 
A urine pregnancy test will be performed on all subjects of childbearing potential. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
Study personnel will discuss with subjects and assess and record all AEs/SAEs. 
Previously recorded AEs/SAEs will be updated as appropriate. 
• 
A targeted physical examination will be performed by a qualified study clinician 
(including vital signs: temperature, heart rate, respiration rate, and blood pressure; and 
genital, rectal, oral, skin, and lymph node examinations). 
• 
Contact information will be reviewed. 

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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
Complete medical history will be obtained by interviewing the subjects at Visit 1 (and reviewing 
medical records for the past 14 days, if available) and will be updated at each clinic visit. At 
follow-up visits, an interim medical history will be obtained by interviewing the subjects (and 
reviewing interval medical records, if available), noting any changes since the previous visit. 
Sexual history for the past 60 days will be obtained by interviewing the subjects at Visit 1. At 
follow-up visits, an interim sexual history will be obtained by interviewing the subjects, noting 
any changes since the previous visit. 
Medications history (concomitant medications) will include a review of all current medications 
and medications taken 30 days before initiating study treatment. Prescription and over-the-
counter drugs will be included as well as vitamins, herbs, and supplements. Assessment of 
eligibility will also include a review of all permitted and prohibited medications per the Subject 
Inclusion and Exclusion Criteria (see Section 5). 
A targeted physical examination (vital signs (temperature, heart rate, respiration rate, and blood 
pressure); genital, rectal, oral, skin, and lymph node examinations) will be performed at each 
visit. All physical examinations will be performed by a qualified study clinician. 
Evaluation for symptoms of a Jarisch-Herxheimer reaction 
Approximately 24 hours after Visit 1, the subjects will be contacted as noted in Section 7.1 and 
evaluated for symptoms of a Jarisch-Herxheimer reaction. During this assessment, subjects 
should refer to the completed Jarisch-Herxheimer checklist distributed at Visit 1. Subjects will be 
asked about fever (confirmed by thermometer at home close to the time of fever onset, if 
possible), chills, myalgia, weakness, flushing, worsening of skin rash, tachycardia (i.e., fast 
heartbeat), heart palpitations, arthralgia, nausea, headache, and dizziness, including time of 
onset and time of resolution of each symptom reported. If subjects cannot be reached after Visit 
1, the evaluation for symptoms of a Jarisch-Herxheimer reaction will be conducted at Visit 2 (per 
Section 7.1, all subjects will be asked to bring the completed checklist with them to Visit 2). Data 
will be recorded on the appropriate eCRF(s) based on subject interview during the non-visit 
contact or at Visit 2 if the contact is not successful; the Jarisch-Herxheimer checklist completed 
by the subject will not be retained.  
Evaluation for resolution of clinical signs of syphilis infection 
At Visit 2 and Visit 3, subjects will be evaluated for resolution of signs of syphilis documented at 
Visit 1, as noted in Section 7. 

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8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
Diagnostic laboratory tests for HIV and other STIs as indicated will be performed locally 
according to local protocols. Phlebotomy for serological testing and serum storage to determine 
study outcomes will be performed locally with testing carried out at the Central Laboratory. 
Serological testing may also be conducted locally according to local protocols. 
A pregnancy test will be performed at all visits on all subjects of childbearing potential; a urine or 
serum pregnancy test is permitted at Visit 1, while a urine pregnancy test is to be performed at 
all other visits. Results must be negative and known prior to randomization at Visit 1. 
8.2.2 Special Assays or Procedures 
At Visit 1, study staff will swab consenting subjects’ oral cavities and primary or secondary 
lesions (if lesions are present per Section 5.1). Swabs will be stored in study-specific medium 
and shipped to the Giacani laboratory at the University of Washington for whole-genome 
sequencing of T. pallidum isolates. Collecting oral swabs and swabs of lesions (if present) is 
optional, and additional details can be found in the protocol-specific swab guidance manual. 
8.2.3 Specimen Preparation, Handling, and Shipping 
8.2.3.1 Instructions for Specimen Preparation, Handling, and Storage 
Specimen preparation, handling, and storage will be done according to local clinic SOPs. 
Additional details can be found in the protocol-specific MOP. 
8.2.3.2 Specimen Shipment 
Specimen shipment to the Central Laboratory will occur according to all applicable International 
Air Transport Association (IATA) requirements. Additional details can be found in the protocol-
specific MOP. 

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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Safety will be monitored throughout the study by physical examination (including vital signs: 
temperature, heart rate, respiration rate, and blood pressure; and genital, rectal, oral, skin, and 
lymph node examinations) and subject reporting. Safety will be assessed by the frequency and 
severity of AEs/SAEs (including solicited reactogenicity AEs and other unsolicited AEs) 
occurring from the time of study product administration through the Month 1 visit. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.2.1 Adverse Events 
Adverse Event:   
ICH E6 GCP defines an AE as any untoward medical occurrence in a clinical research subject 
administered a study drug regardless of its causal relationship to the study drug. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the study drug. The occurrence of an 
AE may come to the attention of study personnel during study visits and interviews of a study 
subject presenting for medical care or upon review by a study monitor. Since the safety profile 
of BPG (both 1 and 3 doses) is well established, and this study is not powered to detect new, 
unknown safety signals, non-serious AEs will not be reported to the DSMB. 
All AEs not meeting the criteria for SAEs should be captured on the appropriate eCRF. 
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study drug (assessed only by those with the training and authority to 
make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution.  
Any medical condition that is present at the time that the subject is screened should be 
considered as a baseline finding and not reported as an AE. However, if it deteriorates at any 
time during the study, it should be recorded as an AE. 
All AEs must be graded for severity and relationship to the study drug.  
The US Food and Drug Administration (FDA) defines an AE as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug-
related. 

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Severity of Event: All AEs will be assessed by the clinician using a protocol-defined grading 
system (see Appendix B).  
Changes in the severity of an AE should be documented to allow an assessment of its duration 
at each level of intensity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Relationship to Study Drug: The clinician’s assessment of an AE's relationship to the study 
drug is part of the documentation process, but it is not a factor in determining what is or is not 
reported in the study. If there is any doubt as to whether a clinical observation is an AE, it 
should be reported. All AEs must have their relationship to the study drug assessed using the 
terms “related” or “not related,” as defined below. In a clinical trial, the study drug must always 
be suspect. 
• 
Related – There is a reasonable possibility that the study drug caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
drug and the AE. 
• 
Not Related – There is not a reasonable possibility that administration of the study drug 
caused the AE. 
9.2.2 Reactogenicity  
Reactogenicity events are AEs that are common and known to occur for the study drug being 
studied. For this protocol, the following reactogenicity events are expected to occur among 
some subjects: 
• 
Systemic reactions: Jarisch-Herxheimer reaction (as described in protocol Section 8.1) 
• 
Local injection site reactions: pain or tenderness, erythema or redness, induration or 
swelling 
Reactogenicity events (as solicited AEs), along with unsolicited AEs, will be assessed at the 
visits specified in protocol Section 7 and will be graded using a protocol-defined grading system 
(see Appendix B). 
9.2.3 Serious Adverse Events 
Serious Adverse Event (SAE):  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
death, 

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• 
a life-threatening AE*,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
• 
a congenital anomaly/birth defect.   
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
* An AE is considered “life-threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
All SAEs will be: 
• 
Assessed for severity and relationship to the study drug and alternate etiology (if not 
related to the study drug) by a licensed study physician. 
• 
Recorded on the appropriate SAE form and eCRF. 
• 
Followed through resolution by a licensed study physician. 
• 
Reviewed and evaluated by the DSMB (periodic review unless related), DMID, and the 
IRB. 
9.3 
Reporting Procedures 
9.3.1 Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study reporting period. 
Resolution of an SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  
 
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address:  
 

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DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. 
 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-
 (US) or 1-301
(outside US) 
SAE FAX Phone Number: 1-800-
 (US) or 1-301
 (outside US) 
SAE Email Address:
 
 
Other supporting documentation of the event may be requested by the DMID 
Pharmacovigilance Group and should be provided as soon as possible.  
 
The DMID Medical Monitor and Clinical Protocol Manager will be notified of the SAE by the 
DMID Pharmacovigilance Group. The DMID Medical Monitor will review and assess the SAE for 
regulatory reporting and potential impact on study subject safety and protocol conduct.  
 
At any time after completion of the study, if the investigator becomes aware of an SAE that is 
suspected to be related to the study drug, the investigator will report the event to the DMID 
Pharmacovigilance Group.  
9.3.2 Regulatory Reporting for Studies Not Conducted Under DMID-Sponsored 
IND 
As this study will not be conducted under an Investigational New Drug application (IND), 
MedWatch will be used only to report SAEs that are both unexpected and deemed related to the 
study drug. DMID should be copied simultaneously when an alternate method of reporting is 
utilized. 
9.3.3 Reporting of Pregnancy 
Subjects of child-bearing potential will be counseled to continue using acceptable forms of birth 
control for the entire duration of their participation in the trial. If a subject becomes pregnant 
during the study, dosing will be discontinued immediately, and early termination assessments 
will be performed. A pregnancy reporting form will be completed for any study subject who 
becomes pregnant during study participation. The site will maintain contact with pregnant study 
subjects to obtain pregnancy outcome information. The pregnant subject will be followed until 
delivery or until the end of pregnancy (in the case of miscarriage or pregnancy termination). 
Infants born to these study subjects will also be monitored for SAEs (congenital anomalies or 
other birth defects) and other complications for up to 2 months after birth. Pregnancy reporting 
forms will be limited to collecting data on the following information: 
• 
prior maternal history including congenital abnormalities or pregnancy complications; 

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• 
estimated date of conception; 
• 
estimated and actual date of delivery or end of pregnancy; 
• 
pregnancy outcome (live birth, stillbirth, miscarriage, or elective termination); 
• 
mode of delivery; 
• 
maternal complications; and 
• 
neonatal complications (i.e., lethal or nonlethal congenital abnormality). 
Pregnancies occurring in subjects will be reported via Advantage eClinical® on the Pregnancy 
Report form.   
9.4 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
All AEs and SAEs will be followed from the time of study treatment through resolution even if 
this extends beyond the study reporting period (i.e., the Month 1 visit). Resolution of an AE/SAE 
is defined as the return to pretreatment status or stabilization of the condition with the 
expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate data 
collection form. 
9.5 
Halting Rules 
Further enrollment will be halted for DSMB review if any of the following are reported: 
• 
If one or more subjects experience an SAE judged by an investigator to be related to the 
study drug  
• 
An overall pattern of clinical events that the DMID Medical Monitor or DSMB consider 
associated with the study drug and that may appear minor in terms of individual events, but 
that may collectively represent a serious potential concern for safety 
If any of the halting rules are met, the study will not continue with the remaining enrollments or 
study treatments without a review by and recommendation from the DSMB to proceed. 
DMID retains the authority to suspend additional enrollment and administration of the study drug 
during the entire study, as applicable. 

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9.6 
Safety Oversight (ISM plus DSMB) 
An ISM at each clinical research site will oversee the safety of research subjects at that site and 
will provide independent written evaluation of SAEs and related Grade 3 AEs to the PI, DMID 
Clinical Project Manager, and DMID Medical Monitor. The ISM will serve as an independent 
consultant for the site PI on subject-related issues. The ISM will communicate with the site PI 
and study PIs to resolve any issues. 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial, 
or other conflict of interest related to the study. The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial. 
The DSMB will review safety and enrollment data when half of the study subjects have been 
enrolled and observed for SAEs through the Month 1 Visit.  
The DSMB will review study progress and subject clinical and safety data at the following time 
points: 
• 
At least annually after the first subject is enrolled. 
• 
Ad hoc when a halting rule is met, for immediate concerns regarding observations during 
the study, or as needed. 
• 
During a final closeout meeting, held at the end of the study after the database is locked 
to review cumulative study data prior to finalizing the Clinical Study Report (CSR). 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. As an outcome of each review/meeting, the DSMB will 
make a recommendation as to the advisability of proceeding with study administrations (as 
applicable), and to continue, modify, or terminate the study. 
DMID or the DSMB chair may convene the DSMB on an ad hoc basis according to protocol 
criteria or if there are immediate concerns regarding observations during the study. The DMID 
Medical Monitor is empowered to stop enrollment and study treatment if SAEs that meet the 
halting criteria are reported. The DMID Medical Monitor will be responsible for reviewing SAEs 
in real time. The DSMB will review SAEs on a regular basis and ad hoc during the study. 

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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
DMID, the sponsoring agency, or its designee will conduct site monitoring visits as detailed in 
the clinical monitoring plan and in accordance with DMID policies. Site monitoring is conducted 
to ensure that the human subject protections, study and laboratory procedures, study 
intervention administration, and data collection processes are of high quality and meet sponsor 
and ICH/GCP guidelines and applicable regulations and that the study is conducted in 
accordance with the protocol, protocol-specific manual of procedures, and applicable sponsor 
SOPs. Monitoring visits will include, but are not limited to, inspection of study facilities; review of 
regulatory files, accountability records, eCRFs, ICFs, printouts of medical and laboratory reports 
from the electronic medical records (EMR) system; and review of protocol and GCP compliance. 
Site monitors will have access to the study site, study personnel, and all study documentation 
according to the DMID-approved site monitoring plan. Study monitors will meet with PIs to 
discuss any problems and actions to be taken and document visit findings and discussions. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID. 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
The primary objective of the study is to compare the serological response to therapy in subjects 
with early (primary, secondary, or early latent) syphilis treated with BPG 2.4 MU once or weekly 
for three successive weeks. In particular, the objective is to demonstrate noninferiority of the 
one-dose regimen compared to the three-dose regimen and to also assess noninferiority within 
the HIV status subgroups (HIV-infected and HIV-uninfected subjects). See Section 11.4.4 for 
the definition of serological response.  
The null hypothesis for the primary objective is that the difference in serological response rate 
between the three-dose and one-dose groups is at least 10%, and the alternative hypothesis is 
that the difference in response rates is less than 10%. The null and alternative hypotheses for 
the secondary HIV status subgroup objective are defined similarly. 
Note that tests will be performed and p-values will be reported for secondary analyses for 
informational purposes and not to make definitive claims. The study is intended and designed to 
formally test the primary hypothesis only, and so no corrections for multiplicity are planned. 
11.2 Sample Size Considerations 
Sample size calculations were performed using PASS 2008 and SAS 9.4. The following 
parameters were used for determining the required sample size for the primary objective: 
• 
1:1 allocation ratio between one-dose and three-dose arms 
• 
Test the difference in response rate between the one-dose and three-dose arms 
(Farrington-Manning test, unadjusted for HIV status) 
• 
Null hypothesis response rate in one-dose arm: 0.688 
• 
Null hypothesis response rate in three-dose arm: 0.788 
• 
Alternative hypothesis response rate in both arms: 0.788 
• 
One-sided 0.05 alpha level 
To achieve 80% power for the primary noninferiority comparison, 420 evaluable subjects (210 in 
each treatment arm) are needed. It is assumed that 25% of subjects will be ineligible for the 
primary analysis, and so 560 enrolled subjects are needed to reach the target of 420 evaluable 
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The study is not powered to assess the secondary noninferiority comparisons in the HIV status 
subgroups. As an illustration, power calculations were performed to assess the power available 
for these subgroup analyses using a sample size of 420. The following parameters were used 
for the calculations:  
• 
Test the difference in response rate between the one-dose and three-dose arms within 
each HIV status stratum. 
• 
Null hypothesis response rate in one-dose arm: 0.738 (HIV-infected); 0.638 (HIV-
uninfected) 
• 
Null hypothesis response rate in three-dose arm: 0.838 (HIV-infected); 0.738 (HIV-
uninfected) 
• 
Alternative hypothesis response rate in both arms: 0.838 (HIV-infected); 0.738 (HIV-
uninfected) 
• 
One-sided 0.05 alpha level 
• 
280 evaluable subjects in the HIV-infected stratum (140 in one-dose arm, 140 in three-
dose arm). 
• 
140 evaluable subjects in the HIV-uninfected stratum (70 in one-dose arm, 70 in three-
dose arm). 
The HIV-infected noninferiority comparison has 72% power, and the HIV-uninfected 
noninferiority comparison has 38% power. 
11.3 Planned Interim Analyses 
11.3.1 Safety Review  
The study will be monitored to determine if any of the safety halting rules described in Section 
9.5 are met. The DSMB will also review study progress and subject safety data at specified 
times during the study and hold a study closeout meeting, as defined in the DSMB Charter. 
11.3.2 Immunogenicity or Efficacy Review 
There are no planned interim analyses of efficacy data. 

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11.4 Final Analysis Plan  
A separate statistical analysis plan document will be generated that will contain the details of the 
analyses. This section outlines the major components of the analyses. 
11.4.1  Analysis Populations 
Intent-to-Treat (ITT) Population: This analysis population includes all randomized subjects. 
 
Modified Intent-to-Treat (mITT) Population: This analysis population includes all randomized 
subjects who are eligible at the baseline visit and whose TPPA result is positive at the baseline 
visit and/or at Visit 5 (Month 3), if repeat testing was performed. 
 
Safety Population: This analysis population includes all randomized subjects who received at 
least one dose of study treatment. 
 
Evaluable Population: This analysis population includes all randomized subjects who are eligible 
at the baseline visit, have a known HIV status determined at or before the baseline visit, have 
positive TPPA results at the baseline visit and/or Visit 5 (Month 3) (if repeat testing was 
performed), received all assigned doses of BPG, have adequate RPR titer data available at 
baseline and applicable follow-up visit(s), and (for HIV-uninfected subjects only) HIV-uninfected 
status persists through applicable follow-up visit(s). 
 
If a subject receives antibiotic(s) active against T. pallidum for reasons other than syphilis 
between enrollment and the applicable follow-up visit(s), the subject will be included in ITT 
analyses but excluded from Evaluable analyses. If a subject receives antibiotic(s) active against 
T. pallidum between enrollment and the applicable follow-up visit(s) due to local RPR testing 
results, the subject will be included in all analyses. 
 
A blinded case review committee will review subjects’ data to determine if treatment with drug(s) 
known to be active against T. pallidum for reasons other than syphilis infection excludes the 
subject from the Evaluable analysis population. 
11.4.2 Baseline Characteristics 
Baseline and demographic characteristics will be summarized overall and by formulation. For 
both continuous and categorical variables, appropriate summary statistics will be applied. For 
continuous variables, descriptive statistics will include the number of non-missing values, mean, 
standard deviation, median, minimum, and maximum. For categorical variables, descriptive 
statistics will include counts and percentages per category. 

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11.4.3 Safety Analysis Plan 
Safety evaluations will be based on the incidence, severity, and type of AEs and SAEs, as 
detailed in Section 9. In addition, the incidence of systemic reactions and local injection site 
reactions will be evaluated. Safety variables will be tabulated and presented for all subjects in 
the safety population, grouped by treatment. 
 
Reactogenicity events will be analyzed by taking the most severe response over the follow-up 
period, dichotomizing into a binary variable (none versus mild, moderate, or severe) and using 
exact confidence intervals to summarize the reactogenicity rates. Tabular and graphical 
summaries of events will be presented for each solicited event, by type (local/systemic), severity 
(none, mild, moderate, severe), and time point post-dose. The proportion of subjects who 
experience a Jarisch-Herxheimer reaction will be summarized overall and by treatment. Logistic 
regression analyses may be used to determine the association of treatment with Jarisch-
Herxheimer reaction after adjusting for HIV co-infection status and time point. 
 
Unsolicited AEs and SAEs will be coded by MedDRA® for preferred term and system organ 
class. The rate and exact 95% confidence intervals of AEs and SAEs in aggregate, as well as 
by MedDRA® categories, will be computed. The number of SAEs will be reported by a detailed 
listing showing the type, MedDRA® coding, relevant dates (treatment dosing date(s) and SAE 
onset and resolution dates), severity, relatedness, and outcome for each event. 
11.4.4 Efficacy Analysis Plan 
11.4.4.1 Primary Efficacy Analysis 
For the primary analysis, serological response to therapy by Month 6 will be defined as follows: 
• 
4-fold or greater decline in RPR titer by Month 6 compared to baseline, OR  
• 
RPR-negative by Month 6 (i.e., seroreversion). 
For the primary analysis, subjects who do not meet either of the above criteria by Month 6 will 
be classified as not experiencing serological response. If a subject has an observed serological 
response prior to meeting one of the Evaluable analysis population exclusion criteria, the 
subject will be included in the analyses as a responder. For subjects who have received BPG 
through the study and subsequently require retreatment for syphilis infection (i.e., per the local 
clinic’s standard protocols), data collected following retreatment will not be used for analyses. 
Exploratory analyses of the primary outcome will consider alternative classifications of subjects 
(see Section 11.4.4.2). 
For the comparison of efficacy of one dose versus three doses of BPG 2.4 MU, the number and 
proportion of subjects with serological response will be summarized overall and by treatment. 

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The point estimates for the treatment-specific proportions and difference in proportions as well 
as corresponding 95% confidence intervals will be reported. A hypothesis test will be conducted 
using the Farrington-Manning test at the 5% one-sided level of significance to formally compare 
the treatment arms. The primary analysis will be performed in the ITT analysis population and 
repeated as a secondary analysis in the mITT and the Evaluable analysis populations. 
As the ITT analyses will include subjects who may not have adequate serological data to 
determine their response status for any reason, the response will need to be imputed. Multiple 
methods for imputation will be explored (e.g., Last Observation Carried Forward); details will be 
provided in the Statistical Analysis Plan. 
 
As a secondary corroborative analysis, the Cochran-Mantel-Haenszel Chi-square test will be 
used to compare the two treatment arms with respect to response rate across HIV status 
subgroups (HIV-infected, HIV-uninfected). The Breslow-Day test for the homogeneity of odds 
ratios will be used to determine if the difference between the two treatment groups with respect 
to response rates varies by HIV status. 
11.4.4.2 Secondary Efficacy Analysis 
The secondary efficacy analyses will be performed in the ITT and Evaluable analysis 
populations. For subjects who have received BPG through the study and subsequently require 
retreatment for syphilis infection (i.e., per the local clinic’s standard protocols), data collected 
following retreatment will not be used for analyses.  
 
For the comparison of efficacy of one dose versus three doses of BPG 2.4 MU by Month 6 in 
each of the HIV status subgroups, the number and proportion of subjects with serological 
response will be summarized overall and by treatment within each HIV status subgroup. The 
point estimates for the treatment-specific proportions and difference in proportions as well as 
corresponding 95% confidence intervals will be reported. For each HIV status subgroup, a 
hypothesis test will be conducted using the Farrington-Manning test at the 5% one-sided level of 
significance to formally compare the treatment arms.  
 
The analyses comparing one dose versus three doses by Month 12, overall and within HIV 
status subgroups, will follow similarly to the above. In addition, geometric mean titers and fold 
declines from baseline will be summarized by time-point for each treatment group, overall and 
within HIV status subgroups. 
 
For the comparison of compliance between the one dose and three dose groups, the number 
and proportion of subjects who receive all assigned doses within the assigned visit windows will 
be summarized overall and by treatment. The point estimates for the treatment-specific 
proportions and difference in proportions as well as corresponding 95% confidence intervals will 
be reported. A hypothesis test will be conducted using a Chi-square test at the 5% two-sided 
level of significance to formally compare the treatment arms.  

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Demographic, sexual history, and other characteristics of subjects will be presented overall and 
within HIV status subgroups at baseline and throughout follow-up. HIV status subgroups will be 
compared with respect to epidemiological characteristics using the Pearson Chi-square test for 
categorical measures and the t-test for independent samples or Wilcoxon rank sum test for 
continuous measures. 
11.4.4.3 Exploratory Efficacy Analysis 
Any exploratory or sensitivity analyses to be performed to support any of the primary or 
secondary objectives will be specified in the Statistical Analysis Plan. As an example, the 
following alternative serological response classifications will be explored:  
• 
Response: 4-fold decline in RPR titer compared to baseline, or RPR-negative (i.e., 
seroreversion). 
• 
Non-Response: Less than 4-fold decline in RPR titer compared to baseline, and RPR-
positive 
• 
Failure: 4-fold or greater increase in RPR titer without a clear history of re-exposure 
A blinded case review committee will review subjects’ data to determine cases of re-exposure. If 
a subject has an observed serological response prior to meeting one of the Evaluable analysis 
population exclusion criteria, the subject will be included in the analyses as a responder. For 
subjects who have received BPG through the study and subsequently require retreatment for 
syphilis infection (i.e., per the local clinic’s standard protocols), data collected following 
retreatment will not be used for analyses. 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9, and regulatory and institutional requirements for the 
protection of confidentiality of subjects. Each participating site will permit authorized 
representatives of DMID, its designees, and appropriate regulatory agencies to examine (and 
when required by applicable law, to copy) clinical study records for the purposes of quality 
assurance reviews, audits, monitoring, and evaluation of the study safety and progress. These 
representatives will be permitted access to all source data, which include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
in the pharmacies, laboratories, and medico-technical departments involved in this clinical trial. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of this trial.  

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the participating site is 
responsible for conducting routine quality assurance (QA) and quality control (QC) activities to 
internally monitor study progress and protocol compliance. The site PI will provide direct access 
to all trial-related sites, source data/data collection forms, and reports for the purpose of 
monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. The 
site PI will ensure all study personnel are appropriately trained and applicable documentations 
are maintained on site. 
The Statistical and Data Coordinating Center (SDCC) will implement QC procedures beginning 
with the data entry system and generate data QC checks that will be run on the database. Any 
missing data or data anomalies will be communicated to the site(s) for clarification and 
resolution. 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The site PI will ensure that this trial is conducted in full conformity with principles of the Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of 
the National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 50 and 56, and ICH E6; 62 
Federal Regulations 25691 (1997), if applicable. The site PI’s institution will hold a current 
Federal Wide Assurance (FWA) issued by the Office of Human Research Protection (OHRP) for 
federally funded research. 
14.2 Institutional Review Board 
Prior to enrollment of subjects into this trial, the approved protocol and ICF will be reviewed and 
approved by the appropriate IRB listed on its FWA. 
The responsible official for the IRB will sign the IRB letter of approval of the protocol before the 
start of this trial, and provide a copy to DMID. The IRB FWA number will be provided to DMID. 
Should amendments to the protocol be required, the amendments will be written by the sponsor 
and provided to the site PI for submission to the IRB. 
14.3 Informed Consent Process 
The site PI, or designated study staff, will choose subjects in accordance with the eligibility 
criteria detailed in Section 5. Before any study procedures are performed, subjects must sign an 
ICF that complies with the requirements of 21 CFR Part 50, 45 CFR Part 46, and the local IRB. 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Before any study procedures 
are performed, subjects will receive a comprehensive explanation of the proposed study 
procedures and study drug, including the nature and risks of the trial, alternate therapies, any 
known AEs, the investigational status of the components, and the other elements that are part 
of obtaining proper informed consent. Subjects will also receive a detailed explanation of the 
proposed use and disclosure of their protected health information, including specifically their 
specimens. Subjects will be allowed sufficient time to consider participation in the trial, after 
having the nature and risks of the trial explained to them, and will have the opportunity to 
discuss the trial with their family, friends, or legally authorized representative or think about it 
prior to agreeing to participate. 

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ICFs describing in detail the study drug, study procedures, risks, and possible benefits are given 
to subjects. The ICF must not include any exculpatory statements. ICFs will be IRB-approved, 
and subjects will be asked to read and review the appropriate document. Upon reviewing the 
appropriate document, the site PI (or designee) will explain the research study to subjects and 
answer any questions that may arise. Subjects must sign the ICF, and written documentation of 
the informed consent process is required prior to starting any study procedures/interventions 
being done specifically for the trial, including administering BPG. 
DMID will provide the site PI, in writing, any new information that significantly affects the 
subjects' risk of receiving BPG. This new information will be communicated by the site PI to 
subjects who consent to participate in the trial in accordance with IRB requirements. The ICF 
will be updated, and subjects will be re-consented per IRB requirements, if necessary. 
Study personnel may employ IRB-approved recruitment efforts before obtaining the subject’s 
consent; however, before any study procedures are performed to determine protocol eligibility, 
an ICF must be signed. Subjects will be given a copy of all ICFs that they sign. 
By signing the ICF, subjects agree to complete all evaluations required by the trial, unless the 
subject withdraws voluntarily or is terminated from the trial for any reason. 
The rights and welfare of subjects will be protected by emphasizing to subjects that the quality 
of their medical care will not be adversely affected if they decline to participate in or withdraw 
from this trial. 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This trial will be inclusive of female and male adults who meet the subject inclusion/exclusion 
criteria, regardless of religion or ethnic background. Should the outcome of this trial be deemed 
acceptable, additional trials may be initiated in other populations.  
14.5 Subject Confidentiality 
Subjects will have code numbers and will not be identified by name. Subject confidentiality is 
strictly held in trust by the participating site PIs, their study personnel, the sponsor(s), and their 
agents. This confidentiality is extended to cover testing of biological samples, in addition to the 
clinical information relating to subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the trial or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 

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All information provided by the sponsor and all data and information generated by the 
participating site as part of the trial (other than a subject’s medical records) will be kept 
confidential by the site PI and other study personnel to the extent permitted by law. This 
information and data will not be used by the site PI or other study personnel for any purpose 
other than conducting the trial. These restrictions do not apply to: (1) information that becomes 
publicly available through no fault of the site PI or other study personnel; (2) information that is 
necessary to disclose in confidence to an IRB solely for the evaluation of the trial; (3) 
information that is necessary to disclose in order to provide appropriate medical care to a study 
subject; or (4) study results that may be published as described in Section 16. If a written 
contract for the conduct of the trial that includes confidentiality provisions inconsistent with this 
statement is executed, that contract’s confidentiality provisions shall apply rather than this 
statement. 
The study monitor, applicable regulatory authorities, such as the FDA, or other authorized 
representatives of the sponsor may inspect all documents and records required to be 
maintained by the site PI. This includes, but is not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this trial. The participating sites will permit 
access to such records. 
To protect privacy, a Certificate of Confidentiality (CoC) has been obtained. With this CoC, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings. The researchers will use the CoC to resist any demands for information that 
would identify the subject, except as explained below. 
The CoC cannot be used to resist a demand for information from personnel of the US 
Government that is used for auditing or evaluation of federally funded projects, like this trial, or 
for information that must be released in order to meet the requirements of the FDA. 
A CoC does not prevent subjects from voluntarily releasing information about themselves or 
their involvement in this research. If any person or agency obtains a written consent to receive 
research information, then the researchers may not use the CoC to withhold that information.   
The CoC does not prevent the researchers from reporting, without the subject’s consent, 
information that would identify the subject as a participant in the research project regarding 
matters that must be legally reported, including: child and elder abuse, sexual abuse, or wanting 
to harm themselves or others. 
14.6 Study Discontinuation 
If the trial is discontinued, subjects who sign the ICF and are randomized and treated will 
continue to be followed for safety assessments. No further study drug will be administered 

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14.7 Future Use of Stored Specimens 
Subjects will be consented to have leftover serum stored for future testing. Storage of samples 
for future testing is optional and is not a requirement for participation in the study. If the subject 
consents to storage and future use of specimens, specimens will be kept at the Central 
Laboratory (University of Alabama at Birmingham). Subjects will not be contacted with the 
results of these future research studies. Future testing on specimens will only occur to the 
extent authorized in each study site’s ICF or as otherwise authorized under applicable law and 
after review and approval by DMID and the IRB of the researcher requesting the specimens. 
Archived specimens will be identified only by the subject number and visit number, which will 
allow linkage of the specimens to study data but not to any personal identifiers.  
There will be no direct benefit to subjects from allowing specimens to be stored and used for 
future purposes. However, the results may provide information that will help in the diagnosis or 
treatment of future patients.  
Subjects’ specimens will be kept until they are used up or destroyed. They may be used to 
develop new tests or products. In some instances, these may have potential commercial value. 
If a subject decides at any time that s/he does not want specimens stored for future research, 
s/he must contact the study staff who will then notify the laboratory/specimen archive staff, who 
will mark the specimens by adding a “destroy” label. Labeled specimens will be destroyed at the 
end of this study or will be removed from storage and destroyed as soon as possible. 

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15 
DATA HANDLING AND RECORD KEEPING 
The site PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. 
Data collection forms will be derived from the eCRFs and provided by the SDCC to record and 
maintain data for each subject enrolled in the study. All data collection forms should be 
completed in a neat, legible manner to ensure accurate interpretation of data. Black or blue ink 
is required to ensure clarity of reproduced copies. When making a change or correction, cross 
out the original entry with a single line and initial and date the change. Do not erase, overwrite, 
or use correction fluid or tape on the original. 
Data reported in the eCRFs derived from the data collection forms should be consistent with the 
data collection forms, or the discrepancies should be explained. 
The sponsor and/or its designee will provide guidance to site PIs and other study personnel on 
making corrections to the data collection forms and eCRFs. 
15.1 Data Management Responsibilities 
All data collection forms and laboratory reports must be reviewed by the clinical team and data 
entry personnel, who will ensure that they are accurate and complete. AEs must be recorded on 
the appropriate data collection form, assessed for severity and relationship, and reviewed by the 
site PI or appropriate sub-investigator. 
Data collection is the responsibility of the study personnel at the participating sites under the 
supervision of the respective site PI. During the study, the site PI must maintain complete and 
accurate documentation for the study. 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
15.2 Data Capture Methods 
Clinical (including, but not limited to, AEs/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values), and immunogenicity data will be entered 
into a 21 CFR 11-compliant Internet Data Entry System, Advantage eClinical®, provided by the 
SDCC. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the data collection forms completed by the study 
personnel.  

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15.3 Types of Data 
Data for this study will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values and immunogenicity data). 
15.4 Timing/Reports 
A final report will be prepared following the availability of all the safety and laboratory data. 
Interim statistical reports may be generated as deemed necessary and appropriate by DMID. 
Safety and laboratory data summary reports may be generated for the DSMB. 
After full analysis and final CSR reporting is complete, and upon request and DMID approval, 
the SDCC will provide the participating sites with a summary of results by treatment group. The 
participating sites requesting such information to share with study subjects must do so in 
compliance with their respective IRB guidelines. 
15.5 Study Records Retention 
Records and documents pertaining to the conduct of this study, including data collection forms, 
source documents, ICFs, laboratory test results, and medication inventory records, must be 
retained by the investigator for at least 2 years following the completion of this study. No records 
may be destroyed without written permission from the sponsor. 
15.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements. The noncompliance may be either on the part of the subject, the 
site PI, or the study site staff. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly.  
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site PI to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. All deviations must be promptly reported to DMID, via the 
SDCC’s Advantage eClinical®.  

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Note: Those sites participating in trials with a designated ‘central unit’ will follow the reporting 
requirements specified in their protocols and MOPs. The ‘central unit’ will be responsible for 
submission of the protocol deviation information to TRI-ICON/DMID-CROMS. 
All protocol deviations, as defined above, must be addressed in study subject data collection 
forms. A completed copy of the DMID Protocol Deviation Form must be maintained in the 
regulatory file, as well as in the subject’s study chart. Protocol deviations must be sent to the 
local IRB per their guidelines. The site PI and other study personnel are responsible for knowing 
and adhering to their IRB requirements. 

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16 
PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic version 
of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly 
available no later than 12 months after the official date of publication. The NIH Public Access 
Policy ensures the public has access to the published results of NIH-funded research. It 
requires investigators to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 
12 months after publication. 
 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH generally need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting, a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this trial, the responsible party is DMID, which will register the trial and post results.  
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 
 

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17 
LITERATURE REFERENCES 
1. 
Hook, E.W., Syphilis. Lancet, 2017. 389(10078): p. 1550-1557. 
2. 
CDC Sexually transmitted disease surveillance 2016. 2017, U.S. Department of Health 
and Human Services: Atlanta. 
3. 
CDC Sexually transmitted disease surveillance 2015. 2016, U.S. Department of Health 
and Human Services: Atlanta. 
4. 
CDC Sexually transmitted disease surveillance 2012. 2013, U.S. Department of Health 
and Human Services: Atlanta. 
5. 
Workowski, K.A. and G.A. Bolan, Sexually transmitted diseases treatment guidelines, 
2015. MMWR Recomm Rep, 2015. 64(Rr-03): p. 1-137. 
6. 
Sena, A.C., et al., Predictors of serological cure and serofast state after treatment in 
HIV-negative persons with early syphilis. Clin Infect Dis, 2011. 53(11): p. 1092-9. 
7. 
Rolfs, R.T., et al., A randomized trial of enhanced therapy for early syphilis in patients 
with and without human immunodeficiency virus infection. The Syphilis and HIV Study 
Group. N Engl J Med, 1997. 337(5): p. 307-14. 
 

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APPENDIX A: SCHEDULE OF EVENTS 
Procedures 
Visit 1 – Screening/ 
Enrollment (Day 1) 
Contact (approx. 24 
hours after Visit 1) 
Visit 2 (Week 1 – 
Day 7 to 13) 
Visit 3 (Week 2 – 6 to 
12 days after Visit 2) 
Visit 4 (Month 1 – 
Day 30 ± 7 days) 
Visit 5 (Month 3 – 
Day 90 ± 21 days) 
Visit 6 (Month 6 – 
Day 180 ± 21 days) 
Visit 7 (Month 9 – 
Day 270 ± 28 days) 
Visit 8 (Month 12 – 
Day 360 ± 28 days) 
Early Termination 
Unscheduled Visit15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history1 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sexual history2 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical exam3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test4 
(X) 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Concomitant medications5  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specimen collection 
RPR titer 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Storage 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CD4 count6  
(X) 
 
 
 
(X) 
 
(X) 
 
(X) 
(X) 
 
HIV testing7 
(X) 
 
 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
 
Other STI screening/ 
diagnosis8 
X 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Oral cavity and lesions (if 
present) swabbed9 
(X) 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
BPG administered10 
X 
 
(X) 
(X) 
 
 
 
 
 
 
 
Contact information 
collected/reviewed11 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Jarisch-Herxheimer checklist12 
X 
X 
(X) 
 
 
 
 
 
 
 
 
Jarisch-Herxheimer reaction assessed13 
 
X 
(X) 
 
 
 
 
 
 
 
 
Resolution of syphilis signs assessed 
 
 
X 
X 
 
 
 
 
 
 
 
AEs/SAEs assessed14 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
(X) – As indicated/appropriate. Refer to footnotes below and protocol Section 7. 
1 At Visit 1, collect complete medical history (including review of medical records for the past 14 days, if available). At 
subsequent visits, review medical history (including interval medical records, if available) and update as appropriate. 
2 At Visit 1, collect sexual history for the past 60 days. At subsequent visits, collect interim sexual history since last visit. 
3 Targeted physical exam includes vital signs: temperature, heart rate, respiration rate, and blood pressure; and genital, 
rectal, oral, skin, and lymph node examinations. 
4 Perform on subjects of childbearing potential. At Visit 1, urine or serum pregnancy test is permitted. At subsequent 
visits, perform urine pregnancy test. 
5 At Visit 1, record concomitant medications taken in the last 30 days before initiating BPG. At subsequent visits, record 
all concomitant medications taken since the last visit and update previously recorded medications as appropriate. 
6 Collect for subjects with known HIV infection whose medical records do not include a CD4 count in the past 30 days; at 
Visit 4, this is only applicable to subjects newly found to have HIV infection from Visit 1 to Visit 4 (inclusive). 
7 Perform for subjects who do not have a previously documented positive HIV test result using locally available tests (e.g., 
nucleic acid tests (NATs), antibody/antigen tests). 
8 At Visit 1, collect specimens at sites of exposure for screening/diagnosis of chlamydia and gonorrhea for all subjects who 
have not been tested since last sexual activity and for all subjects who have been sexually active in the past 14 days and for 
other STIs as indicated by local standard of care and subject history. At subsequent visits, collect specimens at sites of 

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exposure for STI testing per local standard of care and subject history. 
9It is optional to swab subject’s oral cavity and lesions, if lesions are present. See Section 8.2.2. 
10 At Visit 1, administer BPG to all subjects. At Visits 2 and 3, administer BPG to subjects in Arm 2 only. 
11At Visit 1, collect contact information. At subsequent visits, review contact information and update if needed. 
12 Distribute checklist at Visit 1. Subject refers to completed checklist during Jarisch-Herxheimer assessment; see Sections 
7 and 8.1. 
13Assess per protocol Section 8.1. If subject is not reached, assess at Visit 2. 
14 Assess and record all AEs/SAEs (including solicited reactogenicity AEs and other unsolicited AEs). 
15 At Unscheduled Visits, any of the specified evaluations that are relevant to the subject may be performed at the 
discretion of the site PI. 
 

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APPENDIX B: TABLE FOR GRADING THE SEVERITY OF ADVERSE EVENTS 
PARAMETER 
GRADE 1 - MILD 
GRADE 2 - 
MODERATE 
GRADE 3 - SEVERE 
Clinical adverse event 
NOT identified below 
Mild symptoms causing 
no or minimal 
interference with usual 
social and functional 
activities with 
intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social and 
functional activities with 
intervention indicated 
Severe symptoms 
causing inability to 
perform usual social 
and functional activities 
with intervention or 
hospitalization 
indicated 
Vital signs 
 
 
 
Temperature 
38.0 to <38.6°C 
38.6 to <39.3°C 
≥39.3°C 
Blood pressure 
140 – 159 mmHg 
systolic OR  
90 – 99 mmHg 
diastolic 
160 – 179 mmHg 
systolic OR  
100 – 109 mmHg 
diastolic 
≥180 mmHg systolic 
OR ≥110 mmHg 
diastolic OR 
hospitalization 
indicated 
Pulse 
101-115 or 
50-54 or 45-50 if 
baseline <60bpm 
116-130 or 
45-49 or 40-44 if 
baseline <60bpm 
>130 or 
ventricular 
dysrhythmias or <45 
or <40 if baseline 
<60bpm 
Respiration 
23-25 
26-30 
≥30 
Local injection site 
 
 
 
    Pain or tenderness  
    (report only one) 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
    Erythema or redness  
    (report only one) 
2.5 to <5 cm in greatest 
diameter AND 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
≥5 to <10 cm in 
greatest diameter OR 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
≥10 cm in greatest 
diameter OR Ulceration 
OR Secondary infection 
OR Sterile abscess OR 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
    Induration or swelling  
    (report only one) 
2.5 to <5 cm in greatest 
diameter AND 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
≥5 to <10 cm in 
greatest diameter OR 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
≥10 cm in greatest 
diameter OR Ulceration 
OR Secondary infection 
OR Sterile abscess OR 
Symptoms causing 
inability to perform 
usual social and 
functional activities 

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Systemic 
 
 
 
Anaphylaxis ** 
 
 
-- 
-- 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-
related edema or 
angioedema; 
hypotension 
**Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents 
with breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness, and may lead to death. 
    Acute allergic  
    reaction 
Localized urticaria with 
no intervention 
indicated 
Localized urticaria with 
intervention indicated 
OR Mild angioedema 
with no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm 
Hypersensitivity  
Transient flushing or 
rash 
Rash; flushing; 
urticaria; dyspnea 
Symptomatic 
bronchospasm with or 
without urticaria; 
parenteral medication 
indicated; 
allergy-related edema 
or angioedema; 
hypotension 
    Fever 
38.0 to <38.6oC or 
100.4 to <101.5oF 
≥38.6 to <39.3oC or 
≥101.5 to <102.7oF 
≥39.3oC or ≥102.7oF 
    Chills 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
    Headache 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
    Myalgias  
    (generalized) 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
    Fatigue or Malaise     
    (report only one) 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities 

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    Decreased appetite 
Loss of appetite without 
decreased oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Dermatological 
 
 
 
    Skin rash 
Localized rash 
Diffuse rash OR Target 
lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Gastrointestinal 
 
 
 
    Nausea 
Transient (< 24 hours) 
or intermittent AND No 
or minimal interference 
with oral intake 
Persistent nausea 
resulting in decreased 
oral intake for 24-48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours 
OR Rehydration 
indicated (e.g., IV 
fluids) 
    Vomiting 
Transient (< 24 hours) 
or intermittent AND No 
or minimal interference 
with oral intake 
Frequent episodes with 
no or minimal 
dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Rehydration indicated 
(e.g., IV fluids) 
    Diarrhea 
Transient or intermittent 
episodes of unformed 
stools OR Increase of ≤ 
3 stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4-6 stools over baseline 
per 24-hour period 
Increase of ≥ 7 stools 
over baseline per 24-
hour period OR IV fluid 
replacement indicated 
    Abdominal  
    discomfort 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities